Association between variations in coagulation system genes and carotid 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).
Section snippets
Discovery sample Set
Study participants (N = 287 Dominicans) were part of the NINDS Genetic Determinants of Subclinical Carotid Disease Study (Gen-Carotid), a sub-study of the prospective, stroke-free, community-based Northern Manhattan Study (NOMAS) [3] who 1) self-identified to be of Dominican origin through a questionnaire modeled after the U.S. census, 2) had carotid ultrasound imaging, and 3) had a DNA sample available for genetic studies.
Follow-up sample Set
A convenience sample (N = 301 Dominicans) for follow-up was constructed from
Results
Demographic and clinical characteristics of each dataset are presented in Table 1. 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. However, the number of smokers (42% discovery; 47% follow-up) and sex distribution (58% female discovery; 70% female follow-up) was slightly different.
While no single SNP in our discovery analysis met the a priori multiple testing threshold of
Discussion
In the current study, we report on the suggestive associations between variations in the vWF and THBS1 genes and subclinical carotid plaque thickness, and irregularity. The follow-up validation analysis confirmed the association of the vWF gene with thick plaque. In addition, a SERPINE1 haplotype was associated with plaque presence, and vWF haplotypes were associated with both thick and irregular plaque surface. An interaction between THBS1 and vWF was seen for irregular plaque. These
Conflicts of interest
None of the authors has any potential conflicts of interest in relation to this work.
Sources of funding
This research was supported by grants R01 NS 047655 (TR, RLS), K24 NS 062737 (TR), and R01 NS NS40807 (RLS, TR, DDM, CD, MSM, HG, AB, SB) from the National Institute of Neurologic Disorders and Stroke (NINDS).
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