Abstract
Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR = 0.68, p = 0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR = 1.33, p = 0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology.
Highlights
Given increased life expectancy, prevention of diseases with severe manifestations and later life complications has become of tremendous importance
Following QC filtering, the sample consisted of 1,949 subjects, 72.7% of whom were males, with a median 6IQR age of 62616 years, and a mean body mass index (BMI) of 29.064.7 kg/m2
Higher prevalence among cases compared to controls of diabetes, hypertension, hyperlipidemia, family history of coronary artery disease (CAD), raised glucose levels, and reduced HDL levels, were observed (Table 2)
Summary
Prevention of diseases with severe manifestations and later life complications has become of tremendous importance. Researchers’ interest in identifying coronary artery disease (CAD) susceptibility genes reflects the very high mortality associated with both the disease [1] and one of its most serious complications: myocardial infarction (MI). While identifying the primary causes of CAD has been complicated by the multifactorial nature of the disease, genome-wide association studies (GWAS) have been moderately successful in revealing some of the polygenic structure of CAD. They only explain a modest fraction of the total heritability of CAD [2,3]. Linkage disequilibrium is the primary mechanism for generating direct (causal) and indirect (non-causal) genetic associations. In view of the multifactorial nature of CAD, the effects of genes
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