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.