Association between variations in coagulation system genes and carotid plaque

Abstract

Objective

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.

Methods

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 (r² > 0.25) linkage disequilibrium (LD) with those implicated in the discovery analysis (p ≤ 0.01) was performed in an independent sample of 301 Dominicans.

Results

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.

Conclusions

Variation in the vWF, THBS1, and SERPINE1 gene may play an important role in the pathogenesis of atherosclerotic plaque.

Introduction

Atherosclerosis is a complex disorder and the underlying mechanism of cardiovascular diseases (CVD) and stroke, the most common causes of death in western countries [1]. Platelet activation, aggregation and thrombosis play pivotal roles in atherosclerotic plaque formation, progression and plaque rupture, and are accepted as the common pathogenetic pathways of ischemic thromboembolic events [2].

Small, non-stenotic carotid plaque represents a distinct phenotype of subclinical atherosclerosis and is an important marker of incident CVD and stroke [3]. Carotid plaque can be detected non-invasively with reasonable precision in population samples using high-resolution ultrasound imaging [3], [4]. Other carotid plaque phenotypes such as plaque size and plaque morphology are important predictors of increased vascular risk [4], [5]. Subclinical carotid atherosclerotic plaque is a highly heritable phenotype [6]. Much effort has been devoted to discovering and understanding genetic mechanisms regulating the hemostatic system and atherosclerosis [7], but data on the relationship between atherosclerotic plaque and variations in coagulation system genes are sparse. Further investigations in this field may lead to novel treatments for both atherosclerosis and thrombosis.

Therefore, the aim of this study was to examine the association between variation in select coagulation system genes and carotid plaque presence, size, and surface irregularity as part of the Genetic Determinants of Subclinical Carotid Disease Study. In addition to the analysis of single nucleotide polymorphisms (SNPs), haplotype analysis was performed to examine multi-SNP effects within genes, and interaction analysis for the multi-SNP effects between genes. A validation of genes implicated in the single SNP analysis was performed in an independent sample of 301 Dominicans with genotype data available from a genome-wide association study (GWAS).