title: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Beverly H
authors.initials: BH
authors.lastname: Brummett
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Babyak
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America ; Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.affiliation: Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America ; Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.affiliation: Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.affiliation: Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Chryst-Ladd
authors.affiliation: Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Damian M
authors.initials: DM
authors.lastname: Craig
authors.affiliation: Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America ; Epidemiological Research and Information Center, Durham VA Medical Center, Durham, North Carolina, United States of America.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Ilene C
authors.initials: IC
authors.lastname: Siegler
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America ; Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Kuhn
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Abanish
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Redford B
authors.initials: RB
authors.lastname: Williams
mesh_terms: D002318:Cardiovascular Diseases / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D012307:Risk Factors
chemical_list: D044405:Receptor, Serotonin, 5-HT2C