CJBAS Vol.

(01) - September - Issue 02 (2013) 68-76

Association of Paraoxonase1 (PON1) Promoter Polymorphism With Blood Pressure

Variation in a North Indian
Gautam K. Kshatriya1, , Siuli Mitra1, Tabitha Panmei1, Jai Bhagwan Gupta2
1

Department of Anthropology, University of Delhi, Delhi-110007, India

J. B. Gupta Hospital, Baba Nagar, Bhiwani-127021

Keywords:

Blood pressure;
PON1 promoter;
Genotype;
North Indian

Abstract
The list of genetic determinants of blood pressure is presently incomplete in spite of
complete genome scans. The PON enzyme has been identified to play a central role in
cardiovascular health. We hypothesized that the promoter polymorphisms of the PON1
gene are associated with variations in blood pressure. Blood pressure was measured in
one hundred forty seven individuals of Jat community of the state of Haryana, Northern
India and they were classified as hypertensive and normotensive. The two groups were
genotyped for PON gene promoter gene polymorphisms, namely -108C/T, -162A/G
and -909G/C. The -909G/C and -108C/T genotypes exhibited significant differences in
allele and genotype frequencies among the normotensive and hypertensive groups. The
T allele of -108C/T polymorphism was found to be a risk marker for hypertension (OR
1.149, 95%CI 0.135-0.627) and also associated with elevation in diastolic blood
pressure (DBP) and mean arterial pressure (MAP).

Abbriviations
Body Mass Index, (BMI); Confidence Interval, (CI); Cardiovascular Disease, (CVD); Cytochrome
P450 family 17 subfamily A polypeptide 1 (CYP17A); Low Density Lipoprotein, (LDL); High
Density Lipoprotein, (HDL); Polymerase Chain Reaction, (PCR); Diastolic Blood Pressure, (DBP);
Deoxyribo Nucleic Acid, (DNA); Hardy Weinberg Equilibrium, (HWE); Methylene
Tetrahydrofolate Reductase, (MTHFR); Paraoxonase, (PON); Odds Ratio, (OR); Systolic Blood
Pressure, (SBP); Single Nucleotide Polymorphism, (SNP); Statistical Package for Social Sciences,
(SPSS); Chi-square, (2)
1. Introduction
The World Health Report 2002 holds cardiovascular disease (CVD) accountable for most of the
cases of death and disability in India by 2020 [1]. The growing burden of CVD in India can be
explained by the prevalence of CVD risk factors, namely elevated Low Density Lipoprotein (LDL),
low High Density Lipoprotein (HDL), hypertension, elevated glucose, obesity, physical inactivity
and tobacco and alcohol consumption [2]. The prevalence of hypertension in India ranges from 10
to 30.9%. The prevalence in urban and rural populations was reported to be 25% and 10%
respectively.

Corresponding author (E-mail: mitra.siuli@gmail.com, Tel: (+91) 9899915374, Fax: (+91) 11-27666614).

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The heritability of blood pressure estimated
through twin or family studies is significant at
30-60% [3] and enunciates the genetics
underneath. Several approaches have been
adopted to unravel the genetic variants
responsible
for
the
inter-population
differences in blood pressure. An aggressive
meta-analyses of Genome Wide Association
Studies (GWAS) from the Global Blood
Pressure Genetics (Global BPgen) and
Cohorts for Heart and Aging Research in
Genetic Epidemiology (CHARGE) consortia
identified 6 loci for Systolic Blood Pressure
(SBP) and 9 for Diastolic Blood Pressure
(DBP), 2 of which overlapped, yielding 13
independent genome-wide significant signals
[3]. However, they explained less than 0.11%
of total blood pressure (BP) variance leaving
scope for more genetic revelations. Also, the
populations included in these two studies
were of European descent and so not
representative of other world populations.
Another meta-analysis of GWAS was
conducted to uncover common variants
associated with blood pressure in populations
having an East Asian ancestry [4]. Significant
association was replicated for 7 of the 13 loci
in the East Asian populations. This showed
that a substantial portion of the pathways
responsible for elevation of blood pressure
varied with ancestry, indicating ethnic
differentials in the genetic underpinnings of
blood pressure. A gene centric array test
revealed that out of a total of 105 widely
studied candidate genes for BP, replicated
association was seen in only 2 (MTHFR and
CYP17A1) of the 13 genetic loci from the
GWAS studies [5] on European populations.
Hitherto, the candidates for genetic
association have been restricted to renninangiotensin-aldosterone system (RAAS)
genes, vascular-related genes, metabolismrelated genes, and adrenergic pathways genes
[6]. Aviram [7] suggested exploring genetics

of regulatory pathways besides the classic

systems of BP regulation.
Human serum paraoxonase 1 [(PON1);
aryldialkylphosphatase (EC 3.1.8.1)] is
associated with high density lipoprotein
(HDL), and is responsible for the ability of
HDL to prevent LDL peroxidation [7]. The
PON gene family comprises PON1, PON2
and PON3 genes. The PON1 gene (7q21-q22)
[8] has nearly 150 SNPs (Single Nucleotide
Polymorphisms) of which five have been
subjected to genetic association studies,
which are -909G/C (rs854572), -162A/G
(rs705381),
-108C/T
(rs705379)
polymorphisms located in the promoter and
Q192R (rs662) and L55M (rs854560) in the
coding region. PON1 and PON3 are both
expressed in the liver, while PON3 mRNA
expression has been reported in kidneys also.
PON2 has a more ubiquitous expression
pattern extending to tissues like kidneys,
liver, lungs, small intestine, placenta, spleen,
stomach and in the cells of the wall of the
arteries. PON1 has anti-atherogenic and antioxidative activities to prevent lipid oxidation
and to destroy biologically active oxidized
lipids on lipoproteins and in arterial cells [9].
In a study by Bhatnagar and colleagues [10],
the PON1 -108C/T polymorphism was
examined for its association with mean
arterial pressure (MAP). The C allele of
PON1-108 was associated with higher blood
pressure among the younger age group,
suggesting its role in early onset
hypertension. Since the PON1 gene has been
implicated in CVD risk factors, we examined
the relationship of PON1 promoter
polymorphism genotypes with blood pressure
traits among the Jat community of Haryana
belonging to Northern India.
2. Materials and methods
2.1. Study sample:
A total of 147 unrelated adult Jat subjects,
comprising 82 males and 65 females, were
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for each of the markers. Pearsons chi squares
test was used for comparison of genotype and
allele frequencies between normotensive and
hypertensive groups. To find out the effect of
genotypes on blood pressure status, the odds
ratio (OR) with 95% confidence interval was
estimated by binary logistic regression. A p
value less than 0.05 (two-tailed) was
considered significant.

sampled for the study from a clinic at

Bhiwani in the state of Haryana. Weight and
height were measured using standard methods
[11]. Body mass index (BMI) was computed
as weight in kilograms divided by the square
of the height in meters (kg/m2). A mercury
sphygmomanometer was used for BP
measurements. Mean Arterial Pressure (MAP)
was calculated as (2DBP+SBP)/3 [12]. The
subjects were classified into groups basing on
JNC7 criteria for blood pressure classification
[13]. Five millilitres of intravenous blood
were collected from the subjects after taking
an informed written consent. The study was
approved by the Ethical Committee of
Department of Anthropology, University of
Delhi.
2.2. Genotyping
The DNA was extracted from the blood cells
by the method described by Miller et al [14]
and was stored at -20C till genotyping. Three
SNPs were chosen for the present study. The
promoter -909G/C (rs854572), -108C/T
(rs705379) and -162A/G (rs705381) SNPs
were genotyped by the method given by
Gupta et al [15]. The PCR products were run
on 2% agarose gel and visualized by ethidium
bromide staining. The PCR reagents were
purchased from GeNei where as primers
were obtained from Integrated DNA
Technologies (IDT), Coralville, Iowa.

3. Results
3.1. Study sample characteristics
One hundred forty seven individuals
participated in this study. 72% were
hypertensive (HTN) (SBP 140mmHg or
DBP 90mmHg), 12 pre-hypertensive
(SBP=120-139mmHg or DBP=80-89mmHg)
and 29 normotensive (NT) (SBP 120mmHg
and DBP 80mmHg). A mean arterial
pressure (MAP) 110mmHg is hypertensive.
58.4% of the individuals were aged more than
60yrs. The HTN group comprises individuals
in both hypertension stage I and stage II. The
clinical characteristics of the participants by
sex are presented in Table 1. No significant
differences were observed for age, BMI, DBP
and MAP. However, SBP showed a
significant difference between the two
genders (p 0.05). Since the pre-hypertensive
individuals were less in number, the category
was amalgamated with the NT group for the
rest of the analysis.

2.3. Statistical analysis

Statistical analysis was carried out by SPSS
(Version 16.0). All the clinical study variables
are shown as mean standard deviation.
Comparison of means between males and
females were carried out using a t-test. The
genotype and allele frequencies for each
polymorphism were stratified for homozygote
wild, heterozygote and homozygote variant
type of the respective allelic variant. HardyWeinberg equilibrium (HWE) was checked

3.2. Genetic analysis

All the subjects were genotyped for the three
promoter
loci.
Out
of
the
three
polymorphisms, -909G/C and -108C/T
showed significant differences for both
genotype and allele frequencies among NT
and HTN individuals (Table 2).

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Table 1.Clinical characteristics of the study population for the two sexes.
Variable
Age (years)

Males (n=82)
Mean
SD
60.77
12.88

Females (n=65)
Mean
SD
59.26
14.62

p value
0.508

BMI (kg/m2)

26.09

4.33

25.44

4.07

0.376

Systolic blood pressure (mmHg)

149.93

24.17

142.10

19.65

0.018*

Diastolic blood pressure (mmHg)

91.90

10.16

88.77

10.35

0.078

Mean arterial pressure (mmHg)

110.03

13.91

105.90

12.57

0.064

Data presented as meanSD. *p value significant at 5% level

The analyses are based on categorization of

an individual on the basis of a critical blood
pressure threshold. In addition, we considered
blood pressure as a continuous variable in
binary logistic regression models (Table 3).

Logistic regression was done to find out if the

derived alleles of the three promoter
polymorphisms posed risk of higher blood
pressure.

Table 2. Genotype and allele frequencies of the PON1 promoter polymorphisms among
normotensive and pre-hypertensive individuals:

SNPs
-909G/C

-108C/T

Allele frequency
Normotensive
Hypertensive
(NT)
(HTN)
G=62.15

G=45.3

C=37.85

C=54.7

C=65.85

C=47.15

T=34.15

T=52.85

A=42.7

A=48.55

G=57.3

G=51.45

Genotype frequency
Normotensive
Hypertensive
(NT)
(HTN)
GG=46.3
GG=20.8

-162A/G

GC=31.7

GC=49.0

CC=22.0

CC=30.2

CC=48.8

CC=21.7

CT=34.1

CT=50.9

TT=17.1

TT=27.4

AA=24.4

AA=22.6

AG=36.6

AG=51.9

GG=39.0

GG=25.5

Association
Allele
Genotype
(df=1)
(df=2)
2 =5.71*

2 =9.671*

2 =7.11*

2 =10.493*

2 =0.69

2 =3.349

*p<0.05, statistically significant difference between NT and HTN.

-909G/C: The three genotypes showed

significant change in frequencies among the
NT and HTN, with only the wild GG
exhibiting a decreased frequency (20.8%) in
HTN. The derived allele C was present in a
higher frequency among HTN (54.7%)
individuals while NT had a lower frequency
(37.85%). On applying binary logistic
regression, the odds for C allele carriers
(GC+CC) to cause HTN were 0.943 (95% CI,
0.140-0.657). The GC carriers were more

likely to have higher DBP (OR=2.848, 95%

CI 1.154-7.032) and MAP (OR=2.362, 95%
CI 1.042-5.354).
-108C/T: The wild CC genotype had a
decreased frequency (21.7%) in HTN cases.
The CT and TT genotypes had increased
frequencies of 50.9% and 27.4% in the HTN
group. An increase in T allele frequency was
observed in HTN group. The odds for the T
allele carriers to cause hypertension were
1.149 (95%CI, 0.135-0.627). An increase in T
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alleles increased diastolic blood pressure
levels significantly. The T allele carriers
(CT+TT) had an odds ratio of 4.314 while CT
individuals were 3.889 times more likely to

cause an elevation in DBP than a CC

individual. The data showed almost two fold
increase each in SBP and MAP, with a
borderline significance for MAP only.

Table 3. Regression of PON1 promoter polymorphisms on SBP, DBP and MAP.

Genotypes
-108CT vs. CC

SBP
Exp(B)
p
1.909
0.122

DBP
Exp(B)
p
3.889
0.002*

MAP
Exp(B)
p
2.197
0.053

-108TT vs. CC

2.699

0.053

5.333

0.004*

1.853

0.186

-162AG vs. AA

1.290

0.548

1.885

0.158

2.323

0.037*

-162GG vs. AA

1.145

0.784

1.376

0.535

1.635

0.3

-909GC vs. GG

1.844

0.156

2.848

0.023*

2.362

0.039*

-909CC vs. GG

1.987

0.156

2.343

0.091

1.860

0.176

* p value significant at 5% level

-162A/G: No allelic or genotypic association

was seen with HTN in our sample set.
However, AG individuals showed an odds
ratio of 2.323 (95% CI, 1.052-5.127) against
the AA genotype for elevated MAP.
The heterozygotes (-108CT, -162AG, 909GC) were associated with higher level of
MAP in comparison to homozygotes.

Polymorphisms in the PON1 activity was

demonstrated in two ethnic groups [20] and
subsequently found in other world
populations. Humbert and colleagues [8]
found that gln191arg (Q192R) determined
low and high level PON1 activity. Brophy
and colleagues [21] ascertained that the three
regulatory region genotypes (-108C/T, 162A/G, -909A/G) affect plasma PON1
levels. Among the PON1 regulatory region
polymorphisms, -108C/T accounts for 22.8%
of the observed variability in PON1
expression levels which is higher than that
contributed by any of the polymorphisms
independently. PON1 due to its cardioprotective nature has been subject to the
studies of genetic association of coronary
artery disease. The relationship of PON1
activity and PON genotypes in cardiovascular
development has been established by genetic
association studies based on the coding region
polymorphisms and promoter polymorphisms
of PON1. Among the fewer studies conducted
in India to find out the genetic underpinnings
of cardiovascular risk, some examined both
the regions [15, 22] while others limited to
the coding region of PON1 gene [23, 24, 25].

4. Discussion
Hypertension is a complex disorder and hence
subject to be influenced by several genes,
gene-gene and gene-environment interactions.
The genes responsible for blood pressure
regulation have been addressed both in single
gene association studies [10, 16] and genomewide scanning [17, 18]. But the dearth of
genetic determinants of blood pressure lead to
meta-analyses of GWA studies [19] on
hypertension that helped obtain robust and
replicable results. Thirteen independent loci
associated with blood pressure variation were
identified [3]. But all these studies, could
explain a small amount of variance in blood
pressure. This opens avenue for exploring
genes not directly a part of blood pressure
regulation, but significantly affecting it.
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The studies, however, showed variable
findings with respect to PON1 activity and
coding region and promoter region
polymorphisms. This signifies the importance
of examining different population groups for
PON1 activity and gene polymorphisms.
The present study was undertaken to examine
the relationship between three PON1
promoter gene polymorphisms and blood
pressure variation. The allele and genotype
associations were significant for -108C/T and
-909G/C polymorphisms when comparing
HTN and NT individuals. The odds ratio
calculation identified T allele responsible for
predisposition to hypertension, odds of a T
allele carrier (CT+TT) to cause hypertension
being 1.149 (95%CI, 0.135-0.627). The T
allele was also observed to be associated with
increased DBP and MAP (Table 3). The 108C/T polymorphism has a significant effect
on serum paraoxonase levels [21] and the T
allele has been found to be associated with
lower levels [26]. Lower PON levels are due
to lower HDL which is observed in
hypertension. The T allele has also been
shown to pose risk towards coronary artery
disease (CAD) [27]. The result on the C allele
of -108C/T is, however, at variance with the
findings of Bhatnagar and colleagues [10] on
multi-ethnic groups where they found a
significant association of -108C/T with MAP.
Literature is almost silent on association of
promoter
-162A/G
and
-909G/C
polymorphisms with hypertension and CAD.
But we did find an association with elevated
MAP in our study.
The -108C/T PON1 polymorphisms might be
involved in the regulation of blood pressure in
this population. Since there are only few
studies on PON1 in India, it is therefore
essential to undertake further studies on
Indian populations to strengthen the
understanding of genetics of hypertension.
Moreover, resequencing of PON gene, dense
genotyping of all the available SNPs or

expression studies may provide convincing

evidence regarding its role in blood pressure
variation.
Acknowledgement
The authors would like to thank the ViceChancellor, University of Delhi for
sanctioning research grant for this study under
R&D Doctoral Research Program vide letter
no. Dean (R)/R&D/2011/423. S.M was
supported by the Council of Scientific and
Industrial Research (CSIR), Government of
India
with
scholarship
number
JRF/AA/139/F-137/2012-13. We would also
like to convey our gratitude to all the people
who volunteered to donate their blood
samples for the purpose of our study.
Conflict of interest
The authors declare that they have no conflict
of interest.
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