TY - JOUR
T1 - Large scale association analysis identifies three susceptibility loci for coronary artery disease
AU - Saade, Stephanie
AU - Cazier, Jean-Baptiste
AU - Ghassibe-Sabbagh, Michella
AU - Youhanna, Sonia
AU - Badro, Danielle A
AU - Kamatani, Yoichiro
AU - Hager, Jörg
AU - Yeretzian, Joumana S
AU - El-Khazen, Georges
AU - Haber, Marc
AU - Salloum, Angelique K
AU - Douaihy, Bouchra
AU - Othman, Raed
AU - Shasha, Nabil
AU - Kabbani, Samer
AU - Bayeh, Hamid El
AU - Chammas, Elie
AU - Farrall, Martin
AU - Gauguier, Dominique
AU - Platt, Daniel E
AU - Zalloua, Pierre A
AU - FGENTCARD Consortium
N1 - © 2011 Saade et al.
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Coronary Artery Disease
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Phenotype
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-84455169865&partnerID=MN8TOARS
U2 - 10.1371/journal.pone.0029427
DO - 10.1371/journal.pone.0029427
M3 - Article
C2 - 22216278
SN - 1932-6203
VL - 6
SP - e29427
JO - PLoS ONE
JF - PLoS ONE
IS - 12
ER -