BACKGROUND AND PURPOSE The genetic influence on carotid atherosclerotic plaque is mostly unknown. This study examines the association between carotid plaque and single nucleotide polymorphisms (SNPs) in selected genes implicated in inflammation and endothelial function. METHODS A total of 43 genes (197 SNPs) involved in inflammation and endothelial function were interrogated in 287 Dominicans from the Northern Manhattan Study (mean age 64±7 years, 58% women) who had undergone high-resolution B-mode ultrasound for examination of carotid plaque. Using an additive genetic model, multiple logistic regression analyses were conducted, a within gene haplotype analysis was performed and interactions between genes were examined. Results were validated in an independent set of 301 Dominicans. RESULTS Carotid plaque was present in 143(47%) participants. Nine genes had at least one SNP associated (p≤0.01) with carotid plaque phenotypes: TNF, NOS2A, IL6R, TNFSF4, PPARA, IL1A, TLR4, ITGA2, HABP2. SNPs in TNFSF4, PPARA, TLR4, ITGA2, and HABP2 were also implicated with the same carotid phenotype in the validation analysis. Haplotype analysis revealed an additional gene of interest, VCAM1. CONCLUSIONS We report novel associations between variations in ten genes involved in inflammation and endothelial function and carotid plaque phenotypes in a Dominican sample, with replication for five genes in an independent Dominican sample.

Background and Purpose-Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke. Methods-For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study were examined for carotid plaque using high-resolution ultrasound. Sixty-four single nucleotide polymorphisms (SNPs) in 11 lipid-related genes were genotyped. Plaque presence and plaque subphenotypes, including multiple, thick, irregular, and calcified plaque, were analyzed. First, the interaction between each SNP and sex was evaluated for association with each plaque phenotype using multiple logistic regression and controlling for age, smoking, and the main effects of sex and SNP. For SNPs with suggestive evidence for interaction with sex (PϽ0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes. Results-The most compelling finding is with the missense SNP rs11053646 (K167N) in the OLR1 gene, which encodes lectin-like oxidized low-density lipoprotein receptor. Stratification analysis revealed a strong association between rs11053646 and all plaque phenotypes in women (OR, 2.44 to 5.86; Pϭ0.0003 to 0.0081) but not in men (OR, 0.85 to 1.22; Pϭ0.77 to 0.92). Key Words: candidate genes Ⅲ carotid plaque Ⅲ lipids Ⅲ OLR1 Ⅲ sex S ex-dependent differences have been reported in the outcomes and incidence of stroke. [1][2][3][4] The variation in lifestyle factors between the sexes does not fully explain these differences, suggesting sex-dependent genetic risk factors may play a role in stroke burden. 5 A recent meta-analysis showed that women are 50% more likely to have a maternal than a paternal history of stroke, whereas no similar excess exists in men. 4 Given the etiologic heterogeneity of stroke, it may be more advantageous to examine subclinical phenotypes. Carotid atherosclerotic plaque is an important subclinical precursor of stroke and other vascular diseases. 6 Substantial heritability of subclinical carotid atherosclerosis has been reported by us and others. 7,8 A sex difference in carotid plaque area has been reported with women having less plaque area than men at all ages. 9 An important step in the pathogenesis of atherosclerosis involves the uptake of lipoproteins into the arterial wall. 10,11 Therefore, genetic variation in lipid-related genes may influence metabolism of lipoproteins and affect atherogenesis. Numerous studies have examined associations between carotid atherosclerosis and polymorphisms in lipidrelated genes with few exploring the sex-specific genetic effects. [12][13][14] The aim of this study was to examine sex-specific associations between single nucleotide polymorphisms (SNPs) in genes involved in lipid metabolism and carotid plaque phenotypes among...