Gender moderation in the association between mitochondrial uncoupling protein genetic variants and carotid plaque

Abstract

Background and Objective: Sirtuins (SIRTs) and mitochondrial uncoupling proteins (UCPs) have been implicated in cardiovascular diseases through controlling the production of reactive oxygen species. This study sought to investigate the association of SIRT and UCP genetic variants with the presence of carotid plaque and the potential gender moderation in their association. Methods: A total of 1,018 stroke-free subjects (61% female, mean age=70±9 yrs) who underwent ultrasound measurement and genotyping were sampled from a multiethnic cohort of northern Manhattan. Multiple logistic regression were performed to investigate the association of genetic variants (SNPs and haplotypes) in SIRT and UCP genes (SIRT1-7, UCP1-5) with the presence of carotid plaque, after controlling for the significant sociodemographic and vascular covariates (age, gender, smoking, waist-hip ratio, diabetes and hypertension) as well as population stratification identified via principal component approach. SNP-by-sex interaction was examined and stratified analysis was followed if the interaction term in the model yielded an effect of p < 0.1. Multiple testing was adjusted with permutation. Results: After adjustment for covariates, UCP5 SNP rs5977238 showed the strongest association with carotid plaque with an additive effect of OR=0.5 (95%CI=0.3-0.7, p=0.0008, permutation adjusted p=0.03) and 4 other UCP5 SNPs were associated with plaque presence with a nominal P<0.05. A UCP5 haplotype (TTTCACATT) of 9 SNPs were also significantly associated with decreased risk for plaque (OR=0.5, p=0.0002, permutation adjusted p=0.01). Another significant association was found for SIRT6 SNP rs107251 (OR=1.7, 95%CI=1.2-2.4, p=0.001). Interaction analyses revealed a gender-specific effect for UCP3 SNPs (rs1685356, p=0.007; rs1726745, p=0.01) and UCP1 SNPs (rs7693034, p=0.06; rs6818140, p=0.06). Specifically, a significant increased risk was found for A-carrier women at rs1685356 or rs1726745 (OR=1.4, 95%CI=1.1-1.8, p<0.01) but not for men (p ≥ 0.13). In contrast, a significant decreased risk was detected for C-carrier women at rs7693034 or rs6818140 (OR=0.7, 95%CI=0.5-0.9, p = 0.01) but not for men (p≥ 0.61). Conclusion: Our findings suggest that genetic variations in UCP1,3,5 and SIRT6 may be associated with subclinical atherosclerosis. Gender difference in the effect of UCP1,3 variants may indicate a gene-environmental interaction. Further fine mapping studies in larger populations are needed to validate the observed association and evaluate the gene-environmental interaction.