Serotonin receptor 3A polymorphism c.-42C > T is associated with severe dyspepsia.
BACKGROUND
The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity.


METHODS
Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia.


RESULTS
HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90).


CONCLUSIONS
The HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT3 mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.
University Medical Centre Utrecht, Department of Gastroenterology & Hepatology, the Netherlands.
Suhreta
S
Mujakovic
José Jm
JJ
ter Linde
Niek J
NJ
de Wit
Corine J
CJ
van Marrewijk
Gerdine Aj
GA
Fransen
N Charlotte
NC
Onland-Moret
Robert Jf
RJ
Laheij
Jean Wm
JW
Muris
Diederick E
DE
Grobbee
Melvin
M
Samsom
Jan Bmj
JB
Jansen
André
A
Knottnerus
Mattijs E
ME
Numans
D000328:Adult; D003430:Cross-Sectional Studies; D004415:Dyspepsia / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011110:Polymorphism, Genetic; D015995:Prevalence; D016032:Randomized Controlled Trials as Topic; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D012720:Severity of Illness Index; D012737:Sex Factors; D011795:Surveys and Questionnaires
C509409:HTR3A protein, human; D044406:Receptors, Serotonin, 5-HT3; D050486:Serotonin Plasma Membrane Transport Proteins