5-hydroxytryptamine-2A receptor gene (HTR2A) candidate polymorphism (T102C) : Role for human platelet function under pharmacological challenge ex vivo

Although the environmental and life-style factors influencing individual predisposition to acute myocardial infurction (AMI) have been well documented, little is known on the identity of genetic loci that may contribute to risk for AMI. Recently, genetic studies in patients with nonfatal AMI have suggested an association with the T102C polymorphism in the serotonin 5-HT 2A receptor gene (HTR2A). Considering the significant role of the 5-HT 2A receptor in serotonin-induced platelet responses and the contribution of platelet (patho)physiology to thromboembolic events, we postulated that the increased susceptibility to AMI in patients with the T102 homozygosity may he attributable, in part, to altered serotonin-mediated platelet function. In a group of healthy volunteers recruited from the Eskisehir region in central Turkey (N = 37), we investigated the functional consequences of HTR2A T102C polymorphism in relation to platelet pharmacodynamics ex vivo. The platelet shape change and aggregation response to serotonin were measured with use of the platelet aggregometry and expressed as aggregometer output (mm). Because the circulating catecholamine hormone epinephrine can augment platelet aggregation, pharmacodynamic response (aggregation and its inhibition hy 5-HT 2A receptor antagonist cyproheptadine) was measured in the presence of both serotonin and epinephrine, to mimic the clinical situation in patients. The mean platelet aggregation was higher hy 38% in subjects with T102 homozygosity (T/T genotype, N = 13) when compared with the carriers of the 102C-allele (TIC and the C/C genotypic groups. N = 24) (39.5 mm ± 12.3 vs. 28.7 mm ± 16.8, respectively) (mean ± SD) (p 0.05). These findings in healthy subjects may provide a mechanistic explanation for the previously reported genetic association between HTR2A and AMI. Further genetic association studies of the 5-HT 2A receptor in patients with AMI in different populations are warranted.