Abstract
A previous genome-wide association study showed that a single nucleotide polymorphism (SNP) rs2107595 in histone deacetylase 9 (HDAC9) gene was associated with large artery stroke (LAS) in Caucasians. Based on the similar atherosclerotic pathogenesis between LAS and coronary artery disease (CAD), we aimed to evaluate the associations of SNP rs2107595 with CAD risk and the severity of coronary atherosclerosis in a Chinese Han population, and explore the potential gene-environment interactions among SNP rs2107595 and conventional CAD risk factors. In a two-stage case-control study with a total of 2317 CAD patients and 2404 controls, the AG + AA genotypes of SNP rs2107595 were significantly associated with increased CAD risk (Adjusted odds ratio (OR) = 1.23, Padj = 0.001) and higher modified Gensini scores (Adjusted OR = 1.38, Padj < 0.001). These associations remained significant in subtype analyses for unstable angina pectoris (UAP), non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Subgroup and multifactor dimensionality reduction analyses (MDR) further found the gene-environment interactions among SNP rs2107595, body mass index, type 2 diabetes and hyperlipidemia in CAD risk and the severity of coronary atherosclerosis. Moreover, patients with CAD had higher levels of HDAC9 mRNA expression and plasma HDAC9 than controls. Subsequent genotype-phenotype analyses observed the significant correlations of SNP rs2107595 with HDAC9 mRNA expression and plasma HDAC9 levels in controls and patients with NSTEMI and STEMI. Taken together, our data suggest that SNP rs2107595 may contribute to coronary atherosclerosis and CAD risk through a possible mechanism of regulating HDAC9 expression and gene-environment interactions.
Highlights
Coronary artery disease (CAD), the leading cause of death and disability worldwide[1], is mainly caused by multiple interactions between genetic and environmental risk factors of atherosclerosis[2]
Allelic association analyses showed that the minor allele A of single nucleotide polymorphism (SNP) rs2107595 was significantly associated with increased CAD risk (OR = 1.19, P = 0.008).This significant association was further identified in the replication set with an allelic odds ratios (ORs) of 1.20 and a P value of 0.002
The results indicated that the minor allele of SNP rs2107595 had a 1.19-fold (P = 6.08 × 10−5) increased risk of CAD in the merged set
Summary
Coronary artery disease (CAD), the leading cause of death and disability worldwide[1], is mainly caused by multiple interactions between genetic and environmental risk factors of atherosclerosis[2]. The genetic and environmental determinants involved in CAD risk may vary across different stages of atherosclerosis, leading to the underlying heterogeneity between stable and unstable CAD[4, 5] This atherosclerotic pathogenesis applies to the cerebral vessels and contributes to the development of ischemic stroke (IS), especially to the development of large artery stroke (LAS)[6]. HDAC9 deletion could lead to down-regulation of inflammatory genes[14], up-regulation of lipid-associated genes[14], and dramatic reduction of atherosclerotic lesion size in mice[15] Taking all these findings together, we hypothesize that SNP rs2107595 may contribute to the development of coronary atherosclerosis and CAD risk by modifying HDAC9 expression
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