The Role of Genetic Polymorphisms in Periodontitis

Periodontology 2000, Vol.
43, 2007, 102132

Printed in Singapore. All rights reserved
2007 The Authors.

Journal compilation 2007 Blackwell Munksgaard
PERIODONTOLOGY 2000
The role of genetic

polymorphisms in periodontitis
H I R O M A S A Y O S H I E , T E T S U O K O B A Y A S H I , H I D E A K I T A I & J O H N A H C. G A L I C I A
A detailed knowledge of the dynamic between the

host immune responses and oral bacteria is essential
to understand clearly the pathogenesis of periodontal
disease. Periodontopathic bacteria initiate and repeatedly attack the host, stimulating an immune response, but the presence of pathogenic subgingival
flora alone does not always equate to periodontal
destruction. Although bacterial plaque is essential for
the initiation of periodontitis, the amount of plaque
does not necessarily correlate with disease severity
(178). Each person has an individual doseresponse
curve that defines host susceptibility to periodontitis
(180). Certain patients are disease-resistant and will
not progress beyond gingivitis or early periodontitis.
This places the emphasis on host response, rather
than bacterial etiology, as the principal determinant
of disease expression.
The vast number of scientific papers available
support the indispensable role of genes in host responses and, consequently, in progression of the
disease. Specifically, different allelic variants can result in variations in tissue structure (innate immunity), antibody responses (adaptive immunity) and
inflammatory mediators (non-specific inflammation)
(126). Genetic variations may also act as protective or
risk factors for certain conditions, including periodontitis (173). For these reasons, periodontitis is
considered as a complex genetic disease whose
phenotype is determined by both the genetic makeup
and the environmental influences on the affected
individual.
It has already been established that interindividual
variations in the host immune responses and most
human diseases have genetic components in them.
In particular, genetic differences in immune-cell
development and antigen presentation may contribute to the susceptibility to autoimmune and infectious diseases (93, 194). Identifying genes can
therefore result in novel diagnostics for risk assess-
102
ment, early detection and individualized treatment

approaches.
Like any other complex disease, genetic variants at
multiple loci associated with periodontitis synergistically contribute to the overall disease process. Results obtained from numerous genetic reports may be
utilized to identify the candidate genes for periodontal disease profiling in both aggressive and
chronic periodontitis. Identifying genes that contribute to the pathogenesis of periodontitis can have
significant public health, therapeutic and scientific
repercussions. Loss of teeth induced by periodontitis
has a considerable effect on the homeostasis of craniofacial and oral tissues, and consequently on the
general wellbeing of the individual. This global health
concern is instrumental in the continuous quest of
the scientific field to provide evidence linking genetics and periodontitis.
Evidence linking genetics and

periodontitis
Heritability of aggressive periodontitis
Aggressive periodontitis is a specific type of periodontitis with clearly identifiable clinical findings, rapid attachment loss and alveolar bone destruction,
which make it distinct from chronic periodontitis.
Aggressive periodontitis is subdivided into prepubertal, juvenile and rapidly progressive periodontitis,
and early onset periodontitis. Familial aggregation
reports have shown clustering within families, which
strongly suggests a genetic component of the disease
(16, 17, 21, 22, 28, 65, 66, 121, 134, 149, 154, 156, 165,
181, 206, 231, 251). Although these numerous reports
support a genetic basis for aggressive periodontitis,
sufficient consideration must be placed on the extent
of the environmental effects and behavioral patterns
Role of genetic polymorphisms in periodontitis
that families share. These include nutrition, socioeconomic status, sanitation and diseases like diabetes, among others (126). In a large-scale segregation
analysis of more than 100 families, performed by
Marazita et al. (154), a 70% autosomal-dominant
transmission of periodontitis was found in both
Blacks and non-Blacks. Segregation analysis is a
method used to study families to assess the likelihood
that a certain disease is inherited as a genetic trait. A
linkage study has identified a gene locus responsible
for aggressive periodontitis on chromosome 4 [logarithm of odds (LOD) score 3.0] but this finding
was later refuted with suggestions on the genetic
locus heterogeneity of aggressive periodontitis (22,
88). This means that the disease may be a result of
mutations in several loci. Very recently, aggressive
periodontitis was linked to chromosome 1q25 (LOD
score 3.48) (146). The result was established after
performing linkage analysis in four multigenerational
families exhibiting the localized aggressive periodontitis phenotype. Linkage analysis is a way of
localizing a trait to a specific location along a chromosome.
Heritability of chronic periodontitis

Chronic periodontitis (former name; adult periodontitis) is the most frequently occurring form of
periodontitis, characterized by slowly progressing
alveolar bone destruction and attachment loss. Genes
have also been implicated to play a role in chronic
periodontitis, but in contrast to aggressive periodontitis, chronic periodontitis does not typically
follow a simple pattern of familial transmission or
distribution. The twin study is probably the most
popular method that supports the genetic aspects of
chronic periodontitis. This study substantiates the
contribution that genes make vs. the environment in
a phenotypic expression. Monozygous twins, in
contrast to dizygous twins, come from a single ovum
and therefore share exactly the same genes. Discordance in the disease experience of monozygous
twins must be caused by environmental determinants as seen in twins reared apart. In dizygous twins,
differences could be a result of both genetic and
environmental differences. Michalowicz et al. (166)
reported the periodontal condition of 110 pairs of
twins from 16 to 70 years old. The mean probing
depth and attachment level scores were found to vary
less in monozygous twins reared together than in
dizygous twins reared together. In a subsequent
related study of 64 monozygous and 53 dizygous
adult twin pairs, the genetic and environmental var-
iances and heritability in chronic periodontitis,

according to path models, were estimated using
maximum likelihood estimation techniques (167).
Monozygous twins were found to be more similar
than dizygous twins for all clinical measures. Statistically significant genetic variance was found for both
the severity and extent of disease. Adult periodontitis
was estimated to have c. 50% heritability, which was
unaltered following adjustments for behavioral variables, including smoking. It was concluded that there
is indeed a substantial genetic basis for the risk of
chronic periodontitis. A study by Corey et al. (38)
among 4908 twin pairs revealed that of the 116
identical and 233 non-identical twins, 9% reported a
history of periodontitis. The concordance rates were
0.230.36 for monozygous twins and 0.080.16 for
dizygous twins. However, in this study, environmental factors like smoking were not controlled,
thereby creating bias toward establishing a correlation between twins.
Gene polymorphisms in
periodontitis: aiming at the right
targets
Most genetic research in periodontitis has focused on
gene polymorphisms that play roles in immunoregulation or metabolism, such as cytokines, cell-surface
receptors, chemokines, enzymes and others that are
related to antigen recognition (Table 1). The following sections discuss the different studies that were
undertaken to further understand the roles of gene
polymorphisms in periodontitis.
Cytokine gene polymorphisms

Interleukin-1 family
The biological activity, molecular biology and clinical
relevance of the interleukin-1 family [interleukin-1ab,
interleukin-1 receptor I/II/a] have been studied
extensively and reviewed time and again (6, 46, 50,
212, 261). Interleukin-1 is a potent pro-inflammatory
agent that is released by macrophages, platelets and
endothelial cells. The gene encoding this cytokine is
assigned to chromosome 2q1321 (10, 29, 155). Based
on the number of published reports, the interleukin-1
genotypes appear to be the most studied genetic
association with periodontal disease (Table 1).
However, carriage rates of interleukin-1 alleles differ
across populations (Fig. 1). In 1997, Kornman et al.
103
104
0/1, 0/1, 0/1

0/3 0/1, 0/1
2/4, 1/3, 2/4
0/1
18; )656, )607, )137, +113,

+127, codon 35/3
a; )1031, )863, )857, )376,

)308, )238, +489, VNTR
b; +252
)988, )800, )509, L10P, R25P
IIA, IIIA, IIIB
1; )1607
3; )1171
9; )1562
2; )1575, )1306, )790, )735
Others
TGF-b
FCGR
MMP
0/1, 1/1, 1/1, 1/1, 1/1

0/1, 1/1, 1/1
c.301, 306, 329, 348, 378
546, 568, 576
FPR1
0/1, 2/2
ApaI, BsmI, TaqI
VDR
HLA
TNF
0/1, 4/5, 0/1
)0/1
10; )1087, )819, )592 , VNTR
DQA1, DQB1,DR4
6; )597, )572, )373, )190, )174
2/3, 0/1
0/3, 0/3
4; )590, VNTR
DRB1,DRB345, DRBblank
2; )330
1/2, 0/1, 0/1
)4/10, 2/4, 0/6
b; )31, +3954 RNPAG
A, B, Cw
1/8, 1/3
a; )889/+4845, )511
IL-1 cluster
Other interleukins
Aggressive periodontitis*
Position
Gene
1/1, 1/1, 4/5
1/2, 1/2
1/2, 1/1, 1/1
1/2, 1/2, 1/2
0/1
0/2
0/2
0/2
1/4
2/7, 3/6, 1/7
)509 1/2, others 0/1
2/3
1/1, 1/1, 1/1, 0/1

1/7, 0/3, 0/1,
All loci 0/1
1/3, 1/3, 1/3,
0/2, 1/2, 1/1, 0/1, 1/3
0/3, 0/2
1/1
1/1, 5/14, 1/1,5/10
1/11, 0/2
Chronic periodontitis*
Table 1. Reports on the association between periodontitis and polymorphisms in genes affecting host response and metabolism
(85, 278)
(46, 88, 108, 235, 236, 276)
(12, 19, 96, 182, 226, 233, 239)
(233)
(103, 233)
(224, 233)
(113, 233)
(101, 113, 223, 233)
(34, 36, 69, 127, 129, 130,

150, 162, 229, 271)
(99, 222)
(221)
(39, 51, 53, 57, 61, 73, 98, 125,

135, 192, 217)
(64)
(18, 77, 125, 210, 274)
(102, 133, 248)
(51, 79, 122, 168, 195, 209)
(208)
(157, 164, 185, 187, 196, 203,

207, 221, 237, 246, 259)
(4, 8, 49, 74, 78, 80, 96,

136, 141, 147, 151)
References
Yoshie et al.
(104, 233)
D 1/1 B-L 0/1, 0/1
CTS- B//D/G/L, HPGD
See references
PTG-family, RAGE
CARD15, casparase recruitment domain 15; CCR5, crotonyl coenzyme reductase 5; CTS, cathepsin; CYP450, cytochrome P450; ER, estrogen receptor; FCGR, Fc-gamma receptor; FGA, fibrinogen-alpha; FPR1, formyl peptide
receptor 1; GST, glutathione-S-transferase; HLA, human leukocyte antigen; HPDG, hydroprostaglandin dehydrogenase; IL, interleukin; ILF, interleukin enhancing binding factor; IL1RN, IL-1 receptor antagonist; IL6ST, IL-6
signal transducer; LTF, lactoferrin; MMP, matrix metalloproteinases; MPO, myeloperoxidase; NAT2, N-acetyltransferase; PTG, prostaglandin; RAGE, receptor for advanced glycation end-products; TGF-b, transforming growth
factor-b; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; TNFR, TNF receptor; TLR, Toll-like receptor; VDR, vitamin D receptor.
*Number of positive reports/total number of reports; , no report(s).
(142, 224, 233)

0/2, )1 0/2 )2/)3 0/1
CARD15, TIMP-1, -2, -3
0/1, 1/1
(59, 63, 124, 131, 161)

2/2, 0/1, 1/1, 0/1
NAT2, CYP450, GST, CCR5
See references
MPO, FGA, LTF
0/1, 0/1
(163, 202, 253)

1/1, 1/1
1/1
)463, )455, +29
TLR-2, -4
0/1
(51, 100, 218, 279)
(60, 211)
0/1 and 1/1, 2/2, 1/1
0/2, 1/2
0/1
PvuII and XbaI, )159, +587
R677W and R753G, D299G

and T399I
ER, CD14, TNFR
1/1
(233)
All 0/1
All 0/1
IL6ST, IL1RN, ILF
All 0/1
All 0/1
Unspecified
Unspecified
IL 1/4/6/10 receptors
References
Position
Gene
Table 1. Continued
Aggressive periodontitis*
Chronic periodontitis*
(137) described a composite genotype formed by the

two polymorphic loci interleukin-1A ()889) and
interleukin-1B (+3953) single nucleotide polymorphisms that carry a CT transition. This was later
known as periodontitis-associated genotype (136).
The interleukin-1A ()889), however, was superseded
by analysis of the interleukin-1A (+4845) GT
dimorphism, which is technically more straightforward, as the two single nucleotide polymorphisms
are in complete linkage disequilibrium with one another. Thus, analysis of the interleukin-1A (+4845)
single nucleotide polymorphism provides the same
genetic information (135, 242). The two loci comprising the periodontitis-associated genotype were
found to be in linkage disequilibrium (80).
Interleukin-1 genotypes associate more with chronic
periodontitis in Caucasians. Galbraith et al. (74) and
Gore et al. (80) concurred with the 1997 report by
Kornman et al. (136) that either the smoking status or
the interleukin-1 periodontitis-associated genotype
contribute to periodontitis disease severity. Papapanou et al. (185) did not find statistical difference
in the periodontitis-associated genotype between
periodontitis patients and controls, but the periodontitis-associated genotype correlated with the
severity of disease when assessed by clinical attachment level. In addition, periodontitis-associated
genotype-positive patients had a lower systemic
immunoglobulin G response to periodontal microbiota than periodontitis-associated genotype-negative
patients. Laine et al. (141) investigated the distribution of polymorphisms in the interleukin-1 gene
family among periodontitis patients and controls,
taking into account both smoking and microbiological
parameters, including the presence of Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans. The results showed a higher frequency of allele 2
carriage in interleukin-1A ()889) and interleukin-1B
(+3954) single nucleotide polymorphisms and interleukin-1RN variable numbers of tandem repeat polymorphisms in non-smoking periodontitis patients in
whom P. gingivalis and A. actinomycetemcomitans
could not be detected [odds ratio (OR) 5.7; 95%
confidence interval (CI): 1.619.8]. These results provide evidence that polymorphisms in genes of the
interleukin-1 family are associated with severe adult
periodontitis in the absence of other risk factors tested
in the patient population. The subjects enrolled in all
the studies mentioned were Caucasians. In a mixedpopulation study by McDevitt et al. (157), nonsmokers and former light smokers (<5 pack/year),
who were interleukin-1 genotype-positive, showed an
105
Yoshie et al.
Caucasian
Caucasian
37.5%
African-American
African-American
26.9%
IL-1A+4845
Japanese
Japanese
Chinese
Chinese
18.6%
11.6%
59.4%
68.0%
70.5%
IL-1B -511
61.1%
27.0%
9.3%
IL-1B +3954
2.1%
48.6%
20.4%
8.2%
IL-1RN VNTR
17.9%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Carriage rate of IL-1 polymorphic alleles

Fig. 1. Heterogeneity across the population is evident in the distribution of single nucleotide polymorphisms identified in
the interleukin(IL)-1 gene.
increased OR of 3.75 of having moderate to severe

periodontitis (95% CI: 1.0413.50). Performing the
analysis in European Caucasians only increased the
odds ratio to 5.27. This study also demonstrated the
relationship of patients age and former smoking
history with severity of adult periodontitis. On the
other hand, Meisel et al. (164) concluded that the interleukin-1 periodontitis-associated genotype in German Caucasians displayed a strong interaction with
smoking, resulting in an increased chronic periodontitis risk (OR 2.50; 95% CI: 1.215.13). Nonsmokers, even genotype-positive, were not at any increased risk. Studies in Chinese, Greek, Japanese and
Thai populations did not find a relationship between
interleukin-1 genotypes and chronic periodontitis
disease susceptibility or severity (4, 8, 203, 225).
One study investigated the incidence of the interleukin-1 genotypes in a population-based sample of
26-year-old New Zealanders (246). After controlling
for gender, smoking status and plaque levels, the
authors identified a high-risk group consisting of
subjects with the interleukin-1B (+3953) CC/interleukin-1A (+4845) TT genotype. This high-risk
genotype was consistent with the genotype pattern
reported by Diehl et al. (49) for early onset periodontitis, although the New Zealand study found no
association between early onset periodontitis and
interleukin-1 genotypes. In a study of Chilean Caucasians, with ages ranging from 20 to 48 years, the
heterozygous form of the interleukin-1B (+3954)
genotype was significantly higher in patients than in
106
controls and was associated with periodontitis

(OR 3.12; 95% CI 1.596.09; P 0.001) (151).
Homozygosity for allele 1 of the interleukin-1B
(+3954) genotype was a protective factor for periodontitis. The prevalence of positive genotype (at least
one allele 2 present at each locus) was significantly
higher in periodontitis patients than in controls and
was significantly associated with periodontitis, irrespective of the smoking status and periodontitis disease severity. A 5-year longitudinal study in a group of
subjects of essentially European heritage showed an
interaction of the interleukin-1 periodontitis-associated genotype with age, smoking and P. gingivalis
(40). The authors concluded that the interleukin-1
periodontitis-associated genotype was a contributory,
but non-essential, risk factor for periodontal disease
progression.
Studies suggest that periodontitis-associated genotype
does not correlate with aggressive periodontitis. Unlike
chronic periodontitis, reports of aggressive periodontitis indicate that periodontitis-associated genotype is
not associated with this disease (Table 2). Hodge et al.
(95) investigated interleukin-1A and interleukin-1B
gene polymorphisms in unrelated Scottish Caucasian
patients with generalized early onset periodontitis and
found no association between patients and controls
for the periodontitis-associated genotype. Other related studies demonstrated similar results. For example,
the studies by Diehl et al. (49) and Parkhill et al. (187)
actually found that allele 1 rather than 2 of the
Ethnicity
No (3)
No (1)
Japanese
Others
No (5)
Others
Caucasian
Yes (1)*; no (1)
No (3)
No (2)
No (1)
Yes (1); no (2)
In males OR 5.58
Caucasian
African-American
Japanese
Others
Yes (1)
In males OR 3.16
No (1)
No (1)
No (1)
No (1)
)511TC
IL-1B
Numbers in parentheses indicate the number of reports.

PAG, allele 2 of the IL1A +4845 single nucleotide polymorphism (SNP) and allele 2 of the IL1B +3954 SNP.
*Allele 2 + non-smoker + no P. gingivalis and A. actinomycetemcomitans detected odds ratio (OR) 5.7.
Early onset
IL-1A )889/
+4845GT
Caucasian
Aggressive/early onset periodontitis
Severity
Susceptibility
Chronic/adult periodontitis
Disease
association
No (1)
)31CT
Yes (1); no (2)

OR 2.86
No (1)
Yes (1); no (1)

Allele 1: risk
Yes (2); no (2)

Allele 1: OR 2.22
No (1)
No (1)
Yes (2); no (2)

OR 4.67,3.36
No (5)
Yes (1)*; no (2)
+3953/3954CT
No (2)
No (1)
No (1)
No (2)
No (1)
Yes (2); no (1)

In non-smoker
OR 6.8
Yes (1); no (4)

OR 3.75
Yes (1); no (1)

In smoker
OR 2.5
PAG +4845/
+3954
No (1)
Yes (1)
Yes (1); no (1)
Yes (1)*
IL-1RN
VNTR
Table 2. Interleukin-1 (IL-1) gene cluster polymorphisms related to chronic and aggressive periodontitis risk (case-control study)
(147, 196)
(221, 237)
(259)
(49, 79, 96, 187, 203)
(4)
(221)
(74, 80, 136, 185, 203)
(4, 8, 42, 203, 221)
(141, 157, 164, 185)
References
107
Yoshie et al.
interleukin-1B (+3953) significantly correlated with

aggressive periodontitis. A significant difference was
found only in the interleukin-1B genotype distribution after comparison of aggressive periodontitis
smokers with control smokers. In contrast, Quappe et
al. (196) reported that Chilean subjects who were
heterozygous for allele 2 of the interleukin-1B (+3953)
showed a significant association with aggressive
periodontitis (OR 2.86; 95% CI: 1.067.71; P
0.030). In a wholly African-American population,
Walker et al. (259) concluded that because of the high
frequency of allele 1 of the interleukin-1B (+3954)
single nucleotide polymorphism, studies of this
polymorphism could not be carried out in this
population.
A study by Tai et al. (237) showed that generalized
aggressive periodontitis in a Japanese population
failed to find any association between aggressive
periodontitis and genotypes with respect to the interleukin-1B (+3954), interleukin-1B ()511) or the
interleukin-1A (+4845) single nucleotide polymorphisms, although there was a significant association
with the interleukin-1RN intron 2 variable numbers
of tandem repeat genotype (OR 3.81). Recently,
Scapoli et al. (207) indicated a positive association
between generalized aggressive periodontitis and the
interleukin-1RN (variable numbers of tandem repeat)
genotype in Italian Caucasians. The genotype distribution was significantly different between generalized aggressive periodontitis and control subjects,
and the interleukin-1B (+3953) single nucleotide
polymorphism was associated with generalized
aggressive periodontitis. Moreover, a recombination
hot spot between the interleukin-1B (+3953) and interleukin-1B ()511) single nucleotide polymorphisms
was identified. However, there was no similar
association with the interleukin-1RN (variable numbers of tandem repeat) genotype in study of a UK
population (187). Li et al. (147) investigated the
associations of interleukin-1 gene cluster polymorphisms with aggressive periodontitis in a Chinese
population. There was no significant association
of interleukin-1 polymorphisms with generalized
aggressive periodontitis in unstratified subjects.
However, when subjects were stratified by gender,
the positivity and frequency of allele 2 at the interleukin-1A (+4845) single nucleotide polymorphism
were significantly increased in male patients compared with male controls (OR 5.58). The frequency
of the interleukin-1B ()511) heterozygote was also
significantly increased in a male generalized aggressive periodontitis group. Moreover, a possible combined effect of the polymorphism of interleukin-1B
108
()511) and smoking on generalized aggressive periodontitis susceptibility was suggested.

Taken altogether, the interleukin-1 composite
genotype, along with other candidate genes, may
contribute to the pathogenesis of chronic periodontitis, but seemingly not to aggressive periodontitis. The
increase in risk of the periodontitis-associated genotype-positive subjects was demonstrated, irrespective
of confounding factors such as smoking, P. gingivalis
and age, although periodontitis-associated genotype
was shown to interact with these confounding factors.
Owing to ethnic differences, the global applicability of
the interleukin-1 composite genotype as a periodontitis marker may not be established.
Interleukin-1 genotype-positive subjects exhibited increased interleukin-1 protein. The number of reports
describing the functional importance of interleukin-1
gene polymorphisms is relatively few. Thus, a definitive cause and effect could not be pointed out. Several studies, however, have shown some possible
functional implications. For example, carriage of allele 2 in the ()889) locus resulted in an almost fourfold increase of interleukin-1a protein levels in
chronic periodontitis patients (219). Furthermore,
patients who were positive to the composite interleukin-1A (+4845) and interleukin-1B (+3954) periodontitis-associated genotype had a higher level of
interleukin-1b in gingival crevice fluid but not in
gingival tissue before and after treatment (54).
However, positivity to periodontitis-associated genotype did not correlate with higher gingival crevice
fluid volume and percentage bleeding on probing in
experimental gingivitis (114). Periodontitis patients
carrying one or two copies of the rare allele of interleukin-1A ()889), tumor necrosis factor ()308) or
interleukin-6 ()174) polymorphisms displayed significantly higher serum interleukin-6 concentrations.
Similarly, subjects carrying one or two copies of the
allele 2 at interleukin-6 ()174) and interleukin-1A
()889) had significantly higher C-reactive protein
serum levels than subjects homozygous for allele 1.1
(43). The interleukin-1RN tandem repeat polymorphism, in contrast to the non-synonymous, interleukin-1B (+3954) polymorphism, contributed to
interleukin-1b regulation in differentiating monocytes (193, 217).
Tumor necrosis factor
Tumor necrosis factor is a pro-inflammatory cytokine
that possesses a wide range of immunoregulatory
functions. Tumor necrosis factor has the potential to
stimulate the production of secondary mediators,
including chemokines or cyclooxygenase products,

which consequently amplifies the degree of inflammation (115, 179).
Tumor necrosis factor gene polymorphisms and
periodontitis studies display conflicting results. The
tumor necrosis factor gene (TNF) is located in chromosome 6 within the major histocompatibility complex, in the 6p21.3 Class III human leukocyte antigen
zone (148, 197). Eight single nucleotide polymorphisms in the promoter region of this gene have been
described at positions )1031T/C, )863C/A, )857C/T,
)575G/A, )376G/A, )308G/A, )244G/A, and )238G/A
(25, 26, 45, 92, 250, 265). Casecontrol studies of TNF
promoter variations revealed conflicting findings.
The )380 locus was linked to chronic periodontitis
susceptibility (P < 0.01) in Czech Caucasians, but not
in Dutch, Polish, Swedish or US Caucasians (33, 51,
57, 61, 74, 217). The same locus was associated with
chronic periodontitis severity in U.S. Caucasians
(OR 10.2), but an earlier study in the same population reported contrasting results (74, 136). Aggressive periodontitis was not linked to this locus (53,
192, 217). The rest of the promoter polymorphisms
were not associated with periodontitis, except in one
study that found an association between the )1031,
)863, )857 single nucleotide polymorphisms and
chronic periodontitis severity in Japanese people (39,
53, 74, 125, 221). On the other hand, the A/A genotype
of the +252 single nucleotide polymorphism in the
tumor necrosis factor-b gene served as a protective
factor against chronic periodontitis (OR 0.08) in
one study of Caucasian subjects, but this result was
not in accordance with another study of similar
subjects (57, 74). It is not clear why these studies gave
conflicting results. However, performing another
approach, such as meta-analysis, which pools all the
data to extract a common conclusion, would be
helpful. The major cellular source of tumor necrosis
factor is the monocyte/macrophage cell group,
although other cells, such as T lymphocytes and
epithelial cells, can also produce tumor necrosis
factor (120, 191). Ex vivo studies, on the correlation
between single nucleotide polymorphisms and
tumor necrosis factor production by lipopolysaccharide stimulation of monocytes, produced varying
results. Some studies concluded that TNF polymorphisms, particularly )308 G/A did not affect tumor
necrosis factor production (99, 119, 241). On the
contrary, other studies reported that the )308 A allele
correlated with higher levels of tumor necrosis factor
(58, 152, 240). The contradictory results could be
attributed to the differences in size and choice of
subjects, time periods after stimulation, concentrations of stimuli used and the absolute values of tumor
necrosis factor (in pg/ml) reported (15). Tumor
necrosis factor-a production in TNF 1031/)863 or
)857 single nucleotide polymorphism variant allele
carriers tended to be elevated in healthy Japanese
subjects (221). Gene polymorphisms and periodontitis association of TNF and other cytokines, and their
receptors, are summarized in Table 3.
Other cytokines
Interleukin-2. Interleukin-2 is a pro-inflammatory
cytokine produced by T-helper 1 cells. It mediates the
cellular immune response by participating in B lymphocyte activation and macrophage stimulation, as
well as in natural killer and T lymphocyte proliferation (186, 243, 266). Periodontitis patients have been
reported to show higher interleukin-2 levels in the
serum compared with healthy subjects (164). In
addition, interleukin-2 was found to be produced by
lymphocytes cultured from chronically inflamed
periodontal tissues (215). The interleukin-2 gene is
located in chromosome 4q26 (214). Polymorphism at
positions ()330) and (+166), relative to the transcription start site, were identified by John et al.
(116). The (+166) change occurs within the leader
peptide and does not affect the amino acid sequence.
The ()330) polymorphism has two common alleles (T
and G), making it an ideal marker for genetic
association. Homozygotes of the G-allele were found
to be at increased risk of hay fever (175). In a periodontal study in Caucasian subjects, the T-allele
carriers seem to be approximately half as likely to
develop severe periodontal disease (OR 1.99; 95%
CI 1.073.7). Moreover, individuals with the TT
genotype seem to be 2.5-times less likely to develop
severe periodontitis than individuals who are heterozygous or GG homozygous (OR 2.57; 95%
CI 1.155.73) (208).
Interleukin-4. Multiple roles have been identified
with interleukin-4. This cytokine can rescue B
lymphocytes from apoptosis and enhance their survival, thus playing a role in promoting B-lymphocytemediated autoimmunity (107, 170, 220). Interleukin-4
is also a potent down-regulator of macrophage
function (56, 87). In established and advanced
periodontitis lesions, the presence of interleukin-4producing cells and the percentage of interleukin-4+
cells were significantly higher in periodontitis than in
gingivitis tissues (271). Interleukin-4 levels in the
serum of patients was higher in chronic periodontitis
than in controls, although these levels did not cor-
109
110
Chromosome
6p21.3
6p21.3
6p21.3
4q2627
5q31.1
Gene
TNFA
TNFB
TNF-a
IL-2
IL-4
C/A
C/T
G/A
G/A
G/A
G/A
)863
)857
)376
)308
)238
+489
14 alleles
T/G
C/T
VNTR (70 bp)
Microsatellite
)330
)590
VNTR
A/G
T/C
)1031
+252
Allele
Locus
No (1)
No (1)
Brazilian
African-Brazilian
No (1)
Korean
No (1)
African-Brazilian
Japanese
No (1)
Brazilian
Japanese
Caucasian
Yes (1)
OR 1.99
Yes (2); no (1)

AA: protective, OR 0.08
No (1)
Caucasian
Brazilian
Caucasian
Caucasian
Caucasian
No (1)
Japanese
Chilean
No (2)
No (1)
Japanese
Caucasian
Yes (1); no (5)

OR 10.2, GG: risk
No (1)
Yes (1)*
Yes (1)*
Yes (1)*
Chronic
periodontitis
Association (no. of reports)
Caucasian
Caucasian
Japanese
Japanese
Japanese
Ethnicity
Table 3. Gene polymorphisms in other cytokines, cytokine receptors and periodontitis association
No (1)
No (2)
No (1)
No (2)
No (1)
No (1)
No (1)
No (1)
No (1)
No (1)
No (1)
No (1)
Aggressive
periodontitis
(209)
(195)
(79)
(79, 168)
(122)
(195)
(209)
(79)
(79, 167)
(208)
(125)
(57, 73, 98)
(39)
(53, 221)
(39, 73)
(192)
(53, 221)
(57, 61, 73, 74, 217)
(39)
(53, 221)
(53, 221)
(53, 221)
References
Yoshie et al.
Chromosome
7p21
1q3132
Gene
IL-6
IL-10
Table 3. Continued
Allele
A/G
G/C
AnTm: 3 alleles
C/T
G/C
A/G
C/T
C/A
Locus
)597
)572
)373 (microsatellite)
)190
)174
)1082/)1087
)819/)824
)592/)597
No (1)
No (1)
Yes (1)
OR 3.35
Japanese
Brazilian
Yes (1)
OR 3.78
Brazilian
Caucasian
No (1)
Japanese
No (1)
Brazilian
No (1)
No (1)
Japanese
Caucasian
Yes (1)
OR 2.58
No (1)
Japanese
Caucasian
Yes (1); no (1)

OR 3.0, C allele: protective
No (1)
Caucasian
Japanese
Yes (1)
OR 2.96, A9T11: protective
No (1)
Japanese
Japanese
Yes (1)
OR 0.27, GC: protective
No (1)
Japanese
Caucasian
No (1)
Chronic
periodontitis
Caucasian
Ethnicity
No (1)
No (1)
No (1)
No (1)
No (1)
Aggressive
periodontitis
(210)
(273)
(76)
(210)
(273)
(76)
(210)
(273)
(18)
(133)
(102, 248)
(133)
(133)
(133)
(102)
(42)
(102)
References
111
112
(67)
relate with either the degree of bone loss or pocket

formation observed clinically (158). The gene for interleukin-4 is found in chromosome 5q31.1 (232).
Promoter single nucleotide polymorphism at position
()590) and a 70-bp variable numbers of tandem repeat polymorphism at intron 2 have been identified
(173). Casecontrol reports relating to aggressive
periodontitis and chronic periodontitis susceptibility
and severity across several populations have failed to
establish a connection between these loci and periodontal disease (79, 122, 168, 195, 209).
Yes (1)
OR 5.56 in smoker
IL, interleukin; IFN, interferon; OR, odds ratio; TGF, transforming growth factor; TNF, tumor necrosis factor.
Caucasian
13 alleles
6q2324
IFN-cR1
Intronic microsatellite
3p21
CCR5
Coding ()?32)
32-bp deletion
Caucasian
No (1)
(59)
(218)
Yes (1)
OR 2.61
Japanese
T/G (Met196Arg)
1p36.236.3
TNFR2
+857
No (1)
G/C
+915
Caucasian
No (1)
T/C
+869
Caucasian
Yes (1); no (1)

C/T
)509
Caucasian
No (1)
Caucasian
G/A
19q13.113.2
TGF-b1
)800
Chronic
periodontitis
Allele
Locus
Chromosome
Gene
Table 3. Continued
Ethnicity
Aggressive
periodontitis
(99, 222)
References
Yoshie et al.
Interleukin-6. Essential biological activities depend

on interleukin-6. As a result of its wide range of effects, deregulated over-production of interleukin-6
causes various clinical symptoms and abnormal
laboratory findings in vivo (176). The interleukin-6
gene was demonstrated to be localized in chromosome 7p21 (23). Several studies have shown the
association of interleukin-6 gene polymorphisms
with some diseases or conditions such as rheumatoid
arthritis and bone mineral density (184, 189). In
periodontitis, the GC single nucleotide polymorphism at the ()174) position correlated with chronic
periodontitis susceptibility in Brazilian Caucasians
(OR 3.0), but not in Czech Caucasians (57, 259).
With regard to the other interleukin-6 gene single
nucleotide polymorphism locations, the Czech study
suggested that the ()572) G/C polymorphism of the
IL-6 gene may be one of the protective factors associated with lower susceptibility to chronic periodontitis (OR 0.27; 95% CI: 0.120.61). Furthermore, the
study did not find an association between the ()597)
G/A locus and chronic periodontitis susceptibility.
A recent report revealed that the ()174) G/C, ()190)
C/T and ()597) G/A loci were non-polymorphic in a
Japanese population (133). However, an over-representation of the ()373) A9T11 allele was observed
in non-chronic periodontitis subjects (P 0.008;
OR 2.96; 95% CI 1.217.43). The authors also
reported that the interleukin-6 concentration in
subjects homozygous for the C[A10T10] haplotype of
the ()572) G/C and )373 AnTm loci was significantly
higher than in heterozygotes. In another study, periodontitis patients carrying one or two copies of the
rare allele in the interleukin-6 ()174) polymorphism
displayed significantly higher serum interleukin-6
and C-reactive protein concentrations (SE 0.8
1.1 ng/l, P < 0.001 for interleukin-6; SE 0.8
1.1 mg/l, P 0.023 for C-reactive protein) (43).
Cigarette smoking and carriage of the same allele was
associated with less reduction in probing depths
among chronic periodontitis patients after delivery
susceptibility in Brazilians (OR 3.04; CI 1.31

6.91 and OR 3.38; 95% CI 1.298.82, respectively) but not in Japanese and German Caucasian
subjects (77, 210, 273). The ()1087) single nucleotide
polymorphism falls within a putative transcription
factor binding site and was associated with high
in vitro interleukin-10 production (55, 139). The
()819) single nucleotide polymorphism may affect an
estrogen-responsive element, and the ()592) single
nucleotide polymorphism lies within a region with a
negative regulatory function (139, 143).
of standard non-surgical periodontal therapy (44).

It appears that interleukin-6 gene polymorphisms
affect the serum levels of circulating interleukin-6,
and consequently modify the patients response to
periodontal treatment.
Interleukin-10. Interleukin-10 stimulates the production of protective antibodies and down-regulates
pro-inflammatory cytokines produced by monocytes
(200, 256). Periodontitis lesions demonstrated a
significantly higher messenger ribonucleic acid
expression for interleukin-10 than that in autologous
peripheral blood mononuclear cells (272). Moreover,
stimulation of peripheral blood mononuclear cells
with outer membrane antigen from P. gingivalis
induced variable but significantly higher interleukin10 messenger ribonucleic acid expression in periodontitis patients than in healthy controls (5). These
data suggest that controlling mechanisms suppress
an excess production of inflammatory cytokines,
which could affect the inflammatory response in
periodontitis, resulting in different clinical manifestations. The gene encoding interleukin-10 was mapped to chromosome 1q3132 (123). Three promoter
single nucleotide polymorphisms have been described in this gene: ()1087) G/A; ()819) C/T; and
()592) C/A (139, 143). The three loci exhibit strong
LD (260). Microsatellite polymorphisms were also
identified in the 5-flanking region of the gene, but no
association with periodontitis has been established
(55, 125). The ()1087) G/A locus was not associated
with chronic periodontitis susceptibility in Japanese
and Brazilian subjects, but was linked to chronic
periodontitis severity in Swedish Caucasians
(OR 2.58) (18, 210, 273). The ()819) C/T and ()592)
C/A loci correlated with chronic periodontitis
Transforming growth factor-b1. One of the cytokines

released during tissue injury and by inflammatory
cells exposed to bacteria and their products is
transforming growth factor-b (258). This cytokine is
described as a double-edged sword, having both
therapeutic and pathologic potential (20). Periodontopathic microorganisms have been reported to
induce the production, by mononuclear phagocytes,
of transforming growth factor-b in vitro, and the
transforming growth factor-b protein was detected
in the early and late stages of periodontal disease
(257).
The gene for transforming growth factor-b1
(TGFB1) is located in chromosome 19q13.1 (70). One
promoter polymorphism, the ()509) C/T, was associated with chronic periodontitis severity in Brazilian
Caucasians (P 0.04) (224). However, this single
nucleotide polymorphism, together with the other
polymorphisms, was not related to chronic periodontitis susceptibility in Czech Caucasians (100). The
()509) C/T polymorphism was significantly associated with the plasma concentration of transforming
growth factor-b1 and osteoporosis in Japanese
subjects (82, 269).
Fc R polymorphisms
FcRIIIA
-158V -158F
FcRIIA
-H131 -R131
FcRIIIB
-NA1
-NA2
Arg
18
Ser
18
Asn
47
Val
His
131
Arg
131
Val
158
Receptor affinity
(Ligand)
Phe
158
GPI
Cell membrane
High
Low
(IgG2)
High Low
(IgG1, IgG3)
Asp
64
Ser
47
Ile
88
GPI
High
Low
(IgG1, IgG3)
Asn
64
Fig. 2. Human FccR polymorphisms. FccRIIA alleles are distinguised by the presence of either Arg
or His at amino acid position 131,
whereas
FccRIIIA
alleles
are
determined by either a Val or a Phe
at position 158. The FccRIIIB-NA1/
NA2 polymorphism results in 4
amino acid substitutions, leading to
glycosylation differences (blue circles). The FccRIIA alleles interact
differntially with human immunoglobulin G(IgG)2, whereas FccRIIIA
and FccRIIIB affinities are different
upon interaction with human IgG1
and IgG3. GPI glycosylphosphatidylinositol.
113
Yoshie et al.
Receptor and other gene polymorphisms

Fc receptor polymorphisms
Leukocyte receptors for the constant (or Fc-) part of
immunoglobulin (FcR) link cellular and humoral
branches of the immune system, which are considered essential for the host defense against bacteria.
Strong, specific immunoglobulin G responses against
periodontopathic bacteria are observed in the gingival tissue and gingival crevicular fluid (104, 160). FcR
for immunoglobulin G (FccR) may therefore play a
crucial role in the host defense against these bacteria.
FcR profile and gene polymorphisms. The human
leukocyte FccR family consists of three major classes,
and encompasses eight genes (CD64: FccRIA, IB, and
IC; CD32: FccRIIA, IIB and IIC; CD16: FccRIIIA and
IIIB), which have been mapped to the long arm of
chromosome 1 (1q21 and 1q2324) (144, 205, 238).
Most FccR subclasses consist of a separate ligandbinding chain with an extracellular domain that
contains the immunoglobulin G-binding region, and
signaling chains essential for the initiation of signal
transduction. Neutrophil FccRIIIB is a notable
exception, as it is linked to the outer leaflet of the
lipid bilayer via a glycosyl phosphatidylinositol anchor.
Functional bi-allelic polymorphisms have been
identified for three FccR subclasses: FccRIIA, FccRIIIA, and FccRIIIB (Fig. 2) (183, 204, 267). FccRIIA
bears either an arginine (FccRIIA-R131) or a histidine
(FccRIIA-H131) at amino acid position 131 in the
second extracellular immunoglobulin-like domain
(261, 262). This difference strongly affects the receptor affinity for immunoglobulin G2 (188). FccRIIA-H/
H131 neutrophils internalize human immunoglobulin G2-opsonized bacteria more efficiently than
FccRIIA-R/R131 neutrophils (24). The FccRIIIA-158V
allotype exhibits higher affinity for both monomeric
and immune-complexed immunoglobulin G1 and
immunoglobulin G3 than does FccRIIIA-158F (132).
The neutrophil-specific FccRIIIB bears the NA1-NA2
polymorphism caused by four amino acid substitutions within the first extracellular immunoglobulinlike domain (183). Neutrophils from FccRIIIB-NA2
individuals bind immunoglobulin G1 or immunoglobulin G3 less efficiently than those from FccRIIIBNA1 individuals (24) (Fig. 3A). In vitro findings have
suggested that inter-individual differences in the
efficacy of FccR-mediated effector functions depended on FccR polymorphisms.
Association of FcR polymorphisms with periodontitis
risk. Wilson and Kalmar (264) speculated that
FccRIIA-R/R131 subjects were more susceptible to
periodontitis as a result of the diminished capacity to
phagocytose immunoglobulin G2-opsonized periodontopathic bacteria. It has been well documented
that FccR genes are associated with risk for various
types of periodontitis: aggressive periodontitis,
chronic periodontitis, and recurrent chronic periodontitis (Table 4). Associations between FccR
polymorphisms and susceptibility to aggressive periodontitis have been investigated in Caucasian, Asian
(Japanese and Taiwanese), and African-American
populations. Loos et al. (150) studied FccRIIA, IIIA,
Table 4. FccR genes related to periodontitis risk

Periodontitis
Population
FccRIIA
FccRIIIA
FccRIIIB
References
Aggressive
(early onset)
periodontitis
Caucasian
Yes (H131: OR 3.7)
Yes (158V: OR 2.6)
No
(150)
African-American
No
No
Yes (NA2: OR 1.8)
(69)
Japanese
No
No
Yes (NA2: OR 2.0)
(129)
Taiwanese
Yes (R131: OR 2.4)
Not tested
No
(34)
Caucasian
Yes (H/H131)
No
No
(150, 270)
Japanese
No
No
No
(127, 229)
Taiwanese
No
Not tested
No
(34)
Severe chronic (adult)

periodontitis
Caucasian
Yes (H131: OR 2.4)
Yes (158V: OR 2.9)
No
(150, 162, 270)
Japanese
No
Yes (158V: OR 2.0)
No
(130)
Recurrent chronic
(adult) periodontitis
Caucasian
No
No
No
(36)
Japanese
No
Yes (158F: OR 2.9)
Yes (NA2: OR 3.3)
(128, 230)
Chronic (adult)
periodontitis
114
and IIIB genotypes in 12 patients with aggressive

periodontitis and 61 controls of Northern European
Caucasian background. The carriage rate of FccRIIAH131 and FccRIIIA-158V was higher in patients with
aggressive periodontitis than in controls, respectively
(P 0.013 and P 0.044), suggesting a putative
susceptibility factor for aggressive periodontitis.
Chung et al. (34) examined FccRIIA and FccRIIIB
genotypes in 30 patients with aggressive periodontitis
and 74 healthy controls in Taiwan. FccRIIA-R131 was
found more frequently in the group with aggressive
periodontitis than in the group with chronic periodontitis (P 0.01), but not in the control group. In
contrast, Japanese studies have demonstrated an
over-representation of the FccRIIIB-NA2 allele in
patients with aggressive periodontitis compared to
patients with chronic periodontitis and controls (129,
277), which was in accordance with the results of
African-American patients (69). From these results, it
is conceivable that the FccR-encoding genes related
to aggressive periodontitis risk are different among
ethnic populations.
Relationships between FccR polymorphisms and
chronic periodontitis risk have also been investigated
in detail. There is only one report showing a significant association with susceptibility to chronic
periodontitis. Yamamoto et al. (270) indicated a
difference in the FccRIIA genotype distributions
between 213 Caucasian patients with chronic periodontitis and 209 race-matched controls (P 0.036),
with enrichment of the FccRIIA-H/H131 genotype in
the patients compared with the controls. However,
other work failed to show a significant association
with chronic periodontitis susceptibility (34, 127, 130,
162). Caucasian patients with chronic periodontitis
and FccRIIA-H/H131 were found to have more teeth
with severe periodontal breakdown than patients
carrying FccRIIA-R131 (150). Likewise, smokers with
FccRIIA-H/H131 exhibited a greater clinical attachment loss than smokers with FccRIIA-R/H131 and
FccRIIA-R/R131 (270). On the other hand, Meisel
et al. (162) indicated a significant association of
FccRIIIA-158V with chronic periodontitis severity
(P 0.010), which was in accordance with a Japanese
study (130).
Three studies have investigated FccR genotype
distributions in patients with recurrent chronic periodontitis. Colombo et al. (36) found no differences in
FcRIIIB polymorphism and neutrophil function

A
Phagocytosis (%)
Aggressive
periodontitis (n = 38)
IgG1-opsonized
29.0
52.6
18.4
60
Recurrent chronic
40
Chronic
20
Healthy control
(n = 104)
Periodontitis resistant (n = 46)
15
25
22.3
45.9
15.7
31.8
48.2
11.5
36.1
52.9
35.6
56.5
43.5
(min)
0
NA2/NA2
NA1/NA2
Fig. 3. (A) Diminished phagocytosis of immunoglobulin

G(IgG)1-opsonized Porphyromonas gingivalis by neutrophils expressing FccRIIIb-NA2/NA2 (closed circles)
compared with IIIb-NA1/NA1 (open circles) in six healthy
controls. Subjects were matched for their FccRIIA R/H131
genotypes. Values represent means standard error
25
50
75
100 (%)
NA1/NA1
(128). (B) Distribution of FccRIIIB genotypes in Japanese

patients with various types of periodontitis. FccRIIIB-NA2/
NA2 (closed bars) was found more frequently in aggressive
periodontitis patients than in healthy controls (127, 129,
230).
115
Yoshie et al.
Hypothetical role of FcR genotypes in susceptibility to periodontitis

Per i o d ont o pat hi c
ba cte ria
Opsonization
with IgG
IgG-mediated phagocytosis
by neutrophils
Ligation of
m o n o c y t e / m a c r o ph a g e
and lymphocyte
Aggressive periodontitis
Efficient by
NA1-cells
Normal
Inefficient by
NA2-cells
Risk
Normal-production
in R131- or 158F-cells
Normal
Over-production
in H131- or 158V-cells
Risk
TNF- / IL-1 production
CP
Fig. 4. Hypothetical role of FcR genotypes in susceptibility to periodontitis. Inefficient clearance of periodontopathic bacteria by neutrophils expressing the
low-affinity genotype FccRIIIB-NA2/NA2 may result in an
increased level of bacteria in the gingival crevice, leading
to high susceptibility to periodontitis in younger adults.
The high affinity genotype FccRIIA-H131/H131 and

FccRIIIA-158V/158V may contribute to a strong proinflammatory cytokine release by monocytes/macrophages
and lymphocytes upon interaction with immunoglobulin
G(IgG), possibly leading to an increased risk for periodontitis in adults.
FccRIIA and IIIB genotype distributions among the

32 refractory, 54 successfully treated and 27 periodontally healthy groups of Caucasian background.
On the contrary, a significant over-representation of
FccRIIIB-NA2 and FccRIIIA-158F was found in 85
Japanese patients with chronic periodontitis and
disease recurrence as compared with 15 race-matched chronic periodontitis patients without recurrence (P 0.0003 and P 0.009) (127, 229).
Interestingly, FccRIIB polymorphisms may play
an important role in the pathogenesis of periodontitis, because of a large numbers of FccRII-bearing
B lymphocytes in the periodontal lesion. Yasuda
et al. (275) found a significant over-representation
of the FccRIIB-232T allele in 32 patients with
aggressive periodontitis, as compared with 72
patients with chronic periodontitis and 72 controls
(P 0.039 and P 0.006), suggesting an association
with susceptibility to aggressive periodontitis in
Japanese subjects.
Hypothetical role of FcR risk allele in periodontitis. The most convincing FccR genes related to
periodontitis risk might be supported by significant
evidence provided in more than two ethnic population studies. FccRIIIB-NA2 seems to constitute a
gene-predisposing susceptibility to aggressive periodontitis (Fig. 3B), which might be explained by the
hypothesis demonstrated in Fig. 4. FccRIIIB is a
neutrophil-specific receptor and plays a crucial
role in the control of specific immunoglobulin
G-opsonized pathogens in the gingival crevice.
Immunoglobulin G1- and immunoglobulin G3-opsonized P. gingivalis may be more effectively
phagocytosed and killed by FccRIIIB-NA1 than
FccRIIIB-NA2 neutrophils (128). Therefore, inefficient clearance of periodontopathic bacteria by
neutrophils in FccRIIIB-NA2 subjects may result in
an increased level of bacteria in the gingival crevice,
finally leading to be relatively at high risk of
aggressive periodontitis.
116
Possible concept for common polymorphisms
Aggressive
periodontitis
Chronic
Periodontitis
diseases
periodontitis
Master gene
Systemic
Minor genes
Common/shared genes
Fig. 5. Both aggressive and chronic periodontitis may have shared susceptibility genes, in the same manner as periodontitis may share susceptibility genes with other complex, inflammatory or systemic diseases.
Other promising genes influencing susceptibility to

chronic periodontitis are FccRIIA-H131 and FccRIIIA-158V. The significance of these two genes might
be related to a hypothetical role of FccRIIA-bearing
monocytes/macrophages and FccRIIIA-expressing
lymphocytes in the periodontium (Fig. 4). FccRIIA
and IIIA cross-linkings have been shown to produce
pro-inflammatory cytokines, such as tumor necrosis
factor-a and interleukin-1b (47, 156). It is therefore
proposed that the high affinity of FccRIIA-H131 and
FccRIIIA-158V to immunoglobulin G contributes to a
high level of pro-inflammatory cytokine release by
monocytes/macrophages and lymphocytes, possibly
leading to an increased risk for chronic periodontitis.
Cytokine and chemokine receptors
Receptors are important constituents of the whole
cytokine system. Through these membrane-bound or
circulating proteins, cell responses to various cytokines, such as interleukin-6 and tumor necrosis factora, are either elicited or blocked (2, 72). The soluble
form of tumor necrosis factor-receptor 2 (tumor
necrosis factor-R2), which is shed from the cell surface, significantly reduced the loss of connective tissue and alveolar bone in experimental periodontitis
(8, 9, 48). The tumor necrosis factor-R2 (+587) T/G
polymorphism was associated with chronic perio-
dontitis severity in Japanese patients (P 0.0097;

OR 2.61) (218). Given this scenario, this variation
in the tumor necrosis factor-R2 gene could have an
effect on the ability of the receptor to block efficiently
the activity of tumor necrosis factor-a. Using an
intronic (CA)n polymorphic microsatellite marker
within the interferon-c receptor 1 (IFNGR1) gene,
Fraser et al. (67) found a correlation between genetic
polymorphisms and periodontitis in Caucasians
(P 0.014; OR 5.56). It was reported that a strong
correlation exists among the IFNGR1 genotype, cellular responsiveness to interferon-c and clinical disease features (52). On the other hand, the C-C
chemokine receptor 5 delta32 polymorphism was not
related to periodontitis susceptibility in German
Caucasians (59). Recent reports indicate the role of
interleukin-6 receptor gene polymorphisms in diabetes, obesity and serum soluble interleukin-6
receptor level (75, 86, 268). The possible role of variations in the interleukin-6 receptor gene in periodontitis could therefore be investigated in the future.
Metabolism-related polymorphisms
Cathepsin C polymorphisms. Cathepsin C is a proteinase, and is expressed in the hyperkeratotic epithelial lesions such as palms, knees and oral keratinized
117
Yoshie et al.
gingiva (87). Hart et al. (89, 90) analyzed two consanguineous Jordanian families, and identified a gene
on chromosome 11 (11q14) containing the cathepsin
C gene, responsible for prepubertal periodontitis as
well as Papillon-Lefe`vre Syndrome. All patients with
pre-pubertal periodontitis were found to be homozygous for an AG mutation at gene position +1040,
resulting in a substitution of the amino acid tyrosine
by a cysteine. This gene polymorphism was shown to
be functional as there was a diminished activity of
cathepsin C in Papillon-Lefe`vre Syndrome (247).
Interestingly, other mutations found in the cathepsin
C gene have been linked to Papillon-Lefe`vre Syndrome (41, 89). Recently, Cury et al. (41) demonstrated a novel TC mutation at gene position +587 in
exon 4, causing substitution of conserved leucine, at
position 196, by a proline. Another study, by Noack
et al. (177), reported two novel gene mutations at
positions 947 and 1268, which was associated with
these two diseases. Functional mutations in the
cathepsin C gene may therefore be considered as
causative for prepubertal periodontitis and PapillonLefe`vre Syndrome.
Vitamin D receptor polymorphisms. Vitamin D plays
a role in the metabolism of calcium and phosphorus.
The human vitamin D receptor gene is localized in
chromosome 12q12q14 (169), and exhibits functional polymorphisms associated with osteocalcin
levels and bone mineral density (137, 171). Vitamin D
receptor polymorphisms may therefore play a role in
the destruction of alveolar bone. Hennig et al. (91)
studied a restriction fragment length polymorphism
(RFLP) for TaqI in exon 9 in 69 Caucasian patients
with aggressive periodontitis and 72 race-matched
controls. The authors indicated a higher prevalence
of TaqI RFLP (t) in the patients with localized aggressive periodontitis than in the controls
(P 0.017). In contrast, Yoshihara et al. (276) indicated no association between the vitamin D receptor
genotypes and risk for aggressive periodontitis in the
Japanese. Tachi et al. (236) found an increased frequency of the allele TaqI RFLP (T) in chronic periodontitis patients compared with controls (P 0.04).
Another polymorphism for BsmI (B/b) in exon 8 was
analyzed by de Brito et al. (27), who showed that the
vitamin D receptor haplotype was a risk factor for
chronic periodontitis. Inagaki et al. (108) examined
an association of the ApaI (A/a) and TaqI (T/t)
polymorphisms and periodontal disease progression
in 125 subjects for 23 years, and showed that the ApaI
A/A genotype subjects exhibited the highest rate of
the disease progression.
118
Matrix metalloproteinase polymorphisms. Matrix

metalloproteinases play an important role in connective tissue destruction in periodontitis. Increased
levels of the gene transcript and protein for matrix
metalloproteinase-1 (interstitial collagenase) and
matrix metalloproteinase-3 (stromelysin-1, activator
of collagenase) were found in the periodontitis lesions. Therefore, polymorphisms in the promoter
region of matrix metalloproteinase-1 and matrix
metalloproteinase-3 genes may contribute to susceptibility to periodontitis. de Souza et al. (223)
showed that the matrix metalloproteinase-1 ()1607)
2G/2G genotype was more frequently observed in 26
patients with severe chronic periodontitis than in 24
patients with moderate chronic periodontitis and 37
controls, all with a Brazilian background. The authors
also examined the matrix metalloproteinase-9 ()1562
C/T) promoter polymorphism, which was not associated with susceptibility to chronic periodontitis
(224). Holla et al. (101) indicated that three matrix
metalloproteinase-1 polymorphisms ()1607 1G/2G,
)519 A/G, and )422 A/T) showed only a small
effect on chronic periodontitis in the Czech population. Recently, Itagaki et al. (113) studied matrix
metalloproteinase-1 ()1607 1G/2G) and matrix
metalloproteinase-3 ()1171 5A/6A) polymorphisms
in 37 patients with aggressive periodontitis, in 205
patients with chronic periodontitis, and in 142 healthy controls, all with a Japanese background, but
failed to show a significant association with periodontitis.
Antigen recognition-related polymorphisms.
Human leukocyte antigen polymorphisms. The major
histocompatibility complex system is a cluster of
genes encoding the human leukocyte antigens, which
are located on chromosome 6p21.3 (12). The human
leukocyte antigen region is mainly divided into two
classes: major histocompatibility complex class I
molecules (human leukocyte antigen-A, -B, and -C)
are expressed on most nucleated cells, whereas major
histocompatibility complex class II molecules (human leukocyte antigen-DP, -DQ, -DR) are expressed
on B- and T lymphocytes, and on macrophages.
Shapira et al. (216) found that human leukocyte
antigen-A9 and -B15 antigens were elevated in
patients with aggressive periodontitis as compared
with healthy controls. Takashiba et al. (239) indicated
a significant association of the human leukocyte
antigen-DQa gene with susceptibility to aggressive
periodontitis in the Japanese. The DQB1 molecule
has been shown, by Ohyama et al. (182), to be critical
in the pathogenesis of aggressive periodontitis. In
contrast, Hodge et al. (94) reported no association

between the human leukocyte antigen-DQa gene and
aggressive periodontitis in Caucasians. Bonfil et al.
(19) demonstrated an important role of human leukocyte antigen-DR4 in susceptibility to aggressive
periodontitis, in which subtypes 0401, 0404, 0405 and
0408 can be a risk factor for the disease. Recently,
Stein et al. (226) elucidated the variety of human
leukocyte antigen associations and the difficulty of
assigning single human leukocyte antigen markers to
periodontitis in Caucasians. A significant association
of certain human leukocyte antigen alleles (human
leukocyte antigen-A, -B, -Cw, -DRB1, -DRB3/4/5,
-DQB1) has been shown in aggressive periodontitis
and chronic periodontitis by Machulla et al. (153).
CD14 polymorphisms. The CD14 molecule is a
receptor for recognition of lipopolysaccharides, and
initiates the innate immune response to bacterial
invasion. The gene for the CD14 receptor is located
on chromosome 5q2123, consisting of c. 3900 bp
organized in two exons (81). A single nucleotide
polymorphism (CT) was identified in the promoter
region at position )159 upstream from the major
transcriptional site (110), affecting transcriptional
activity (145) and CD14 density (13). Four additional
polymorphisms have recently been identified at
positions )1619, )1359, )1145 and )809, which
influence soluble CD14 levels (254). Holla et al. (100)
found that in Czech patients, the )1359 C/T genotype
was associated with severity of chronic periodontitis,
while the )159 G/T genotype was not. Yamazaki et al.
(274) studied the )159 G/T genotype distribution in
163 Japanese patients and 104 race-matched controls, and indicated that the )159 G/T genotype was
not associated with development of periodontitis, but
may be related to early disease activity. Folwaczny
et al. (62) reported that the )159 G/T genotype was
associated with periodontitis in women, but not in
men, in Germany. These results were consistent with
a recent study with Caucasian subjects by Donati
et al. (51).
n-Formyl-L-methionyl-L-leucyl-L-phenylalanine receptor polymorphisms. The n-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) is a structural analogue of
bacterial products involved in neutrophil chemotaxis.
The fMLP receptors are also involved in the activation
and subsequent response to certain chemotactic
stimuli. The fMLP receptor genes are localized in
chromosome 19 (14). Gwinn et al. (85) examined the
fMLP receptor gene, and found that two single nucleotide base alterations (329 T/C and 378 C/G) were
associated with aggressive periodontitis. These

alterations resulted in amino acid changes (110 Phe/
Ser and 126 Cys/Try) in the fMLP receptor, suggesting a role in ligand binding and G-protein activation.
Differences in fMLP expression levels and chemotaxis
towards fMLP were examined between the fMLP
polymorphisms by Jones et al. (118). More defective
chemotaxis was found in the 126 Cys/Try mutant
than in the 110 Phe/Ser mutant, suggesting a more
severe form of aggressive periodontitis. In contrast,
Zhang et al. (278) found no association of these fMLP
receptor polymorphisms (329 T/C and 378 C/G) with
susceptibility to aggressive periodontitis.
Issues and concerns on the

candidate gene approach in
periodontitis
The candidate gene approach tries to identify one
allele of a gene that is more frequently seen in subjects with the disease than in subjects without the
disease. Most of the studies mentioned above have
utilized this approach. These association studies,
which may include members of an affected family or
unrelated cases and controls, can be performed relatively quickly and inexpensively and may allow
identification of genes with small effects (140). Authors assert that candidate gene studies are better
suited for detecting genes underlying common and
more complex disease where the risk associated with
any gene is relatively small (35).
Candidate genes are chosen on the basis of their
known or presumed functions that are thought to
have some plausible role in the disease. There are
three types of candidate genes: functional candidate
genes; positional candidate genes; and expressional
candidate genes (105). Functional candidate genes
are derived from an existing knowledge of the phenotype and the potential function of the gene involved after clinical or physiological studies of
affected individuals. Positional candidate genes are
based on the involvement of the gene to a marked
location after genetic linkage analyses. Expressional
candidate genes are determined through differences
in gene expression using microarrays.
For several genes, which have been individually
sequenced for association with periodontitis, we see
a scattered picture from different studies of varied
populations and ethnicities. To produce scientifically
sound and meaningful disease-association studies,
some issues and concerns that should be addressed
119
Yoshie et al.
when sequencing candidate genes are discussed

below.
Ethnic heterogeneity
In designing a casecontrol study, subjects should be
carefully matched by ethno-geographic origin in
addition to other potential confounding factors in
order to avoid systematic differences in genetic
composition between the two groups (37). Failing to
do so could result in different frequencies of single
nucleotide polymorphism alleles and the unsuspecting investigator might then draw unwarranted conclusions about localizations of susceptibility genes
(97). There is also a clear statement that in the presence of large biological and environmental variability,
genetic effects can differ across different populations,
or even among generations within the population
(111). Ideally, twin studies can be useful in sorting out
genetic heterogeneity and environmental factors, but
there are certain limitations in carrying out twin
studies in subjects with periodontitis (166).
Frequencies of the genetic marker of interest may
also show large heterogeneity between races (112).
Variation in genotype frequencies across diverse
populations may affect the number of individuals at
increased risk for a disease, and population substructure imbalances may create spurious differences in
genotype frequencies of the compared groups in genedisease association studies (245). For example, specific
interleukin-1 gene variations of interleukin-1A+4845,
interleukin-1A-889 and interleukin-1B+3954 have
been associated with increased severity of periodontitis in multiple Caucasian studies. However, these
interleukin-1 single single nucleotide polymorphisms
are found in low prevalence among Asians, including
Japanese, Koreans, and Chinese (Fig. 1). Moreover,
association studies of the same candidate genes in
supposedly related populations or ethnicities produced mixed or conflicting results (53, 95, 96, 133, 136,
187, 234). Stephens et al. (227) reported that 3899 distinct genetic variations at 313 genes exist in unrelated
individuals, including Caucasians, African-Americans,
Asians and Latinos, and thus the diagnostic use of
genes in periodontitis might be limited to a specific
population and may not apply globally or across an
ethnic group.
Considering the issues mentioned, it is prudent
to select a more homogenous population (age- and
race-matched), and to study, with caution, the
applicability of a certain gene marker before commencing with any attempts to replicate the same
study in the population under investigation.
120
Clinical classification
Classifying periodontal diseases has been a longstanding dilemma largely influenced by paradigms
that reflect the understanding of the nature of periodontal diseases during a given historical period (7).
As a result of its familial tendency, aggressive periodontitis generally appears in individuals before the
age of 35 years, but age alone is not sufficient to
establish diagnosis. On the other hand, chronic
periodontitis is quite complex and much more
dependent on environmental factors that confront
the patient during his lifetime. In addition, microbial
plaque deposition, smoking and systemic diseases
largely influence the phenotypic expression of the
disease. For these combined reasons, chronic periodontitis is considered to appear later in life. The
periodontist is therefore challenged regarding into
which classification a patient would properly fall.
Another critical problem related to genetics research in periodontitis is the similarity of the following clinical findings: deepening of the periodontal
pocket; and attachment and alveolar bone loss.
Therefore, investigators should strictly adhere to the
classification set during the American Academy of
Periodontology workshop in 1999 (31). Moreover,
subjects falling into the gray zone between aggressive
and chronic periodontitis should be excluded in the
study. Aggressive and chronic periodontitis probably
share a common pathogenic pathway, so several
common polymorphisms may exist and/or overlap
between the two.
Functional polymorphisms and direct

evidence
In the 2001 report of the International SNP Map
Working Group, they approximated around
1.42 million single nucleotide polymorphisms in the
human genome (201). Sixty thousand of these single nucleotide polymorphisms fall within exons.
Structural gene defects can affect the qualitative
response, and regulatory polymorphisms can alter
the response quantitatively. However, many studies
fail to provide functional evidence for gene polymorphisms and periodontal diseases. The majority
only statistically demonstrated an association between polymorphisms and periodontitis. Moreover,
some of the studied alleles may not be associated
with disease themselves, but instead may be in LD
with the disease-associated allele. If so, because LD
breaks down differently in different populations,
variations in the estimated OR may reflect variable
LD rather than variation in the true genetic effect

(112).
Kinane et al. (126) outlined the requirements in
providing a disease-polymorphism association: the
polymorphism must influence the gene product;
biases in the study population should be recognized
and controlled for; confounders such as smoking and
socio-economic class must be sorted out; and the
affected gene product should be part of the disease
etiopathology. Genetic markers for proposed genedisease associations vary in frequency across populations, but their biological impact on the risk for
common diseases may usually be consistent across
traditional racial boundaries (112).
Common guidelines for association

studies
When performing candidate gene casecontrol
studies, factors such as study design, methods of
recruitment of case and controls, selection of candidate genes, functional significance of polymorphisms chosen for study, and statistical analysis
require close attention to ensure that only genuine
associations are detected (37, 83, 84, 109, 110).
These factors are frequently debated upon in cases
of conflicting results from a similar study.
Size of study groups

One major concern related to genotype studies is the
sample size of the study subjects. Owing to limited
number of samples, most sample sizes in genetics are
small. This scenario describes very well the small
number of cases in aggressive periodontitis association studies. The number of subjects in studies of
chronic periodontitis tends to be larger, but variations do occur. The results of small studies might
differ significantly from the results of larger studies,
but large studies with thousands of participants
might not be carried out (109). Experience from other
clinical domains suggests that small studies may
mistakenly yield more favorable outcomes than larger studies (112). Wang et al. (260) demonstrated that
if susceptibility alleles have minor allele frequencies
(MAFs) of <0.1 and their effect sizes are less than an
OR of 1.3, then unrealistically large sample sizes of
more than 10,000 cases and 10,000 controls (or 10,000
families) would be required to achieve convincing
statistical support for a disease association. They
stated further that even the best designed studies
aimed at a minimum MAF of 10% and an OR of 1.3

will have less power than expected owing to many
factors, including genotype and phenotype misclassification and confounding factors, so even larger
samples might be required. The size of subjects
clearly contributes to the differences in statistical
power of the results, especially in a complex disease
like periodontitis.
Choice of controls
Defining the appropriate controls for a casecontrol
study in periodontitis still lacks clarity. Some reports
generally described their control as healthy, while
others specifically characterized controls as patients
with gingivitis or slight periodontitis. Owing to the
high prevalence of chronic periodontitis, the latter
seems to be more realistic and appropriate, as the
final point in a casecontrol study is to select controls
that represent those at risk of becoming a case (199).
Data presentation
Expressing the results in P-values only is extremely
popular in all types of studies in periodontitis.
However, the overuse and misuse of the venerable
P-value has been criticized (83, 228, 255). It was
suggested that the data should be presented be
evaluated using CI and relative risk (RR) values, as
these portray the effect size with a description of its
precision. This is in contrast to the P-value, which
tests against the null hypothesis of no association and
could provide false-positive conclusions. Furthermore, RR and 95% CI provide readers with more
useful information that does use hypothesis testing.
For a detailed discussion on this topic, readers are
directed to some publications that proposed guidelines and procedures in performing casecontrol
studies, including DNA polymorphism disease
association (37, 84, 213).
The post-genome era and

periodontitis research
Information leading to the understanding of the
genomes architecture is obviously one of the main
thrusts of the human genome project. Now that it has
been completed, the scientific community is supplied
by a wealth of new discoveries and inventions aiming
to provide clues for the complexity of human
infirmities in an unprecedented speed, number and
121
Yoshie et al.
accuracy. A commentary by Aderem and Hood (1)

summarized the impact of the completion of the
human genome project on biology in general. They
discussed the shifting of approaches in biology, the
effect to small university-based laboratories, academic vs. industrial strengths and integrating largeand small-scale sciences. In the succeeding parts,
we discuss several genetic methods and research
advances that could be useful in clarifying the role of
genetic polymorphisms in periodontitis.
Multigene model for periodontitis

From the overview of publications mentioned above,
it is reasonable to conclude that both aggressive
periodontitis and chronic periodontitis are not single-gene but polygenic diseases. A polygenic model
for periodontitis is presented in Fig. 5. A good
example to describe this model is the risk for Alzheimers disease that has been considered to be
substantially influenced by a total of 10 genetic
polymorphisms of inflammation-related molecules,
including pro-inflammatory cytokines and protease
inhibitors (126). It is thought that several of these
relatively common high-risk polymorphisms may be
inherited by an individual, giving them a susceptibility profile (159).
Similarly to other complex diseases, it is estimated
that between 10 and 50 genes with several major
master genes may be involved in periodontitis. So, it
would be more efficient to simultaneously analyze a
large sample size for multiple gene polymorphisms.
Recently, a large-scale investigation of genomic
markers for severe periodontitis was performed (234).
In this study, subjects were genotyped at 637 single
nucleotide polymorphisms in 244 genes using Taqman polymerase chain reaction. Genes encoding
gonadotropin-releasing hormone 1, phosphatidylinositol 3-kinase regulatory 1, dipeptidylpeptidase 4,
fibrinogen-like 2, and calcitonin receptor were found
to be associated with severe periodontitis. A previous
study performed by the same group sequenced a
total of 310 single nucleotide polymorphisms in 125
candidate genes for their association with aggressive
periodontitis and severe chronic periodontitis in a
Japanese population using the Taqman allelic discrimination assay (233). Single nucleotide polymorphisms in genes encoding collagen type 4 a1,
collagen type 1 a1 and gp130, among others, were
associated with chronic periodontitis. On the other
hand, single nucleotide polymorphisms in cathepsin
D, collagen type 17 and others were linked with severe chronic periodontitis. Polymorphisms in the
122
inflammatory mediators and structural factors of

periodontal tissues were associated with periodontitis in Japanese.
Genome screening and linkage analysis

With the concerns for the candidate gene approach
and association studies (e.g. inter- and intra-population heterogeneity of periodontitis genes), the
search for genes contributing to periodontitis would
be more effective using genome-wide screening and
linkage analysis of affected families or ethnic groups.
In these approaches, all genes are systematically
scanned using panels of microsatellite or single nucleotide polymorphism DNA markers uniformly distributed along the entire genome.
Numerous papers have employed genomic
screening and linkage analysis as common tools in
the search for genes of other complex diseases, such
as diabetes, inflammatory bowel disease and obesity
(11, 32, 33, 174, 263, 280). The results obtained from
the screenings and analyses of the disorders mentioned provide promising results that are worth
considering in the search for periodontitis genes in
the future. However, practical concerns may still
surface in using these methods: models of the allelic
architecture of common diseases, sample size, map
density and sample-collection biases (260).
Other questions that arise in linkage studies of
complex diseases include the number of marker loci
that should be included in the whole genome screen,
and whether single nucleotide polymorphisms or the
highly polymorphic microsatellite markers, which are
less common throughout the genome but are more
informative, should be preferred (198). Kruglyak (138)
concluded that single nucleotide polymorphisms
could be as informative as microsatellites when there
is a sufficiently dense map, and marker densities of
one per centimorgan or less were sufficient for an
initial screening for linkage. However, difficulties still
existed in linkage studies and the need for larger
samples was encouraged (3).
In 2003, localized aggressive periodontitis was
linked to human chromosome 1q25 (146). In this
study, a genetic linkage analysis was performed first
with four multigenerational families exhibiting the
localized aggressive periodontitis phenotype. Fourteen chromosome locations were analyzed using a
directed genomic screening approach. The localized
aggressive periodontitis phenotype was linked to a
DNA marker, D1S492, with the LAP locus spanning
about 26 million DNA base pairs between D1S196
and D1S533. In addition, a gene of major effect for
The human genome sequence is thought to contain more than 10 million single nucleotide polymorphisms with a frequency of >1% (244). The
combination of closely linked alleles observed on a
chromosome and inherited as a unit is called a
haplotype. Single nucleotide polymorphisms are
present in the millions but a limited number were
sufficient to define all of the common haplotypes,
and a collection of single nucleotide polymorphisms
can represent at least 95% of the haplotypes studied
(117). The selected limited number of single nucleotide polymorphisms is termed haplotype-tagging
single nucleotide polymorphisms. Most of the genetic
variation represented by the 10 million common
single nucleotide polymorphisms in the population
could be provided by genotyping between 200,000
and 1,000,000 tag single nucleotide polymorphisms
across the genome (30, 71, 76, 190, 244). Some of the
studied alleles, however, may not be associated with
disease themselves, but instead may be in LD with
the disease-associated allele (111). Therefore, knowledge of LD may result in a substantial reduction in
the amount of genotyping, with little loss of information. Wang et al. (260) placed the general consensus of r2 (degree of LD between alleles) at 0.8,
which is sufficient for tag single nucleotide polymorphism mapping to obtain a good coverage of
untyped single nucleotide polymorphisms, allowing
genotyping of a lower number of marked single nucleotide polymorphisms with relatively small losses
in power. They added that if the LD between single
nucleotide polymorphisms is strong, this could result
in the need to carry out up to 7080% less genotyping. On the other hand, if LD in a region is low,
almost every single nucleotide polymorphism might
have to be genotyped to ensure comprehensive coverage of the region.
determinant of the severity and progression of periodontitis. A number of aspects of the inflammatory
and immune response that are suspected to play a
role in the development of periodontitis have a
clearly defined genetic basis. Currently, the presence
of interleukin genetic variations appears to identify
individuals who are at increased risk for more severe
chronic periodontitis and for a less predictable response to therapy. A correlation of genetic polymorphisms with periodontitis, such as that demonstrated
in the Fc receptor gene, appear to provide the
promising use of genetic determinants in periodontitis.
Applying genetic information and technology to
the diagnosis and treatment of periodontitis is conceptually compelling, but it is important that one
maintains a realistic perspective of the clinical utility
of the genetic information (68, 126, 252). Researchers
are also encouraged to further assess the importance
and newsworthiness of association reports in order to
avoid publications of numerous weak associations
that will eventually turn out to be spurious at
repeated testing (37, 109). It is not enough that only
the racial and ethnic backgrounds of the subjects are
taken into account. Studies must have sufficient
numbers of cases and controls, with the controls
carefully chosen to make the association between
polymorphisms and periodontitis much clearer. The
choice of candidate genes must also be well-founded
and the data clearly presented to show the range of
effect and the risk attributable to the gene variation.
Investigators could also make use of the recent progress in the genome-scan or genome-wide technology that shows promise in facilitating new strategies
for mapping disease-causing and disease-susceptibility genes.
It is possible that periodontitis may be explained
by several tens of relatively common high-risk polymorphisms with cumulative high-susceptibility profiles. This genetic information would be valuable in
therapeutic intervention on individualized approaches and preventive strategies of the development of
periodontitis.
Conclusion
References
prepubertal periodontitis was localized by Hart et al.

(90) in chromosome 11q14.
Haplotypes and tag single nucleotide

polymorphisms
With the completion of the human genome project

and the availability of cutting-edge technology,
researchers have turned from studying genetic sequences to analyzing a larger number of proteins
encoded by them. Recent studies from multiple
groups have pointed to genetics as an important
1. Aderem A, Hood L. Immunology in the post-genomic era.

Nat Immunol 2001: 2: 373375.
2. Aderka D. The potential biological and clinical significance
of the soluble tumor necrosis factor receptors. Cytokine
Growth Factor Rev 1996: 7: 231240.
3. Altmuller J, Palmer LJ, Fischer G, Scherb H, Wjst M.
Genomewide scans of complex human diseases: true
123
Yoshie et al.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
linkage is hard to find. Am J Hum Genet 2002: 70: 818

819.
Anusaksathien O, Sukboon A, Sitthiphong P, Teanpaisan R.
Distribution of interleukin-1beta(+3954) and IL-1alpha(889) genetic variations in a Thai population group.
J Periodontol 2003: 74: 17961802.
Aoyagi T, Yamazaki K, Kabasawa-Katoh Y, Nakajima T,
Yamashita N, Yoshie H, Hara K. Elevated CTLA-4 expression on CD4 T cells from periodontitis patients stimulated
with Porphyromonas gingivalis outer membrane antigen.
Clin Exp Immunol 2000: 119: 280286.
Arend WP. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 2002: 13: 323340.
Armitage GC. Classifying periodontal disease a longstanding dilemma. Periodontol 2000 2002: 30: 923.
Armitage GC, Wu Y, Wang HY, Sorrell J, di Giovine FS, Duff
GW. Low prevalence of a periodontitis-associated interleukin-1 composite genotype in individuals of Chinese
heritage. J Periodontol 2000: 71: 164171.
Assuma R, Oates T, Cochran D, Amar S, Graves DT. IL-1
and TNF antagonists inhibit the inflammatory response
and bone loss in experimental periodontitis. J Immunol
1998: 160: 403409.
Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A,
Wolff SM, Dinarello CA. Nucleotide sequence of human
monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci
USA 1984: 81: 79077911.
Avery CL, Freedman BI, Heiss G, Kraja A, Rice T, Arnett D.
Linkage analysis of diabetes status among hypertensive
families: the Hypertension Genetic Epidemiology Network
study. Diabetes 2004: 53: 33073312.
Bach FH, Amos DB. Hu-1: major histocompatibility locus
in man. Science 1967: 156: 15061508.
Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG,
Martinez FD. A polymorphism in the 5 flanking region of
the CD14 gene is associated with circulating soluble CD14
levels and with total serum immunoglobulin E. Am J Respir
Cell Mol Biol 1999: 20: 976983.
Bao L, Gerard NP, Eddy RL Jr, Shows TB, Gerard C. Mapping of genes for the human C5a receptor (C5AR), human
FMLP receptor (FPR), and two FMLP receptor homologue
orphan receptors (FPRH1, FPRH2) to chromosome 19.
Genomics 1992: 13: 437440.
Bayley JP, Ottenhoff TH, Verweij CL. Is there a future for TNF
promoter polymorphisms? Genes Immun 2004: 5: 315329.
Beaty TH, Boughman JA, Yang P, Astemborski JA, Suzuki
JB. Genetic analysis of juvenile periodontitis in families
ascertained through an affected proband. Am J Hum Genet
1987: 40: 443452.
Benjamin SD, Baer PN. Familial patterns of advanced
alveolar bone loss in adolescence (periodontosis). Periodontics 1967: 5: 8288.
Berglundh T, Donati M, Hahn-Zoric M, Hanson LA,
Padyukov L. Association of the -1087 IL 10 gene polymorphism with severe chronic periodontitis in Swedish
Caucasians. J Clin Periodontol 2003: 30: 249254.
Bonfil JJ, Dillier FL, Mercier P, Reviron D, Foti B, Sambuc
R, Brodeur JM, Sedarat C. A case control study on the role
of HLA DR4 in severe periodontitis and rapidly progressive
periodontitis. Identification of types and subtypes using
molecular biology (PCR.SSO). J Clin Periodontol 1999: 26:
7784.
124
20. Border WA, Noble NA. Fibrosis linked to TGF-beta in yet

another disease. J Clin Invest 1995: 96: 655656.
21. Boughman JA, Halloran SL, Roulston D, Schwartz S, Suzuki
JB, Weitkamp LR, Wenk RE, Wooten R, Cohen MM. An
autosomal-dominant form of juvenile periodontitis: its
localization to chromosome 4 and linkage to dentinogenesis imperfecta and Gc. J Craniofac Genet Dev Biol 1986: 6:
341350.
22. Boughman JA, Astemborski JA, Suzuki JB. Phenotypic
assessment of early onset periodontitis in sibships. J Clin
Periodontol 1992: 19: 233239.
23. Bowcock AM, Kidd JR, Lathrop GM, Daneshvar L, May LT,
Ray A, Sehgal PB, Kidd KK, Cavalli-Sforza LL. The human
interferon-beta 2/hepatocyte stimulating factor/interleukin-6 gene: DNA polymorphism studies and localization
to chromosome 7p21. Genomics 1988: 3: 816.
24. Bredius RG, Fijen CA, De Haas M, Kuijper EJ, Weening RS,
Van de Winkel JG, Out TA. Role of neutrophil FC gamma
RIIa (CD32) and Fc gamma RIIIb (CD16) polymorphic
forms in phagocytosis of human IgG1- and IgG3-opsonized
bacteria and erythrocytes. Immunology 1994: 83: 624630.
25. Brinkman BM, Giphart MJ, Verhoef A, Kaijzel EL, Naipal
AM, Daha MR, Breedveld FC, Verweij CL. Tumor necrosis
factor alpha-308 gene variants in relation to major histocompatibility complex alleles and Feltys syndrome. Hum
Immunol 1994: 41: 259266.
26. Brinkman BM, Kaijzel EL, Huizinga TW, Giphart MJ,
Breedveld FC, Verweij CL. Detection of a C-insertion
polymorphism within the human tumor necrosis factor
alpha (TNFA) gene. Hum Genet 1995: 96: 493.
27. de Brito RB Jr, Scarel-Caminaga RM, Trevilatto PC,
de Souza AP, Barros SP. Polymorphisms in the vitamin D
receptor gene are associated with periodontal disease.
J Periodontol 2004: 75: 10901095.
28. Butler JH. A familial pattern of juvenile periodontitis
(periodontosis). J Periodontol 1969: 40: 115118.
29. Cameron P, Limjuco G, Rodkey J, Bennett C, Schmidt JA.
Amino acid sequence analysis of human interleukin 1 (IL1). Evidence for biochemically distinct forms of IL-1. J Exp
Med 1985: 162: 790801.
30. Carlson CS, Eberle MA, Rieder MJ, Smith JD, Kruglyak L,
Nickerson DA. Additional SNPs and linkage-disequilibrium
analyses are necessary for whole-genome association
studies in humans. Nat Genet 2003: 33: 518521.
31. Caton J. International workshop for a classification of
periodontal disease and conditions. Chicago, IL: American
Academy of Periodontology, 1999.
32. Chen G, Adeyemo AA, Johnson T, Zhou J, Amoah A, Owusu
S, Acheampong J, Agyenim-Boateng K, Eghan BA, Oli J,
Okafor G, Abbiyesuku F, Dunston GM, Chen Y, Collins F,
Rotimi C. A genome-wide scan for quantitative trait loci
linked to obesity phenotypes among West Africans. Int J
Obes Relat Metab Disord 2005: 29: 255259.
33. Chiu YF, Chuang LM, Hsiao CF, Hung YJ, Lin MW, Chen YT.
An autosomal genome-wide scan for loci linked to pre-diabetic phenotypes in nondiabetic Chinese subjects from the
Stanford Asia-Pacific Program of Hypertension and Insulin
Resistance Family Study. Diabetes 2005: 54: 12001206.
34. Chung H-Y, Lu H-C, Chen W-L, Lu C-T, Yang Y-H, Tsai
C-C. Gm(23) allotypes and Fcgamma receptor genotypes
as risk factors for various forms of periodontitis. J Clin
Periodontol 2003: 30: 954960.

35. Collins FS, Guyer MS, Charkravarti A. Variations on a
theme: cataloging human DNA sequence variation. Science
1997: 278: 15801581.
36. Colombo AP, Eftimiadi C, Haffajee AD, Cugini MA,
Socransky SS. Serum IgG2 level, Gm(23) allotype and
Fc gamma IIa and Fc gamma IIIb receptors in refractory periodontal disease. J Clin Periodontol 1998: 25:
465474.
37. Cooper DN, Nussbaum RL. Proposed guidelines for papers
describing DNA polymorphism-disease associations. Hum
Genet 2002: 110: 207208.
38. Corey LA, Nance WE, Hofstede P, Schenkein HA. Selfreported periodontal disease in a Virginia twin population.
J Periodontol 1993: 64: 12051208.
39. Craandijk J, van Krugten MV, Verweij CL, van der Velden U,
Loos BG. Tumor necrosis factor-alpha gene polymorphisms in relation to periodontitis. J Clin Periodontol 2002:
29: 2834.
40. Cullinan MP, Westerman B, Hamlet SM, Palmer JE, Faddy
MJ, Lang NP, Seymour GJ. A longitudinal study of interleukin-1 gene polymorphisms and periodontal disease in a
general adult population. J Clin Periodontol 2001: 28: 1137
1144.
41. Cury VF, Costa JE, Gomez RS, Boson WL, Loures CG, Marco
LD. A novel mutation of the cathepsin C gene in PapillonLefe`vre Syndrome. J Periodontol 2002: 73: 307312.
42. Cutler CW, Stanford TW, Abraham C, Cederberg RA,
Boardman TJ, Ross C. Clinical benefits of oral irrigation for
periodontitis are related to reduction of pro-inflammatory
cytokine levels and plaque. J Clin Periodontol 2000: 27:
134143.
43. DAiuto F, Parkar M, Brett PM, Ready D, Tonetti MS. Gene
polymorphisms in pro-inflammatory cytokines are associated with systemic inflammation in patients with severe
periodontal infections. Cytokine 2004: 28: 2934.
44. DAiuto F, Ready D, Parkar M, Tonetti MS. Relative contribution of patient-, tooth-, and site-associated variability
on the clinical outcomes of subgingival debridement. I.
Probing depths. J Periodontol 2005: 76: 398405.
45. DAlfonso S, Richiardi PM. A polymorphic variation in a
putative regulation box of the TNFA promoter region.
Immunogenetics 1994: 39: 150154.
46. Dayer JM. Evidence for the biological modulation of IL-1
activity: the role of IL-1Ra. Clin Exp Rheumatol 2002: 20:
S14S20.
47. Debets JM, Van de Winkel JG, Ceuppens JL, Dieteren IE,
Buurman WA. Cross-linking of both Fc gamma RI and Fc
gamma RII induces secretion of tumor necrosis factor by
human monocytes, requiring high affinity Fc-Fc gamma R
interactions. J Immunol 1990: 144: 13041310.
48. Delima AJ, Oates T, Assuma R, Schwartz Z, Cochran D,
Amar S, Graves DT. Soluble antagonists to interleukin-1
(IL-1) and tumor necrosis factor (TNF) inhibits loss of
tissue attachment in experimental periodontitis. J Clin
Periodontol 2001: 28: 233240.
49. Diehl SR, Wang Y, Brooks CN, Burmeister JA, Califano JV,
Wang S, Schenkein HA. Linkage disequilibrium of interleukin-1 genetic polymorphisms with early-onset periodontitis. J Periodontol 1999: 70: 418430.
50. Dinarello CA. An update on human interleukin-1: from
molecular biology to clinical relevance. J Clin Immunol
1985: 5: 287297.
51. Donati M, Berglundh T, Hytonen A-M, Hahn-Zoric M,

, Padyukov L. Association of the -159 CD14
Hanson L-A
gene polymorphism and lack of association of the )308
TNFA and Q551R IL-4RA polymorphisms with severe
chronic periodontitis in Swedish Caucasians. J Clin Periodontol 2005: 32: 474479.
52. Dorman SE, Picard C, Lammas D, Heyne K, van Dissel JT,
Baretto R, Rosenzweig SD, Newport M, Levin M, Roesler J,
Kumararatne D, Casanove JL, Holland SM. Clinical features
of dominant and recessive interferon gamma receptor 1
deficiencies. Lancet 2004: 364: 21132121.
53. Endo M, Tai H, Tabeta K, Kobayashi T, Yamazaki K, Yoshie
H. Analysis of single nucleotide polymorphisms in the 5flanking region of tumor necrosis factor-alpha gene in
Japanese patients with early-onset periodontitis. J Periodontol 2001: 72: 15541559.
54. Engebretson SP, Lamster IB, Herrera-Abreu M, Celenti RS,
Timms JM, Chaudhary AG, di Giovine FS, Kornman KS.
The influence of interleukin gene polymorphism on
expression of interleukin-1beta and tumor necrosis factoralpha in periodontal tissue and gingival crevicular fluid.
J Periodontol 1999: 70: 567573.
55. Eskdale J, Kube D, Tesch H, Gallagher G. Mapping of the
human IL10 gene and further characterization of the 5
flanking sequence. Immunogenetics 1997: 46: 120128.
56. Essner R, Rhoades K, McBride WH, Morton DL, Economou
JS. IL-4 down-regulates IL-1 and TNF gene expression in
human monocytes. J Immunol 1989: 142: 38573861.
57. Fassmann A, Holla LI, Buckova D, Vasku A, Znojil V, Vanek
J. Polymorphisms in the +252(A/G) lymphotoxin-alpha and
the -308(A/G) tumor necrosis factor-alpha genes and susceptibility to chronic periodontitis in a Czech population.
J Periodontal Res 2003: 38: 394399.
58. Fernandes H, Koneru B, Fernandes N, Hameed M, Cohen
MC, Raveche E, Cohen S. Investigation of promoter
polymorphisms in the tumor necrosis factor-alpha and
interleukin-10 genes in liver transplant patients. Transplantation 2002: 73: 18861891.
59. Folwaczny M, Glas J, Torok HP, Fricke K, Folwaczny C.
Prevalence of the chemokine receptor CCR5-Delta32 gene
mutation in periodontal disease. Clin Immunol 2003: 109:
325329.
60. Folwaczny M, Glas J, Torok HP, Limbersky O, Folwaczny C.
Toll-like receptor (TLR) 2 and 4 mutations in periodontal
disease. Clin Exp Immunol 2004: 135: 330335.
61. Folwaczny M, Glas J, Torok HP, Mende M, Folwaczny C.
Lack of association between the TNF alpha G -308 A promoter polymorphism and periodontal disease. J Clin
Periodontol 2004: 31: 449453.
62. Folwaczny M, Glas J, Torok H-P, Fricke K, Folwaczny C.
The CD14159C-to-T promoter polymorphism in periodontal disease. J Clin Periodontol 2004: 31: 991995.
63. Folwaczny M, Glas J, Torok HP, Mauermann D, Folwaczny
C. The 3020insC mutation of the NOD2/CARD15 gene in
patients with periodontal disease. Eur J Oral Sci 2004: 112:
316319.
64. Folwaczny M, Glas J, Torok HP, Tonenchi L, Paschos E,
Bauer B, Limbersky O, Folwaczny C. Polymorphisms of the
interleukin-18 gene in periodontitis patients. J Clin Periodontol 2005: 32: 530534.
65. Fourel J. Periodontosis: a periodontal syndrome. J Periodontol 1972: 43: 240255.
125
Yoshie et al.
66. Fourel J. Periodontosis, juvenile periodontosis or Gottlieb
syndrome? A report of 4 cases. J Periodontol 1974: 45: 234
237.
67. Fraser DA, Loos BG, Boman U, van Winkelhoff AJ, van der
Velden U, Schenck K, Dembic Z. Polymorphisms in an
interferon-gamma receptor-1 gene marker and susceptibility to periodontitis. Acta Odontol Scand 2003: 61: 297302.
68. Friedrich MJ. Relating genomic research to patient care.
J Am Med Assoc 2000: 284: 25812582.
69. Fu Y, Korostoff JM, Fine DH, Wilson ME. Fc gamma
receptor genes as risk markers for localized aggressive
periodontitis in African-Americans. J Periodontol 2002: 73:
517523.
70. Fujii D, Brissenden JE, Derynck R, Francke U. Transforming growth factor beta gene maps to human chromosome
19 long arm and to mouse chromosome 7. Somat Cell Mol
Genet 1986: 2: 281288.
71. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, LiuCordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R,
Lander ES, Daly MJ, Altshuler D. The structure of haplotype
blocks in the human genome. Science 2002: 21: 22252229.
72. Gaillard JP, Liautard J, Klein B, Brochier J. Major role of the
soluble interleukin-6/interleukin-6 receptor complex for
the proliferation of interleukin-6-dependent human
myeloma cell lines. Eur J Immunol 1997: 27: 33323340.
73. Galbraith GM, Steed RB, Sanders JJ, Pandey JP. Tumor
necrosis factor alpha production by oral leukocytes:
influence of tumor necrosis factor genotype. J Periodontol
1998: 69: 428433.
74. Galbraith GM, Hendley TM, Sanders JJ, Palesch Y, Pandey
JP. Polymorphic cytokine genotypes as markers of disease
severity in adult periodontitis. J Clin Periodontol 1999: 26:
705709.
75. Galicia JC, Tai H, Komatsu Y, Shimada Y, Akazawa K,
Yoshie H. Polymorphisms in the IL-6 receptor (IL-6R)
gene: strong evidence that serum levels of soluble IL-6R are
genetically influenced. Genes Immun 2004: 5: 513516.
76. Goldstein DB, Ahmadi KR, Weale ME, Wood NW. Genome
scans and candidate gene approaches in the study of
common diseases and variable drug responses. Trends
Genet 2003: 19: 615622.
77. Gonzales JR, Michel J, Diete A, Herrmann JM, Bodeker RH,
Meyle J. Analysis of genetic polymorphisms at the interleukin-10 loci in aggressive and chronic periodontitis.
J Clin Periodontol 2002: 29: 816822.
78. Gonzales JR, Michel J, Rodriguez EL, Herrmann JM,
Bodeker RH, Meyle J. Comparison of interleukin-1 genotypes in two populations with aggressive periodontitis. Eur
J Oral Sci 2003: 111: 395399.
79. Gonzales JR, Kobayashi T, Michel J, Mann M, Yoshie H,
Meyle J. Interleukin-4 gene polymorphisms in Japanese
and Caucasian patients with aggressive periodontitis. J Clin
Periodontol 2004: 31: 384389.
80. Gore EA, Sanders JJ, Pandey JP, Palesch Y, Galbraith GM.
Interleukin-1beta+3953 allele 2: association with disease
status in adult periodontitis. J Clin Periodontol 1998: 25:
781785.
81. Goyert SM, Ferrero E, Rettig WJ, Yenamandra AK, Obata F,
Le Beau MM. The CD14 monocyte differentiation antigen
maps to a region encoding growth factors and receptors.
Science 1988: 239: 497500.
126
82. Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR,

Metcalfe JC, Carter ND, Spector TD. Genetic control of the
circulating concentration of transforming growth factor
type beta1. Hum Mol Genet 1999: 8: 9397.
83. Grimes DA. Interpreting study results: a refresher for clinicians. Contracept Rep 2003: 14: 48.
84. Grimes DA, Schulz KF. Compared to what? Finding controls for case-control studies. Lancet 2005: 365: 14291433.
85. Gwinn MR, Sharma A, De Nardin E. Single nucleotide
polymorphisms of the N-formyl peptide receptor in
localized juvenile periodontitis. J Periodontol 1999: 70:
11491201.
86. Hamid YH, Urhammer SA, Jensen DP, Glumer C,
Borch-Johnsen K, Jorgensen T, Hansen T, Pedersen O.
Variation in the interleukin-6 receptor gene associates with
type 2 diabetes in Danish whites. Diabetes 2004: 53: 3342
3345.
87. Hart PH, Vitti GF, Burgess DR, Whitty GA, Piccoli DS,
Hamilton JA. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis
factor alpha, interleukin 1, and prostaglandin E2. Proc Natl
Acad Sci USA 1989: 86: 38033807.
88. Hart TC, Marazita ML, McCanna KM, Schenkein HA, Diehl
SR. Reevaluation of the chromosome 4q candidate region
for early onset periodontitis. Hum Genet 1993: 91: 416422.
89. Hart TC, Hart PS, Bowden DW, Michalec MD, Callison SA,
Walker SJ, Zhang Y, Firatli E. Mutations of the cathepsin C
gene are responsible for Papillon-Lefe`vre Syndrome. J Med
Genet 1999: 36: 881887.
90. Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML,
Cooper M, Yassin OM, Nusier M, Walker S. Localisation of
a gene for prepubertal periodontitis to chromosome 11q14
and identification of a cathepsin C gene mutation. J Med
Genet 2000: 37: 95101.
91. Hennig BJW, Parkhill JM, Chapple ILC, Heasman PA,
Taylor JJ. Association of a vitamin D receptor gene polymorphism with localized early-onset periodontal diseases.
J Periodontol 1999: 70: 10321038.
92. Higuchi T, Seki N, Kamizono S, Yamada A, Kimura A, Kato
H, Itoh K. Polymorphism of the 5-flanking region of the
human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens 1998: 51: 605612.
93. Hill AV. Immunogenetics. Defence by diversity. Nature
1999: 22: 668669.
94. Hodge PJ, Riggio MP, Kinane DF. No association with HLADQB1 in European Caucasians with early-onset periodontitis. Tissue Antigens 1999: 54: 205207.
95. Hodge PJ, Teague PW, Wright AF, Kinane DF. Clinical and
genetic analysis of a large North European Caucasian
family affected by early-onset periodontitis. J Dent Res
2000: 79: 857863.
96. Hodge PJ, Riggio MP, Kinane DF. Failure to detect an
association with IL1 genotypes in European Caucasians
with generalised early onset periodontitis. J Clin Periodontol 2001: 28: 430436.
97. Hoh J, Ott J. Genetic dissection of diseases: design and
methods. Curr Opin Genet Dev 2004: 14: 229232.
98. Holla LI, Fassmann A, Vasku A, Znojil V, Vanek J, Vacha J.
Interactions of lymphotoxin alpha (TNF-beta), angiotensin-converting enzyme (ACE), and endothelin-1 (ET-1)
gene polymorphisms in adult periodontitis. J Periodontol
2001: 72: 8589.

99. Holla LI, Fassmann A, Benes P, Halabala T, Znojil V. 5
polymorphisms in the transforming growth factor-beta 1
gene (TGF-beta 1) in adult periodontitis. J Clin Periodontol
2002: 29: 336341.
100. Holla LI, Buckova D, Fassmann A, Halabala T, Vasku A,
Vacha J. Promoter polymorphisms in the CD14 receptor gene and their potential association with the severity of
chronic periodontitis. J Med Genet 2002: 39: 844848.
101. Holla LI, Jurajda M, Fassmann A, Dvorakova N, Znojil V,
Vacha J. Genetic variations in the matrix metalloproteinase-1 promoter and risk of susceptibility and/or severity of
chronic periodontitis in the Czech population. J Clin
Periodontol 2004: 31: 685690.
102. Holla LI, Fassmann A, Stejskalova A, Znojil V, Vanek J,
Vacha J. Analysis of the interleukin-6 gene promoter
polymorphisms in Czech patients with chronic periodontitis. J Periodontol 2004: 75: 3036.
103. Holla LI, Fassmann A, Vasku A, Goldbergova M, Beranek
M, Znojil V, Vanek J, Vacha J. Genetic variations in the
human gelatinase a (matrix metalloproteinase-2) promoter
are not associated with susceptibility to, and severity of,
chronic periodontitis. J Periodontol 2005: 76: 10561060.
104. Horino K, Yoshie H, Hara K. Correlation between serum
and gingival crevicular fluid antibodies and periodontal
status. J Dent Res 1989: 68: 16881690.
105. Huang QY, Recker RR, Deng HW. Searching for osteoporosis genes in the post-genome era: progress and challenges. Osteoporos Int 2003: 14: 701715.
106. Hubacek JA, Rothe G, Pitha J, Skodova Z, Stanek V, Poledne R. C(-260)?T polymorphism in the promoter of the
CD14 monocyte receptor gene as a risk factor for myocardial infarction. Circulation 1999: 99: 32183220.
107. Illera VA, Perandones CE, Stunz LL, Mower DA Jr, Ashman
RF. Apoptosis in splenic B lymphocytes. Regulation by
protein kinase C and IL-4. J Immunol 1993: 151: 2965
2973.
108. Inagaki K, Krall EA, Fleet JC, Garcia RI. Vitamin D receptor
alleles, periodontal disease progression, and tooth loss in
the VA dental longitudinal study. J Periodontol 2003: 74:
161167.
109. Ioannidis JPA, Nitzani EE, Trikalinos TA, ContopoulosIoannidis DG. Replication validity of genetic association
studies. Nat Genet 2001: 29: 306309.
110. Ioannidis JP, Trikalinos TA, Ntzani EE, ContopoulosIoannidis DG. Genetic associations in large versus small
studies: an empirical assessment. Lancet 2003: 361: 567571.
111. Ioannidis JP, Ntzani EE, Trikalinos TA. Racial differences
in genetic effects for complex diseases. Nat Genet 2004: 36:
13121318.
112. Ioannidis JP, Cappelleri JC, Lau J. Issues in comparisons
between meta-analyses and large trials. JAMA 1998: 279:
10891093.
113. Itagaki M, Kubota K, Tai H, Shimada Y, Morozumi T,
Yamazaki K. Matrix metalloproteinase-1 and -3 gene promoter polymorphisms in Japanese patients with periodontitis. J Clin Periodontol 2004: 31: 764769.
114. Jepsen S, Eberhard J, Fricke D, Hedderich J, Siebert R, Acil
Y. Interleukin-1 gene polymorphisms and experimental
gingivitis. J Clin Periodontol 2003: 30: 102106.
115. Jiang Y, Magli L, Russo M. Bacterium-dependent induction
of cytokines in mononuclear cells and their pathologic
consequences in vivo. Infect Immun 1999: 67: 21252130.
116. John S, Turner D, Donn R, Sinnott P, Worthington J, Ollier

WE, Hutchinson IV, Hajeer AH. Two novel biallelic polymorphisms in the IL-2 gene. Eur J Immunogenet 1998: 25:
419420.
117. Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J,
Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge
F, Twells RC, Payne F, Hughes W, Nutland S, Stevens H,
Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SC,
Clayton DG, Todd JA. Haplotype tagging for the identification of common disease genes. Nat Genet 2001: 29:
233237.
118. Jones BE, Miettinen HM, Jesaitis AJ, Mills JS. Mutations of
F110 and C126 of the formyl peptide receptor interfere
with G-protein coupling and chemotaxis. J Periodontol
2003: 74: 475484.
119. de Jong BA, Westendorp RG, Bakker AM, Huizinga TW.
Polymorphisms in or near tumour necrosis factor (TNF)gene do not determine levels of endotoxin-induced TNF
production. Genes Immun 2002: 3: 2529.
120. Jongeneel CV. Transcriptional regulation of the tumor
necrosis factor alpha gene. Immunobiology 1995: 193: 210
216.
121. Jorgenson RJ, Levin LS, Hutcherson ST, Salinas CE. Periodontitis in sibs. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1975: 39: 396402.
122. Kang BY, Choi YK, Choi WH, Kim KT, Choi SS, Kim K,
Ha NJ. Two polymorphisms of interleukin-4 gene in
Korean adult periodontitis. Arch Pharm Res 2003: 26:
482486.
123. Kim JM, Brannan CI, Copeland NG, Jenkins NA, Khan TA,
Moore KW. Structure of the mouse IL-10 gene and chromosomal localization of the mouse and human genes.
J Immunol 1992: 148: 36183623.
124. Kim JS, Park JY, Chung WY, Choi MA, Cho KS, Park KK.
Polymorphisms in genes coding for enzymes metabolizing
smoking-derived substances and the risk of periodontitis.
125. Kinane DF, Hodge P, Eskdale J, Ellis R, Gallagher G. Analysis of genetic polymorphisms at the interleukin-10 and
tumour necrosis factor loci in early-onset periodontitis.
126. Kinane DF, Shiba H, Hart TC. The genetic basis of periodontitis. Periodontol 2000 2005: 39: 91117.
127. Kobayashi T, Westerdaal NA, Miyazaki A, van der Pol WL,
Suzuki T, Yoshie H, van de Winkel JG, Hara K. Relevance of
immunoglobulin G Fc receptor polymorphism to recurrence of adult periodontitis in Japanese patients. Infect
Immun 1997: 65: 35563560.
128. Kobayashi T, van der Pol WL, van de Winkel JG, Hara K,
Sugita N, Westerdaal NA, Yoshie H, Horigome T. Relevance
of IgG receptor IIIb (CD16) polymorphism to handling of
Porphyromonas gingivalis: implications for the pathogenesis of adult periodontitis. J Periodontal Res 2000: 35:
6573.
129. Kobayashi T, Sugita N, van der Pol WL, Nunokawa Y,
Westerdaal NA, Yamamoto K, van de Winkel JG, Yoshie H.
The Fcgamma receptor genotype as a risk factor for generalized early-onset periodontitis in Japanese patients.
J Periodontol 2000: 71: 14251432.
130. Kobayashi T, Yamamoto K, Sugita N, van der Pol WL, Yasuda K, Kaneko S, van de Winkel JG, Yoshie H. The Fc
gamma receptor genotype as a severity factor for chronic
127
Yoshie et al.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
periodontitis in Japanese patients. J Periodontol 2001: 72:

13241331.
Kocher T, Sawaf H, Fanghanel J, Timm R, Meisel P.
Association between bone loss in periodontal disease and
polymorphism of N-acetyltransferase (NAT2). J Clin Periodontol 2002: 29: 2127.
Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AEGKr, de Haas M. Fc gamma RIIIa-158V/F polymorphism
influences the binding of IgG by NK cell Fc gamma RIIIa,
independently of the Fc gamma RIIIa-48L/R/H phenotype.
Blood 1997: 90: 11091114.
Komatsu Y, Tai H, Galicia JC, Shimada Y, Endo M, Akazawa
K, Yamazaki K, Yoshie H. Interleukin-6 (IL-6)373 A9T11
allele is associated with reduced susceptibility to chronic
periodontitis in Japanese subjects and decreased serum
IL-6 level. Tissue Antigens 2005: 65: 110114.
ber die erbliche Disposition zur paradenKorkhaus G. U
tose. Dtsch Zahnarztl Z 1952: 7: 441448.
Kornman KS, di Giovine FS. Genetic variations in cytokine
expression: a risk factor for severity of adult periodontitis.
Ann Periodontol 1998: 3: 327338.
Kornman KS, Crane A, Wang HY, di Giovine FS, Newman
MG, Pirk FW, Wilson TG Jr, Higginbottom FL, Duff GW.
The interleukin-1 genotype as a severity factor in adult
periodontal disease. J Clin Periodontol 1997: 24: 7277.
Kroger H, Mahonen A, Ryhanen S, Turunen A-M, Alhava E,
Maenpaa P. Vitamin D receptor genotypes and bone
mineral density. Lancet 1995: 345: 1238.
Kruglyak L. The use of a genetic map of biallelic markers in
linkage studies. Nat Genet 1997: 17: 2124.
Kube D, Platzer C, von Knethen A, Straub H, Bohlen H,
Hafner M, Tesch H. Isolation of the human interleukin 10
promoter. characterization of the promoter activity in
Burkitts lymphoma cell lines. Cytokine 1995: 7: 17.
Kwon JM, Goate AM. The candidate gene approach. Alcohol Res Health 2000: 24: 164168.
Laine ML, Farre MA, Gonzalez G, van Dijk LJ, Ham AJ,
Winkel EG, Crusius JB, Vandenbroucke JP, van Winkelhoff
AJ, Pena AS. Polymorphisms of the interleukin-1 gene
family, oral microbial pathogens, and smoking in adult
periodontitis. J Dent Res 2001: 80: 16951699.
Laine ML, Murillo LS, Morre SA, Winkel EG, Pena AS,
van Winkelhoff AJ. CARD15 gene mutations in periodontitis. J Clin Periodontol 2004: 31: 890893.
Lazarus M, Hajeer AH, Turner D, Sinnott P, Worthington J,
Ollier WE, Hutchinson IV. Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol 1997: 24: 23142317.
Le Coniat M, Kinet JP, Berger R. The human genes for the
alpha and gamma subunits of the mast cell receptor for
immunoglobulin E are located on human chromosome
band 1q23. Immunogenetics 1990: 32: 183186.
LeVan TD, Bloom JW, Bailey TJ, Karp CL, Halonen M,
Martinez FD, Vercelli D. A common single nucleotide
polymorphism in the CD14 promoter decreases the affinity
of Sp protein binding and enhances transcriptional activity. J Immunol 2001: 167: 58385844.
Li Y, Xu L, Hasturk H, Kantarci A, DePalma SR, Van Dyke
TE. Localized aggressive periodontitis is linked to human
chromosome 1q25. Hum Genet 2004: 114: 291297.
Li QY, Zhao HS, Meng HX, Zhang L, Xu L, Chen ZB, Shi D,
Feng XH, Zhu XL. Association analysis between interleu-
128
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
kin-1 family polymorphisms and generalized aggressive

periodontitis in a Chinese population. J Periodontol 2004:
75: 16271635.
a M, Gomez-Reino Carnota J. Tumour necrosis
Liz-Gran
factor. Genetics, cell action mechanism and involvement
in inflammation. Allergol Immunol Clin 2001: 16: 140149.
Long JC, Nance WE, Waring P, Burmeister JA, Ranney RR.
Early onset periodontitis: a comparison and evaluation of
two proposed modes of inheritance. Genet Epidemiol 1987:
4: 1324.
Loos BG, Leppers-van den Straat FGJ, van de Winkel JGJ, van
der Velden U. Fc gamma receptor polymorphisms in relation to periodontitis. J Clin Periodontol 2003: 30: 595602.
Lopez NJ, Jara L, Valenzuela CY. Association of interleukin1 polymorphisms with periodontal disease. J Periodontol
2005: 76: 234243.
Louis E, Franchimont D, Piron A, Gevaert Y, SchaafLafontaine N, Roland S, Mahieu P, Malaise M, De Groote
D, Louis R, Belaiche J. Tumour necrosis factor (TNF) gene
polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture
in healthy humans. Clin Exp Immunol 1998: 113: 401406.
Machulla HKG, Stein J, Gautsch A, Langner J, Schaller H-G,
Reichert S. HLA-A, B, Cw, DRB1, DRB3/4/5, DQB1 in
German patients suffering from rapidly progressive periodontitis (RPP) and adult periodontitis (AP). J Clin Periodontol 2002: 29: 573579.
Marazita ML, Burmeister JA, Gunsolley JC, Koertge TE,
Lake K, Schenkein HA. Evidence for autosomal dominant
inheritance and race-specific heterogeneity in early-onset
periodontitis. J Periodontol 1994: 65: 623630.
March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price
V, Gillis S, Henney CS, Kronheim SR, Grabstein K. Cloning,
sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature 1985: 315: 641647.
Marsh CB, Lowe MP, Rovin BH, Parker JM, Liao Z, Knoell
DL, Wewers MD. Lymphocytes produce IL-1 gamma in
response to Fc gamma receptor cross-linking: effects on
parenchymal cell IL-8 release. J Immunol 1998: 160: 3942
3948.
McDevitt MJ, Wang HY, Knobelman C, Newman MG, di
Giovine FS, Timms J, Duff GW, Kornman KS. Interleukin-1
genetic association with periodontitis in clinical practice.
J Periodontol 2000: 71: 156163.
McFarlane CG, Meikle MC. Interleukin-2, interleukin-2
receptor and interleukin-4 levels are elevated in the sera of
patients with periodontal disease. J Periodontal Res 1991:
26: 402408.
McGeer PL, McGeer EG. Polymorphisms in inflammatory
genes and the risk of Alzheimer disease. Arch Neurol 2001:
58: 17901792.
McGhee ML, Ogawa T, Pitts AM, Moldoveanu Z, Mestecky
J, McGhee JR, Kiyono H. Bacteroides-specific IgG and IgA
subclass antibody-secreting cells isolated from chronically
inflamed gingival tissues. Clin Exp Immunol 1989: 76: 103
110.
Meisel P, Timm R, Sawaf H, Fanghanel J, Siegmund W,
Kocher T. Polymorphism of the N-acetyltransferase
(NAT2), smoking and the potential risk of periodontal
disease. Arch Toxicol 2000: 74: 343348.
Meisel P, Carlsson LE, Sawaf H, Fanghaenel J, Greinacher
A, Kocher T. Polymorphisms of Fcgamma-receptors RIIa,
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
RIIIa, and RIIIb in patients with adult periodontal disease.

Genes Immun 2001: 2: 258262.
Meisel P, Krause T, Cascorbi I, Schroeder W, Herrmann F,
John U, Kocher T. Gender and smoking-related risk
reduction of periodontal disease with variant myeloperoxidase alleles. Genes Immun 2002: 3: 102106.
Meisel P, Siegemund A, Grimm R, Herrmann FH, John U,
Schwahn C, Kocher T. The interleukin-1 polymorphism,
smoking, and the risk of periodontal disease in the
population-based SHIP study. J Dent Res 2003: 82: 189
193.
Melnick M, Shields ED, Bixler D. Periodontosis: a phenotypic and genetic analysis. Oral Surg Oral Med Oral Pathol
1976: 42: 3241.
Michalowicz BS, Aeppli D, Virag JG. Periodontal findings in
adult twins. J Periodontol 1991: 62: 293299.
Michalowicz BS, Diehl SR, Gunsolley JC, Sparks BS, Brooks
CN, Koertge TE, Califano JV, Burmeister JA, Schenkein HA.
Evidence of a substantial genetic basis for risk of adult
periodontitis. J Periodontol 2000: 71: 16991707.
Michel J, Gonzales JR, Wunderlich D, Diete A, Herrmann
JM, Meyle J. Interleukin-4 polymorphisms in early onset
periodontitis. J Clin Periodontol 2001: 28: 483488.
Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, Inoue Y, Morita K, Takeda E, Pike JW.
Structural organization of the human vitamin D receptor
chromosomal gene and its promoter. Mol Endocrinol 1997:
11: 11651179.
Mori M, Morris SC, Orekhova T, Marinaro M, Giannini E,
Finkelman FD. IL-4 promotes the migration of circulating
B cells to the spleen and increases splenic B cell survival.
J Immunol 2000: 164: 57045712.
Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution
of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA 1992: 89:
66656669.
Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV,
Sambrook PN, Eisman JA. Prediction of bone density from
vitamin D receptor alleles. Nature 1994: 367: 284287.
Mout R, Willemze R, Landegent JE. Repeat polymorphisms
in the interleukin-4 gene (IL4). Nucleic Acids Res 1991: 19:
3763.
Nawata H, Shirasawa S, Nakashima N, Araki E, Hashiguchi
J, Miyake S, Yamauchi T, Hamaguchi K, Yoshimatsu H,
Takeda H, Fukushima H, Sasahara T, Yamaguchi K, Sonoda
N, Sonoda T, Matsumoto M, Tanaka Y, Sugimoto H, Tsubouchi H, Inoguchi T, Yanase T, Wake N, Narazaki K, Eto T,
Umeda F, Nakazaki M, Ono J, Asano T, Ito Y, Akazawa S,
Hazegawa I, Takasu N, Shinohara M, Nishikawa T, Nagafuchi S, Okeda T, Eguchi K, Iwase M, Ishikawa M, Aoki
M, Keicho N, Kato N, Yasuda K, Yamamoto K, Sasazuki T.
Genome-wide linkage analysis of type 2 diabetes mellitus
reconfirms the susceptibility locus on 11p13-p12 in Japanese. J Hum Genet 2004: 49: 629634.
Nieters A, Linseisen J, Becker N. Association of polymorphisms in Th1, Th2 cytokine genes with hayfever and atopy
in a subsample of EPIC-Heidelberg. Clin Exp Allergy 2004:
34: 346353.
Nishimoto N, Kishimoto T. Inhibition of IL-6 for the
treatment of inflammatory diseases. Curr Opin Pharmacol
2004: 4: 386391.
177. Noack B, Gorgens H, Hoffmann T, Fanghanel J, Kocher T,

Eickholz P, Schackert HK. Nobel mutations in the cathepsin C gene in patients with pre-pubertal aggressive
periodontitis and Papillon-Lefe`vre Syndrome. J Dent Res
2004: 83: 368370.
178. Offenbacher S. Periodontal diseases: pathogenesis. Ann
Periodontol 1996: 21: 206209.
179. Offenbacher S, Odle BM, Braswell LD, Johnson HG, Hall
CM, McClure H, Orkin JL, Strobert EA, Green MD. Changes
in cyclooxygenase metabolites in experimental periodontitis in Macaca mulatta. J Periodontal Res 1989: 24: 63
74.
180. Offenbacher S, Heasman PA, Collins JG. Modulation of
host PGE2 secretion as a determinant of periodontal disease expression. J Periodontol 1993: 64: 432444.
181. Ohtonen S, Kontturri-Narki L, Markkanen H, Synjanen S.
Juvenile periodontitis a clinical and radiological familial
study. J Pedod 1983: 8: 2833.
182. Ohyama H, Takashiba S, Oyaizu K, Nagai A, Naruse T,
Inoko H, Kurihara H, Murayama Y. HLA genotypes associated with early-onset periodontitis: DQB1 molecule primarily confers susceptibility to the disease. J Periodontol
1996: 67: 888894.
183. Ory PA, Clark MR, Kwoh EE, Clarkson SB, Goldstein IM.
Sequences of complementary DNAs that encode the NA1
and NA2 forms of Fc receptor III on human neutrophils.
J Clin Invest 1989: 84: 16881691.
184. Ota N, Nakajima T, Nakazawa I, Suzuki T, Hosoi T, Orimo
H, Inoue S, Shirai Y, Emi M. A nucleotide variant in the
promoter region of the interleukin-6 gene associated with
decreased bone mineral density. J Hum Genet 2001: 46:
267272.
185. Papapanou PN, Neiderud AM, Sandros J, Dahlen G.
Interleukin-1 gene polymorphism and periodontal status.
A case-control study. J Clin Periodontol 2001: 28: 389
396.
186. Parkes M, Satsangi J, Jewell D. Contribution of the IL-2 and
IL-10 genes to inflammatory bowel disease (IBD) susceptibility. Clin Exp Immunol 1998: 113: 2832.
187. Parkhill JM, Hennig BJ, Chapple IL, Heasman PA, Taylor JJ.
Association of interleukin-1 gene polymorphisms with
early-onset periodontitis. J Clin Periodontol 2000: 27: 682
689.
188. Parren PW, Warmerdam PA, Boeije LC, Arts J, Westerdaal
NA, Vlug A, Capel PJ, Aarden LA, van de Winkel JG. On the
interaction of IgG subclasses with the low affinity Fc
gamma RIIa (CD32) on human monocytes, neutrophils,
and platelets. Analysis of a functional polymorphism to
human IgG2. J Clin Invest 1992: 90: 15371546.
189. Pascual M, Nieto A, Mataran L, Balsa A, Pascual-Salcedo D,
Martin J. IL-6 promoter polymorphisms in rheumatoid
arthritis. Genes Immun 2000: 1: 338340.
190. Patil N, Berno AJ, Hinds DA, Barrett WA, Doshi JM,
Hacker CR, Kautzer KM, Lee DH, Marjoribanks C,
McDonough DP, Nguyen BT, Norris MC, Sheehan JB,
Shen N, Stern D, Stokowski RP, Thomas DJ, Trowlson
MO, Vyas KR, Frazer KA, Fawdor SP, Cox DR. Blocks of
limited haplotype diversity revealed by high-resolution
scanning of human chromosome 21 Science 2001: 23:
17191723.
191. Pauli U. Control of tumor necrosis factor gene expression.
Crit Rev Eukaryot Gene Expr 1994: 4: 323344.
129
Yoshie et al.
192. Perez C, Gonzalez FE, Pavez V, Araya AV, Aguirre A,
Cruzat A, Contreras-Levicoy J, Dotte A, Aravena O,
Salazar L, Catalan D, Cuenca J, Ferreira A, Schiattino I,
Aguillon JC. The -308 polymorphism in the promoter
region of the tumor necrosis factor-alpha (TNF-alpha)
gene and ex vivo lipopolysaccharide-induced TNF-alpha
expression in patients with aggressive periodontitis and/
or type 1 diabetes mellitus. Eur Cytokine Netw 2004: 15:
364370.
193. Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A
TaqI polymorphism in the human interleukin-1 beta (IL-1
beta) gene correlates with IL-1 beta secretion in vitro. Eur J
Clin Invest 1992: 22: 396402.
194. van der Pol W-L, van de Winkel JGJ. IgG receptor polymorphisms: risk factors for disease. Immunogenetics 1998:
48: 222232.
195. Pontes CC, Gonzales JR, Novaes AB Jr, Junior MT, Grisi MF,
Michel J, Meyle J, de Souza SL. Interleukin-4 gene polymorphism and its relation to periodontal disease in a
Brazilian population of African heritage. J Dent 2004: 32:
241246.
196. Quappe L, Jara L, Lopez NJ. Association of interleukin-1
polymorphisms with aggressive periodontitis. J Periodontol
2004: 75: 15091515.
197. Ragoussis J, Bloemer K, Weiss EH, Ziegler A. Localization of
the genes for tumor necrosis factor and lymphotoxin between the HLA class I and III regions by field inversion gel
electrophoresis. Immunogenetics 1988: 27: 6669.
198. Rannala B. Finding genes influencing susceptibility to
complex diseases in the post-genome era. Am J Pharmacogenomics 2001: 1: 203221.
199. Rothman KJ. Modern epidemiology. Boston, MA: Little
Brown and Company, 1986.
200. Rousset F, Garcia E, Defrance T, Peronne C, Vezzio N, Hsu
DH, Kastelein R, Moore KW, Banchereau J. Interleukin 10 is
a potent growth and differentiation factor for activated
human B lymphocytes. Proc Natl Acad Sci USA 1992: 89:
18901893.
201. Sachidanandam R, Weissman D, Schmidt SC, Kakol JM,
Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ,
Willey DL, Hunt SE, Cole CG, Coggill PC, Rice CM, Ning Z,
Rogers J, Bentley DR, Kwok PY, Mardis ER, Yeh RT, Schultz
B, Cook L, Davenport R, Dante M, Fulton L, Hillier L,
Waterston RH, McPherson JD, Gilman B, Schaffner S, Van
Etten WJ, Reich D, Higgins J, Daly MJ, Blumenstiel B,
Baldwin J, Stange-Thomann N, Zody MC, Linton L, Lander
ES, Altshuler D; International SNP Map Working Group. A
map of human genome sequence variation containing 1.42
million single nucleotide polymorphisms. Nature 2001:
409: 928933.
202. Sahingur SE, Sharma A, Genco RJ, De Nardin E. Association
of increased levels of fibrinogen and the )455G/A fibrinogen gene polymorphism with chronic periodontitis.
J Periodontol 2003: 74: 329337.
203. Sakellari D, Koukoudetsos S, Arsenakis M, Konstantinidis
A. Prevalence of IL-1A and IL-1B polymorphisms in a
Greek population. J Clin Periodontol 2003: 30: 3541.
204. Salmon JE, Millard S, Schachter LA, Arnett FC, Ginzler EM,
Gourley MF, Ramsey-Goldman R, Peterson MG, Kimberly
RP. Fc gamma RIIA alleles are heritable risk factors for
lupus nephritis in African Americans. J Clin Invest 1996: 97:
13481354.
130
205. Sammartino L, Webber LM, Hogarth PM, McKenzie IF,

Garson OM. Assignment of the gene coding for human
FcRII (CD32) to bands q23q24 on chromosome 1. Immunogenetics 1988: 28: 380381.
206. Saxen L, Nevanlinna HR. Autosomal recessive inheritance
of juvenile periodontitis: test of a hypothesis. Clin Genet
1984: 25: 332335.
207. Scapoli C, Trombelli L, Mamolini E, Collins A. Linkage
disequilibrium analysis of case-control data: an application to generalized aggressive periodontitis. Genes Immun
2005: 6: 4452.
208. Scarel-Caminaga RM, Trevilatto PC, Souza AP, Brito RB,
Line SR. Investigation of an IL-2 polymorphism in patients
with different levels of chronic periodontitis. J Clin Periodontol 2002: 29: 587591.
209. Scarel-Caminaga RM, Trevilatto PC, Souza AP, Brito RB
Jr, Line SR. Investigation of IL4 gene polymorphism in
individuals with different levels of chronic periodontitis
in a Brazilian population. J Clin Periodontol 2003: 30:
341345.
210. Scarel-Caminaga RM, Trevilatto PC, Souza AP, Brito RB,
Camargo LE, Line SR. Interleukin 10 gene promoter polymorphisms are associated with chronic periodontitis.
211. Schroder NW, Meister D, Wolff V, Christan C, Kaner D,
Haban V, Purucker P, Hermann C, Moter A, Gobel UB,
Schumann RR. Chronic periodontal disease is associated
with single-nucleotide polymorphisms of the human TLR4 gene. Genes Immun 2005: 6: 448451.
212. Schultz RM. Interleukin 1 and interferon-gamma: cytokines that provide reciprocal regulation of macrophage and
T cell function. Toxicol Pathol 1987: 15: 333337.
213. Schulz KF, Grimes DA. Case-control studies: research in
reverse. Lancet 2002: 360: 259260.
214. Seigel LJ, Harper ME, Wong-Staal F, Gallo RC, Nash WG,
OBrien SJ. Gene for T-cell growth factor: location on human chromosome 4q and feline chromosome B1. Science
1984: 223: 175178.
215. Seymour GJ, Cole KL, Powell RN, Lewins E, Cripps AW,
Clancy RL. Interleukin-2 production and bone-resorption
activity in vitro by unstimulated lymphocytes extracted
from chronically-inflamed human periodontal tissues.
Arch Oral Biol 1985: 30: 481484.
216. Shapira L, Eizenberg S, Sela MN, Soskolne A, Brautbar H.
HLA A9 and B15 are associated with the generalized form,
but not the localized form, of early-onset periodontal diseases. J Periodontol 1994: 65: 219223.
217. Shapira L, Stabholz A, Rieckmann P, Kruse N. Genetic
polymorphism of the tumor necrosis factor (TNF)-alpha
promoter region in families with localized early-onset
periodontitis. J Periodontal Res 2001: 36: 183186.
218. Shimada Y, Tai H, Endo M, Kobayashi T, Akazawa K,
Yamazaki K. Association of tumor necrosis factor receptor
type 2 +587 gene polymorphism with severe chronic periodontitis. J Clin Periodontol 2004: 31: 463469.
219. Shirodaria S, Smith J, McKay IJ, Kennett CN, Hughes FJ.
Polymorphisms in the IL-1A gene are correlated with levels
of interleukin-1alpha protein in gingival crevicular fluid of
teeth with severe periodontal disease. J Dent Res 2000: 79:
18641869.
220. Singh RR. IL-4 and many roads to lupuslike autoimmunity.
Clin Immunol 2003: 108: 7379.

221. Soga Y, Nishimura F, Ohyama H, Maeda H, Takashiba S,
Murayama Y. Tumor necrosis factor-alpha gene (TNF-alpha) -1031/-863, -857 single-nucleotide polymorphisms
(SNPs) are associated with severe adult periodontitis in
Japanese. J Clin Periodontol 2003: 30: 524531.
222. de Souza AP, Trevilatto PC, Scarel-Caminaga RM, de Brito
RB, Line SR. Analysis of the TGF-beta1 promoter polymorphism (C-509T) in patients with chronic periodontitis.
RB Jr, Line SRP. MMP-1 promoter polymorphism: association with chronic periodontitis severity in a Brazilian
population. J Clin Periodontol 2003: 30: 154158.
RB Jr, Barros SP, Line SRP. Analysis of the MMP-9 (C1562T) and TIMP-2 (G-418C) gene promoter polymorphisms in patients with chronic periodontitis. J Clin Periodontol 2005: 32: 207211.
225. Stabholtz A, Mann J, Agmon S, Soskolne WA. The description of a unique population with a very high prevalence of localized juvenile periodontitis. J Clin Periodontol
1998: 25: 872878.
226. Stein J, Reichert S, Gautsch A, Machulla HKG. Are there
HLA combinations typical supporting for or making
resistant against aggressive and/or chronic periodontitis?
227. Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T,
Stanley SE, Jiang R, Messer CJ, Chew A, Han JH, Duan J,
Carr JL, Lee MS, Koshy B, Kumar AM, Zhang G, Newell WR,
Windemuth A, Xu C, Kalbfleisch TS, Shaner SL, Arnold K,
Schulz V, Drysdale CM, Nandabalan K, Judson RS, Ruano
G, Vovis GF. Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001: 293: 489493.
228. Sterne JA, Davey Smith G. Sifting the evidence-whats
wrong with significance tests? Br Med J 2001: 322: 226231.
229. Sugita N, Yamamoto K, Kobayashi T, Van Der Pol W,
Horigome T, Yoshie H, Van De Winkel JG, Hara K. Relevance of FcgammaRIIIa-158V-F polymorphism to recurrence of adult periodontitis in Japanese patients. Clin Exp
Immunol 1999: 117: 350354.
230. Sugita N, Kobayashi T, Ando Y, Yoshihara A, Yamamoto K,
van de Winkel JG, Miyazaki H, Yoshie H. Increased frequency of FcgRIIIb-NA1 allele in periodontitis-resistant
subjects in an elderly Japanese population. J Dent Res 2001:
80: 914918.
231. Sussman HI, Baer PN. Three generations of periodontosis:
case reports. Ann Dent 1978: 37: 811.
232. Sutherland GR, Baker E, Callen DF, Hyland VJ, Wong G,
Clark S. Interleukin 4 is at 5q31 and interleukin 6 is at 7p15.
Hum Genet 1988: 79: 335337.
233. Suzuki A, Ji G, Numabe Y, Muramatsu M, Gomi K, Kanazashi M, Ogata Y, Shimizu E, Shibukawa Y, Ito A, Ito T,
Sugaya A, Arai T, Yamada S, Deguchi S, Kamoi K. Single
nucleotide polymorphisms associated with aggressive
periodontitis and severe chronic periodontitis in Japanese.
Biochem Biophys Res Commun 2004: 317: 887892.
234. Suzuki A, Ji G, Numabe Y, Ishii K, Muramatsu M, Kamoi K.
Large-scale investigation of genomic markers for severe
periodontitis. Odontology 2004: 92: 4347.
235. Tachi Y, Shimpuku H, Nosaka Y, Kawamura T, Shinohara
M, Ueda M, Imai H, Ohura K, Sun J, Meng H, Cao C.
Association of vitamin D receptor gene polymorphism with
236.
237.
238.
239.
240.
241.
242.
243.
244.
245.
246.
247.
248.
249.
250.
periodontal diseases in Japanese and Chinese. Nucleic

Acids Res Suppl 2001: 1: 111112.
Tachi Y, Shimpuku H, Nosaka Y, Kawamura T, Shinohara
M, Ueda M, Imai H, Ohura K. Vitamin D receptor gene
polymorphism is associated with chronic periodontitis.
Life Sci 2003: 73: 33133321.
Tai H, Endo M, Shimada Y, Gou E, Orima K, Kobayashi T,
Yamazaki K, Yoshie H. Association of interleukin-1 receptor antagonist gene polymorphisms with early onset periodontitis in Japanese. J Clin Periodontol 2002: 29: 882888.
Takai S, Kasama M, Yamada K, Kai N, Hirayama N, Namiki
H, Taniyama T. Human high-affinity Fc gamma RI (CD64)
gene mapped to chromosome 1q21.2-q21.3 by fluorescence in situ hybridization. Hum Genet 1994: 93: 1315.
Takashiba S, Noji S, Nishimura F, Ohyama H, Kurihara H,
Nomura Y, Taniguchi S, Murayama Y. Unique intronic
variations of HLA-DQB gene in early-onset periodontitis.
J Periodontol 1994: 65: 379386.
Tang GJ, Huang SL, Yien HW, Chen WS, Chi CW, Wu CW,
Lui WY, Chiu JH, Lee TY. Tumor necrosis factor gene
polymorphism and septic shock in surgical infection. Crit
Care Med 2000: 28: 27332736.
Tarkowski E, Liljeroth AM, Nilsson A, Ricksten A, Davidsson
P, Minthon L, Blennow K. TNF gene polymorphism and its
relation to intracerebral production of TNFalpha and TNFbeta in AD. Neurology 2000: 54: 20772081.
Taylor JJ, Preshaw PM, Donaldson PT. Cytokine gene
polymorphism and immunoregulation in periodontal disease. Periodontol 2000 2004: 35: 158182.
Tew J, Engel D, Mangan D. Polyclonal B-cell activation in
periodontitis. J Periodontal Res 1989: 24: 225241.
The International HapMap Consortium. The International
HapMap Project. Nature 2003: 18: 789796.
Thomas DC, Witte JS. Point: population stratification: a
problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomarkers Prev 2002: 11: 505
512.
Thomson WM, Edwards SJ, Dobson-Le DP, Tompkins GR,
Poulton R, Knight DA. IL-1 genotype and adult periodontitis among young New Zealanders. J Dent Res 2001: 80:
17001703.
Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench
N, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham
A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein
IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ,
Thakker NS. Loss-of-function mutations in the cathepsin C
gene result in periodontal disease and palmoplantar
keratosis. Nat Genet 1999: 23: 421424.
Trevilatto PC, Scarel-Caminaga RM, de Brito RB Jr, de
Souza AP, Line SR. Polymorphism at position )174 of IL-6
gene is associated with susceptibility to chronic periodontitis in a Caucasian Brazilian population. J Clin Periodontol 2003: 30: 438442.
Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott
PJ, Hutchinson IV. An investigation of polymorphism in
the interleukin-10 gene promoter. Eur J Immunogenet
1997: 24: 18.
Uglialoro AM, Turbay D, Pesavento PA, Delgado JC,
McKenzie FE, Gribben JG, Hartl D, Yunis EJ, Goldfeld AE.
Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene
promoter. Tissue Antigens 1998: 52: 359367.
131
Yoshie et al.
251. Van Dyke TE, Schweinebraten M, Cianciola LJ, Offenbacher S, Genco RJ. Neutrophil chemotaxis in families with
localized juvenile periodontitis. J Periodontal Res 1985: 20:
503514.
252. Varmus H. Getting ready for gene-based medicine. N Engl J
Med 2002: 347: 15261527.
253. Velliyagounder K, Kaplan JB, Furgang D, Legarda D,
Diamond G, Parkin RE, Fine DH. One of two human lactoferrin variants exhibits increased antibacterial and transcriptional activation activities and is associated with
localized juvenile periodontitis. Infect Immun 2003: 71:
61416147.
254. Vercelli D, Baldini M, Martinez FD. The monocyte/IgE
connection: may polymorphisms in the CD14 gene teach
us about IgE regulation? Int Arch Allergy Immunol 2001:
124: 2024.
255. Visintainer PF, Tejani N. Understanding and using confidence intervals in clinical research. J Matern Fetal Med
1998: 7: 201206.
256. de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL10 on subsets of human CD4+ T cell clones and resting T
cells. Specific inhibition of IL-2 production and proliferation. J Immunol 1993: 150: 47544765.
257. Wahl SM, Mergenhagen SE, Skaleric U, Allen JB. TGF-b in
development and inflammation of oral diseases. In: Hamada S, Holt SC, McGhee JR, editors. Periodontal disease:
pathogens and host immune responses. Tokyo: Quintessence Publishing Co., 1991: 321327.
258. Wahl SM, Costa GL, Mizel DE, Allen JB, Skaleric U, Mangan
DF. Role of transforming growth factor beta in the pathophysiology of chronic inflammation. J Periodontol 1993:
64: 450455.
259. Walker SJ, Van Dyke TE, Rich S, Kornman KS, di Giovine
FS, Hart TC. Genetic polymorphisms of the IL-1alpha and
IL-1beta genes in African-American LJP patients and an
African-American control population. J Periodontol 2000:
71: 723728.
260. Wang WY, Barratt BJ, Clayton DG, Todd JA. Genome-wide
association studies: theoretical and practical concerns. Nat
Rev Genet 2005: 6: 109118.
261. Warmerdam PAM, van de Winkel JGJ, Gosselin EJ, Capel
PJA. Molecular basis for a polymorphism of human
Fcgamma receptor II (CD32). J Exp Med 1990: 172: 1925.
262. Warmerdam PAM, van de Winkel JGJ, Vlug A, Westerdaal
NAC, Capel PJA. A single amino acid in the second Ig-like
domain of the human Fcg receptor II is critical for human
IgG2 binding. J Immunol 1991: 147: 13381343.
263. Wild WE, Rioux JD. Genome scan analyses and positional
cloning strategy in IBD: successes and limitations. Best
Pract Res Clin Gastroenterol 2004: 18: 541553.
264. Wilson ME, Kalmar JR. FcgRIIa (CD32): a potential marker
defining susceptibility to localized juvenile periodontitis.
J Periodontol 1996: 67: 323331.
265. Wilson AG, di Giovine FS, Blakemore AI, Duff GW. Single
base polymorphism in the human tumour necrosis factor
alpha (TNF alpha) gene detectable by NcoI restriction of
PCR product. Hum Mol Genet 1992: 1: 353.
266. Wilson M, Reddi K, Henderson B. Cytokine-inducing
components of periodontopathogenic bacteria. J Periodontal Res 1996: 31: 393407.
132
267. van de Winkel JGJ, Capel PJA. Human IgG Fc receptor

heterogeneity: molecular aspects and clinical implications.
Immunol Today 1993: 14: 215221.
268. Wolford JK, Colligan PB, Gruber JD, Bogardus C. Variants
in the interleukin 6 receptor gene are associated with
obesity in Pima Indians. Mol Genet Metab 2003: 80: 338
343.
269. Yamada Y, Miyauchi A, Takagi Y, Tanaka M, Mizuno M,
Harada A. Association of the C-509 T polymorphism,
alone of in combination with the T869 C polymorphism, of the transforming growth factor-beta1 gene with
bone mineral density and genetic susceptibility to osteoporosis in Japanese women. J Mol Med 2001: 79: 149156.
270. Yamamoto K, Kobayashi T, Grossi S, Ho AW, Genco RJ,
Yoshie H, De Nardin E. Association of Fcgamma receptor
IIa genotype with chronic periodontitis in Caucasians.
J Periodontol 2004: 75: 515520.
271. Yamazaki K, Nakajima T, Gemmell E, Polak B, Seymour GJ,
Hara K. IL-4- and IL-6-producing cells in human periodontal disease tissue. J Oral Pathol Med 1994: 23: 347353.
272. Yamazaki K, Nakajima T, Kubota Y, Gemmell E, Seymour
GJ, Hara K. Cytokine messenger RNA expression in chronic
inflammatory periodontal disease. Oral Microbiol Immunol 1997: 12: 281287.
273. Yamazaki K, Tabeta K, Nakajima T, Ohsawa Y, Ueki K, Itoh
H, Yoshie H. Interleukin-10 gene promoter polymorphism
in Japanese patients with adult and early-onset periodontitis. J Clin Periodontol 2001: 28: 828832.
274. Yamazaki K, Ueki-Maruyama K, Oda T, Tabeta K, Shimada
Y, Tai H, Nakajima T, Yoshie H, Herawati D, Seymour GJ.
Single-nucleotide polymorphism in the CD14 promoter
and periodontal disease expression in a Japanese population. J Dent Res 2003: 82: 612616.
275. Yasuda K, Sugita N, Kobayashi T, Yamamoto K, Yoshie H.
FcgammaRIIB gene polymorphisms in Japanese periodontitis patients. Genes Immun 2003: 4: 541546.
276. Yoshihara A, Sugita N, Yamamoto K, Kobayashi T, Miyazaki
H, Yoshie H. Analysis of vitamin D and Fcgamma receptor
polymorphisms in Japanese patients with generalized
early-onset periodontitis. J Dent Res 2001: 80: 20512054.
277. Yoshihara A, Sugita N, Yamamoto K, Kobayashi T, Hirotomi T, Ogawa H, Miyazaki H, Yoshie H. FcgammaRIIIb
genotypes and smoking in periodontal disease progression
among community-dwelling older adults in Japan. J Periodontol 2005: 76: 250255.
278. Zhang Y, Syed R, Uygar C, Pallos D, Gorry MC, Firatli E,
Cortelli JR, Van Dyke TE, Hart PS, Feingold E, Hart TC.
Evaluation of human leukocyte N-formylpeptide receptor
(FPR1) SNPs in aggressive periodontitis. Genes Immun
2003: 4: 2229.
279. Zhang L, Meng H, Zhao H, Li Q, Xu L, Chen Z, Shi D, Feng
X. Estrogen receptor-alpha gene polymorphisms in patients with periodontitis. J Periodontal Res 2004: 39: 362
366.
280. Zhao JY, Xiong MM, Huang W, Wang H, Zuo J, Wu GD. An
autosomal genomic scan for loci linked to type 2 diabetes
in northern Han Chinese. J Mol Med 2005: 83: 209215.

The Role of Genetic Polymorphisms in Periodontitis

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Periodontology 2000, Vol.

43, 2007, 102132

2007 The Authors.

The role of genetic

A detailed knowledge of the dynamic between the

ment, early detection and individualized treatment

Evidence linking genetics and

Role of genetic polymorphisms in periodontitis

Heritability of chronic periodontitis

iances and heritability in chronic periodontitis,

Cytokine gene polymorphisms

0/1, 0/1, 0/1

2/4, 1/3, 2/4

18; )656, )607, )137, +113,

a; )1031, )863, )857, )376,

)988, )800, )509, L10P, R25P

IIA, IIIA, IIIB

2; )1575, )1306, )790, )735

0/1, 1/1, 1/1, 1/1, 1/1

c.301, 306, 329, 348, 378

546, 568, 576

ApaI, BsmI, TaqI

0/1, 4/5, 0/1

10; )1087, )819, )592 , VNTR

6; )597, )572, )373, )190, )174

1/2, 0/1, 0/1

)4/10, 2/4, 0/6

b; )31, +3954 RNPAG

1/1, 1/1, 4/5

1/2, 1/1, 1/1

1/2, 1/2, 1/2

2/7, 3/6, 1/7

)509 1/2, others 0/1

1/1, 1/1, 1/1, 0/1

All loci 0/1

1/3, 1/3, 1/3,

0/2, 1/2, 1/1, 0/1, 1/3

1/1, 5/14, 1/1,5/10

(46, 88, 108, 235, 236, 276)

(12, 19, 96, 182, 226, 233, 239)

(101, 113, 223, 233)

(34, 36, 69, 127, 129, 130,

(39, 51, 53, 57, 61, 73, 98, 125,

(18, 77, 125, 210, 274)

(102, 133, 248)

(51, 79, 122, 168, 195, 209)

(157, 164, 185, 187, 196, 203,

(4, 8, 49, 74, 78, 80, 96,

(142, 224, 233)

(59, 63, 124, 131, 161)

MPO, FGA, LTF

(163, 202, 253)

(51, 100, 218, 279)

0/1 and 1/1, 2/2, 1/1

PvuII and XbaI, )159, +587

R677W and R753G, D299G

ER, CD14, TNFR

IL6ST, IL1RN, ILF

Role of genetic polymorphisms in periodontitis

(137) described a composite genotype formed by the

Carriage rate of IL-1 polymorphic alleles

increased OR of 3.75 of having moderate to severe

controls and was associated with periodontitis