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Association between variations in coagulation system genes and carotid plaque.

ABSTRACT: Genetic variation in coagulation and fibrinolysis may affect the development of subclinical atherosclerosis modifying the risk of stroke and cardiovascular disease. However, data on the relationship between subclinical atherosclerosis and genes involved in the coagulation system are sparse. The objective of this study is to examine the association between single nucleotide polymorphisms (SNPs) in coagulation system genes and subclinical carotid plaque phenotypes.From the Genetic Determinants of Subclinical Carotid Disease Study, 287 Dominicans were examined for carotid plaque presence, thickness, and surface irregularity by high-resolution B-mode carotid ultrasound. Logistic regression was used to test for association between 101 SNPs in 23 coagulation system genes and plaque phenotypes while controlling for age, sex, smoking, hypertension, dyslipidemia, and diabetes. Within gene haplotypes and interactions between genes were examined. A follow-up of SNPs in moderate to high (r(2)>0.25) linkage disequilibrium (LD) with those implicated in the discovery analysis (p ? 0.01) was performed in an independent sample of 301 Dominicans.The prevalence of carotid plaque (47% discovery; 46% follow-up) as well as the mean age (65 ± 8 discovery; 65 ± 9 follow-up) of the participants was similar in both datasets. Two genes (vWF and THBS1) were associated (p ? 0.01) with plaque size and surface irregularity. In follow-up, 5 SNPs in vWF were associated (p ? 0.05) with plaque size. SERPINE1 was an additional gene of interest in the haplotype and interaction analyses.Variation in the vWF, THBS1, and SERPINE1 gene may play an important role in the pathogenesis of atherosclerotic plaque.

SUBMITTER: Della-Morte D

PROVIDER: S-EPMC3483411 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Association between variations in coagulation system genes and carotid plaque.

Della-Morte David D Beecham Ashley A Dong Chuanhui C Wang Liyong L McClendon Mark S MS Gardener Hannah H Blanton Susan H SH Sacco Ralph L RL Rundek Tatjana T

Journal of the neurological sciences 20120913 1-2

<h4>Objective</h4>Genetic variation in coagulation and fibrinolysis may affect the development of subclinical atherosclerosis modifying the risk of stroke and cardiovascular disease. However, data on the relationship between subclinical atherosclerosis and genes involved in the coagulation system are sparse. The objective of this study is to examine the association between single nucleotide polymorphisms (SNPs) in coagulation system genes and subclinical carotid plaque phenotypes.<h4>Methods</h4 ...[more]

PMID: 22982001

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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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Association between variations in coagulation system genes and carotid plaque.

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Association between variations in coagulation system genes and carotid plaque.

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