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

ABSTRACT: Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (SNP), rs6318 on the HTR2C gene located on the X-chromosome, is associated with hypothalamic-pituitary-adrenal axis response to a laboratory stress recall task. The present paper reports a validation of the cortisol response to stress in a second, independent sample. The study population consisted of 60 adult participants (73.3% males). Consistent with our prior findings, compared to Cys23 G allele carriers, persons homozygous for the Ser23C allele had a significantly greater average cortisol response (p=0.007) and area under the curve (p=0.021) over the course of an emotional stress recall protocol. Also parallel to our prior report, the change in cortisol from baseline to the average during the stress protocol was roughly twice as large among Ser23C homozygotes than among persons with Cys23 G. These findings validate our initial observation of association between rs6318 and cortisol response to an acute stressor, and extend the results to include females.

SUBMITTER: Brummett BH

PROVIDER: S-EPMC4258145 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Brummett Beverly H BH Babyak Michael A MA Kuhn Cynthia M CM Siegler Ilene C IC Williams Redford B RB

Biological psychology 20141020

Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (SNP), rs6318 on the HTR2C gene located on the X-chromosome, is associated with hypothalamic-pituitary-adrenal axis response to a laboratory stress recall task. The present paper reports a validation of the cortisol response to stress in a second, independent sample. The study population consisted of 60 adult participants (73.3% males). Consistent with our prior findings, compared to Cys23 G allele carriers, ...[more]

PMID: 25457638

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Project description: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.

Project description:BackgroundAntipsychotic-induced weight gain (AIWG) is a crucial factor for the medication cessation of patients with schizophrenia. Multiple studies have shown that the functional polymorphism -759 C/T (rs3813929) in the HTR2C promoter region could possibly be correlated with AIWG.AimTo evaluate the genetic association of the HTR2C-759C/T polymorphism and AIWG in patients with schizophrenia with antipsychotic drugs (APDs) administration.MethodsEligible studies were identified by searching the following databases: PubMed, Embase, Web of Science, China Nation Knowledge Infrastructure (CNKI), VIP, Wanfang Data, Chinese Biomedical Literature Database (CBM) and the Airiti Library. The quality of studies was evaluated based on the Newcastle-Ottawa Scale. The pooled OR and 95% CI were calculated for the dominant (CT/TT/T vs CC/C) mode, and subgroup analyses were performed based on ethnicity, antipsychotic medication and gender; all statistical analyses were performed using the statistical software STATA V.12.0.ResultA total of 17 studies with 3170 patients with schizophrenia were included in our meta-analysis. The result of the meta-analysis has shown that the association between the -759 C/T polymorphism and AIWG is statistically significant (OR 0.34, 95% CI: 0.20 to 0.57, z=4.11, p<0.001). The subgroup analyses revealed significant correlations between the -759 C/T polymorphism and AIWG in the Caucasian population (OR 0.33, 95% CI: 0.14 to 0.77, z=2.55, p=0.011), the Asian population (OR 0.31, 95% CI: 0.18 to 0.52, z=4.46, p<0.001), the patients with APDs administration (CT/TT/T vs CC/C: OR 0.63, 95% CI: 0.40 to 1.00, z=1.97, p=0.049) and the patients with atypical antipsychotic drug administration (CT/TT/T vs CC/C: OR 0.21, 95% CI: 0.09 to 0.47, z=3.83, p<0.001). The sensitivity analysis showed that the results were stable. Begg's test (after correction z=1.07, p=0.287) and Egger's test (t=-2.41, p=0.029) show that the included articles have no significant publication bias.ConclusionThere is a significant genetic association between HTR2C-759C/T and AIWG, and patients with T allele are less likely to have AIWG.

Project description:BACKGROUND:Lipoxygenases (LOXs) play significant roles in abiotic stress responses, and identification of LOX gene promoter function can make an important contribution to elucidating resistance mechanisms. Here, we cloned the CmLOX08 promoter of melon (Cucumis melo) and identified the main promoter regions regulating transcription in response to signalling molecules and abiotic stresses. RESULTS:The 2054-bp promoter region of CmLOX08 from melon leaves was cloned, and bioinformatic analysis revealed that it harbours numerous cis-regulatory elements associated with signalling molecules and abiotic stress. Five 5'-deletion fragments obtained from the CmLOX08 promoter-2054 (LP1), 1639 (LP2), 1284 (LP3), 1047 (LP4), and 418?bp (LP5)-were fused with a GUS reporter gene and used for tobacco transient assays. Deletion analysis revealed that in response to abscisic acid, salicylic acid, and hydrogen peroxide, the GUS activity of LP1 was significantly higher than that of the mock-treated control and LP2, indicating that the -?2054- to -?1639-bp region positively regulates expression induced by these signalling molecules. However, no deletion fragment GUS activity was induced by methyl jasmonate. In response to salt, drought, and wounding treatments, LP1, LP2, and LP4 promoted significantly higher GUS expression compared with the control. Among all deletion fragments, LP4 showed the highest GUS expression, indicating that -?1047 to -?1?bp is the major region regulating promoter activity and that the -?1047 to -?418-bp region positively regulates expression induced by salt, drought, and wounding, whereas the -?1284 to -?1047-bp region is a negative regulatory segment. Interestingly, although the GUS activity of LP1 and LP2 was not affected by temperature changes, that of LP3 was significantly induced by heat, indicating that the -?1284- to -?1-bp region is a core sequence responding to heat and the -?2054- to -?1284-bp region negatively regulates expression induced by heat. Similarly, the -?1047- to -?1-bp region is the main sequence responding to cold, whereas the -?2054- to -?1047-bp region negatively regulates expression induced by cold. CONCLUSIONS:We cloned the CmLOX08 promoter and demonstrated that it is a signalling molecule/stress-inducible promoter. Furthermore, we identified core and positive/negative regulatory regions responding to three signalling molecules and five abiotic stresses.

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

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

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