Genetic polymorphisms at SIRT1 and FOXO1 are associated with carotid atherosclerosis in the SAPHIR cohort

Background: SIRT1 and FOXO1 interact with each other in multiple pathways regulating aging, metabolism and resistance to oxidative stress and control different pathways involved in atherosclerotic process. It is not known, if genetic polymorphisms (SNPs) at the SIRT1 and FOXO1 have an influence on carotid atherosclerosis. Methods: Intima-media thickness (IMT) was measured on the common and internal carotid arteries. Morphological alterations of the carotid arteries and size of these alterations were included in the B-score grading on a five point scale. Eleven SNPs at SIRT1 and FOXO1 gene loci were genotyped in the SAPHIR cohort (n = 1742). The association of each SNP with common carotid IMT, internal carotid IMT and B-score was analyzed using linear regression models. Results: A significant association was found between common carotid IMT and two SNPs at FOXO1 -rs10507486, rs2297627 (beta = -0.00168, p = 0.0007 and beta = -0.00144, p = 0.0008 respectively) and at least a trend for rs12413112 at SIRT1 (beta = 0.00177, p = 0.0157) using an additive model adjusting for age and sex. Additional adjustment for traditional cardiovascular risk factors and markers (BMI, smoking status, hypertension, total cholesterol, HDL-cholesterol, hsCRP) even improved the strength of this association (p = 0.0037 for SIRT1 and p = 0.0002 for both SNPs at FOXO1). Analysis for internal carotis IMT and B-score did not reveal any significant association. One haplotype in FOXO1 showed a moderate effect on common carotid IMT and B-score in comparison to the reference haplotype of this gene. Several SNPs within SIRT1 showed differential effects for men and women with higher effect sizes for women: rs3740051 on all three investigated phenotypes (interaction p-value < 0.0069); rs2236319 on common and internal carotid IMT (interaction p-value < 0.0083), rs10823108, rs2273773 on common carotid IMT and rs1467568 on B-score (interaction p-value = 0.0007). The latter was significant in women only (beta(women) = 0.111, p(women) = 0.00008; beta(men) = -0.009, p(men) = 0.6464). Conclusions: This study demonstrated associations of genetic variations at the SIRT1 and FOXO1 loci with carotid atherosclerosis and highlighted the need for further investigation by functional studies.