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A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque.

ABSTRACT: 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.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 (P<0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes.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; P=0.0003 to 0.0081) but not in men (OR, 0.85 to 1.22; P=0.77 to 0.92).Genetic variation in genes involved in lipid metabolism may have sex-dependent effects on carotid plaque burden. Our findings provide a plausible biological basis underlying the sex difference in cardiovascular risk.

SUBMITTER: Wang L

PROVIDER: S-EPMC3042493 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque.

Wang Liyong L Yanuck Danielle D Beecham Ashley A Gardener Hannah H Slifer Susan S Blanton Susan H SH Sacco Ralph L RL Rundek Tatjana T

Stroke 20110121 3

<h4>Background and purpose</h4>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.<h4>Methods</h4>For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study were examined for carotid plaque us ...[more]

PMID: 21257822

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Project description:Objectives: We aimed to explore sex-specific association between genes involved in inflammation and endothelial function and vulnerable carotid plaque, a subclinical precursor of ischemic stroke. Methods: Carotid plaque and plaque phenotype were assessed by carotid ultrasound in high-risk participants for stroke drawn from a multicenter, cross-sectional survey in southwestern China. We examined 18 single nucleotide polymorphisms (SNPs) in 10 genes related to inflammation and endothelial function. Sex differences in the genotype of the candidate SNPs and risk of vulnerable carotid plaques were assessed. Interaction tests were performed to identify the SNPs that might modify the association between the sex and vulnerable plaques. For SNPs with suggestive evidence for interaction with sex (p for interaction<0.05), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and vulnerable plaques. Results: 2,644 high-risk individuals were enrolled, comprising 1,202 (45.5%) men and 1,442 (54.5%) women. Vulnerable carotid plaques were detected in 425 (16.1%) participants. Among candidate SNPs, the genotype frequencies of 5 SNPs (TNFSF4 rs11811788, TNFSF4 rs1234313, IL6R rs4845625, VCAM1 rs2392221, and ITGA2 rs1991013) were significantly different between sex (all p < 0.05). Univariable and multivariable analyses suggested that male individuals had a significantly higher prevalence of vulnerable carotid plaques (20.0% vs. 12.8%, adjusted OR 1.72, 95% CI 1.12-2.66, p = 0.014), while none of the candidate SNPs was significantly associated with vulnerable plaques (all p > 0.05). Interaction tests found the association between sex and vulnerable plaques is affected by the genotype of IL6R rs4845625 (p for interaction = 0.031). Stratification analysis revealed a strong association between IL6R rs4845625 and vulnerable carotid plaque in man (dominant model TT vs. CT + CC: adjusted OR 1.52, 95% CI 1.12-2.07, p = 0.007; codominant model TT vs. CC: adjusted OR 1.50, 95% CI 1.00-2.25, p = 0.048) but not in women (p > 0.05 in all genetic models). Conclusion: The rs4845625 polymorphism in IL6R has sex-specific effects on vulnerable carotid plaque in Chinese Han high-risk individuals for stroke. Our findings provide a plausible genetic basis underlying the sex difference in carotid plaque vulnerability.

Project description:ImportanceIt remains unknown whether in an asymptomatic community-based cohort magnetic resonance imaging (MRI) measures of plaque characteristics are independently associated with incident cardiovascular disease (CVD) events when adjusted for carotid artery (CA) wall thickness, a measure of plaque burden.ObjectiveTo assess associations of CA MRI plaque characteristics with incident CVD events.Design, setting, and participantsThe Atherosclerosis Risk in Communities (ARIC) study is a prospective epidemiologic study of the incidence of CVD in 15 792 adults of which 2066 women and men were enrolled in the ARIC Carotid MRI substudy. ARIC participants were enrolled from 1987 to 1989, and the substudy was conducted between January 2004 and December 2005. Analysis began January 2017 and ended August 2020.ExposuresIncident CVD events during a median (interquartile range [IQR]) follow-up time of 10.5 (8.1-10.9) years were assessed.Main outcomes and measuresProportional hazards Cox analyses were performed to ascertain associations between MRI variables of CA plaque burden and plaque characteristics.ResultsOf 15 792 ARIC participants, 2066 were enrolled in the substudy, of whom 1256 (701 women [55.8%]) had complete data and were eligible for incident CVD analyses. Carotid artery plaques in participants with incident CVD events (172 [13.7%]) compared with those without (1084 [86.3%]) had a higher normalized wall index (median [IQR], 0.48 [0.36-0.62] vs 0.43 [0.34-0.55]; P = .001), maximum CA wall thickness (median [IQR], 2.22 [1.37-3.52] mm vs 1.96 [1.29-2.85] mm; P = .01), maximum CA stenosis (median [IQR], 5% [0%-22%] vs 0% [0%-13%]; P < .001), and when present, a larger lipid core volume (median [IQR], 0.05 [0.02-0.11] mL vs 0.03 [0.01-0.07] mL; P = .03), respectively. The presence of a lipid core was independently associated with incident CVD events when adjusted for traditional CVD risk factors and maximum CA wall thickness (hazard ratio, 2.48 [95% CI, 1.36-4.51]; P = .003), whereas the presence of calcification was not. The frequency of intraplaque hemorrhage presence in this population of individuals free of CVD at baseline who were not recruited for carotid stenosis was too small to draw any meaningful conclusions (intraplaque hemorrhage presence: 68 of 1256 participants [5.4%]). Carotid artery lumen area and maximum stenosis, which were overall low, were independently associated with incident CVD events when adjusted for traditional CVD risk factors, as anticipated.Conclusions and relevanceThe presence of a CA lipid core on MRI is associated with incident CVD events independent of maximum CA wall thickness in asymptomatic participants.

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A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque.

Publications

A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque.

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