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Molecular Medicine Unit, University of Leeds, St. Jamess University Hospital, Leeds, United Kingdom
Yorkshire Centre for Eating Disorders, Seacroft Hospital, York Road, Leeds, United Kingdom
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SmithKline Beecham Pharmaceuticals, Essex, United Kingdom
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INTRODUCTION
Previous studies have demonstrated aberrant expression of serotonin in individuals
with an eating disorder. Given this the serotonin transporter gene (5-HTT) is a strong
candidate to contribute to the genetic component of the aetiology of eating disorders.
To determine the role of this particular gene
in the susceptibility to anorexia nervosa
(AN) we have examined a tandemly repeated sequence close to the promotor region of the 5-HTT gene, which is represented by a long (L) and short (S) variant.
Previous studies have shown that the transcriptional activity of the 5-HTT gene differs
significantly between these two alleles. A
group of 138 Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) criteria AN patients and 90 controls were genotyped at the 5-HTT gene linked polymorphism (5-HTTLPR). Statistical analysis
showed no significant difference in allele or
genotype frequencies between the two
groups. These data suggest that there is no
association between 5-HTTLPR genotype
and susceptibility to AN, in our population.
Am. J. Med. Genet. (Neuropsychiatr. Genet.)
96:5355, 2000. 2000 Wiley-Liss, Inc.
KEY WORDS: anorexia nervosa; serotonin;
serotonin transporter; polymorphism; association
analysis
The human serotonin transporter gene (5-HTT) localises to chromosome 17q11-12 and encodes a transmembrane protein that functions in the reuptake of
serotonin [5-HT; Ramamoorthy et al., 1993]. By facilitating 5-HT reuptake, 5-HTT protein is thought to be
involved in the regulation of some anxiety-related
traits [Risch et al., 1992]. Deregulation of 5-HTT protein function has also been implicated in the pathophysiology of a number of neuropsychiatric disorders
including depression [Owens et al., 1994], schizophrenia [Joyce et al., 1993], neurodegeneration [Meltzer et
al., 1981], and eating disorders [Di Bella et al., 1998].
Recently Heils et al. [1996] reported an allelic variation in the 5-HTT gene in a tandemly repeated sequence 1 kb upstream of the transcription initiation
site. This polymorphism consists of a long variant (L)
composed of 16 repeat elements or a short variant (S)
generated by a deletion of 44 bp. These two alleles are
found to modulate 5-HTT gene expression, with the
S-allele being associated with reduced transcriptional
efficiency of the 5-HTT gene promoter, resulting in decreased protein production and, by inference, decreased 5-HT reuptake [Heils et al., 1995, 1996].
Abnormal levels of serum serotonin have previously
been described in anorexia nervosa (AN) [Kaye et al.,
1991]. A recent study by Hinney et al. [1997] reported
no association between allele or genotype frequencies
at the 5-HTTLPR polymorphism and weight regulation. Further comparisons of allele and genotype frequencies in their AN population failed to demonstrate
an association between this region of the genome and
genetic susceptibility to AN. However, the numbers of
patients in each group were relatively small (n 55 for
AN) and the study by Hinney et al. [1997] lacked a
healthy, normal weight, unrelated control population.
To try and replicate the data of Hinney et al. [1997] and
clarify the relative importance of the serotonin transporter gene polymorphism as a possible etiological factor in AN, we performed a case-control, association
study in a group of 90 controls and 138 anorexics. Ethical approval for this study was obtained from Leeds
(East) Medical Research (Ethics) committee. Written
informed consent was obtained from all individuals.
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Sundaramurthy et al.
TABLE I. 5-HTTLRP Genotype and Combined Genotype Distribution (Frequency) in
Anorexia Nervosa Patients and Controls
Genotype
Group
AN patients
Controls
Combined genotype
Long/Long
Long/Short
Short/Short
Long/Long
-/Short
40 (0.29)
34 (0.38)
63 (0.46)
40 (0.44)
35 (0.25)
16 (0.18)
40 (0.29)
34 (0.38)
98 (0.71)
56 (0.62)
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Meltzer H, Arora R, Baber R, et al. 1981. Serotonin uptake in blood platelets of psychiatric patients. Arch Gen Psych 38:13221329.
Owens MJ, Nemeroff CB. 1994. Role of serotonin in the pathophysiology of
depression: focus on the serotonin transporter. Clin Chem 40:288295.
Ramamoorthy S, Bauman AL, Moore KR, et al. 1993. Antidepressant and
cocaine sensitive human serotonin transporter: molecular cloning, expression and chromosomal localisation. Proc Natl Acad Sci USA 90:
25422546.
Risch SC, Nemeroff CB. 1992. Neurochemical alterations of serotonergic
neuronal systems in depression. J Clin Psych 53(suppl):37.
Sham PC, Curtis D. 1995. Monte Carlo test for association between disease
and alleles at highly polymorphic loci. Ann Hum Genet 59:97105.