A Functional Polymorphism in the 5HTR2C Gene Associated with Stress Responses Also Predicts Incident Cardiovascular Events

Abstract

Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (rs6318) of the 5HTR2C gene located on the X-chromosome is associated with hypothalamic-pituitary-adrenal axis response to a stress recall task, and with endophenotypes associated with cardiovascular disease (CVD). These findings suggest that individuals carrying the rs6318 Ser23 C allele will be at higher risk for CVD compared to Cys23 G allele carriers. The present study examined allelic variation in rs6318 as a predictor of coronary artery disease (CAD) severity and a composite endpoint of all-cause mortality or myocardial infarction (MI) among Caucasian participants consecutively recruited through the cardiac catheterization laboratory at Duke University Hospital (Durham, NC) as part of the CATHGEN biorepository. Study population consisted of 6,126 Caucasian participants (4,036 [65.9%] males and 2,090 [34.1%] females). A total of 1,769 events occurred (1,544 deaths and 225 MIs; median follow-up time = 5.3 years, interquartile range = 3.3–8.2). Unadjusted Cox time-to-event regression models showed, compared to Cys23 G carriers, males hemizygous for Ser23 C and females homozygous for Ser23C were at increased risk for the composite endpoint of all-cause death or MI: Hazard Ratio (HR) = 1.47, 95% confidence interval (CI) = 1.17, 1.84, p = .0008. Adjusting for age, rs6318 genotype was not related to body mass index, diabetes, hypertension, dyslipidemia, smoking history, number of diseased coronary arteries, or left ventricular ejection fraction in either males or females. After adjustment for these covariates the estimate for the two Ser23 C groups was modestly attenuated, but remained statistically significant: HR = 1.38, 95% CI = 1.10, 1.73, p = .005. These findings suggest that this functional polymorphism of the 5HTR2C gene is associated with increased risk for CVD mortality and morbidity, but this association is apparently not explained by the association of rs6318 with traditional risk factors or conventional markers of atherosclerotic disease.

A functional polymorphism in the HTR2C gene associated with stress responses: A validation study

“…The present findings, along with studies linking the Ser23 C allele with affective disorders, also suggest that the rs6318 effects on HT2C receptor-mediated effects on emotion and the HPA axis may moderate, at least in part, the linkages between depression and dysregulated HPA axis function. In addition, the present findings also may point to a mechanism underlying the association we previously reported between Ser23 C and incidence of death or MI in a large CHD patient sample(Brummett, et al, 2013). …”

“…This prior study, however, consisted of males only. In related recent study of 6,126 men and women referred for diagnostic cardiac catheterization, we also showed that over a 7-year follow-up period, males hemizygous for Ser23 C and females homozygous for Ser23 C allele had an increase in cardiovascular disease event (death and/or MI) risk (hazard ratio = 1.38) compared to those with other rs6318 genotypes (Brummett et al, 2013). One possible mechanism that might explain the increased prognostic risk associated with Ser23C might be the tendency to respond to psychological stress during daily life with heightened HPA-axis activity, which, over time is thought to promote atherogenesis (Rozanski, Blumenthal, Davidson, Saab, & Kubzansky, 2005).…”

Pharmacogenetics of citalopram-related side effects in children with depression and/or anxiety disorders

“…Genotyping of the 5-HTR2C G68C nonsynonymous (Ser23Cys) polymorphism (rs6318) was carried out using a modified version of a method described by Lappalainen et al (1995b). Research indicates that the Ser 23 allele is constitutively more active than the Cys 23 allele, with allele-specific analysis of receptor function showing functional differences in the activity of the Ser 23 minor allele relative to the Cys 23 allele (Brummett et al 2013). …”

Association of 5-HT2A (A-1438G) receptor genotypes with the debut of coronary artery disease and personal anxiety

“…Од-нако у психологически здоровых людей с генотипом ТТ гена 5-HT2A (T102C) выявлена повышенная скорость свя-зывания тромбоцитов [30], которая зарегистрирована и у лиц с депрессивными расстройствами [63]. Кроме этого, в недавно выполненном крупном исследовании обнаруже-но, что аллель Ser23C гена 5HT2C (полиморфизм rs6318) связан с тяжестью ИБС, а также с повышенным риском смерти от всех причин, в том числе ИМ [11].…”

“…Также на уровне тенденции определяются раз-личия по уровню личностной тревоги между генотипами AG (47,11) и АА (44,1) (p=0,078), а также между генотипа-ми AG (47,11) и GG (44,67) (p=0,072).…”