Abstract P368: Genome Wide Association Study Identifies Susceptibility Loci for Coronary Artery Calcium in Smokers
Introduction: Coronary artery calcium (CAC) is a measure of coronary atherosclerosis, which is strongly associated with the presence of coronary artery disease and predicts future coronary disease events and mortality. CAC is a heritable trait. Numerous candidate gene studies and more recently genome-wide association studies (GWAS) have identified susceptibility loci for CAC. In addition, cardiovascular disease risk factors such as smoking are associated with CAC.
Hypothesis: We hypothesized that we would identify new genetic loci and replicate known genomic regions for CAC by performing a GWAS among heavy smokers in the COPDGene study, a multi-center observational study designed to identify genetic factors associated with risk of COPD.
Methods: We conducted a GWAS of CAC in COPDGene, a study of 10,192 current and former smokers with at least 10 pack-years of smoking history. CAC was measured from chest CT scans using an established protocol and was available in 8,739 individuals (6,150 non-Hispanic Whites and 2,589 African Americans). The analysis was performed using PLINK v1.07 adjusting for genetic ancestry using principal components as well as and cardiovascular disease risk factors (age, gender, BMI, smoking status, pack-years of smoking history, diabetes, high blood pressure, steroid use, high cholesterol, and presence of a coronary stent).
Results: Using the log transformation of CAC plus 1 as the outcome, there were 9 single nucleotide polymorphisms (SNPs) on chromosome 9 [CDKN2B-AS1] that reached genome wide significance in non-Hispanic Whites, with the most significant result being rs10757272 (p = 3.572e-11). Additional top loci that have been previously identified were rs9349379 on chromosome 6 [PHACTR1] (p =8.760e-08) and rs1263982 on chromosome 17 [CA10] (p =4.654e-06). Among African Americans, no genome-wide significant associations were identified; however, one of the top findings was rs7412 on chromosome 19 [APOE] (p = 1.597e-06).
Conclusions: This study confirms genome wide significance for CAC for CDKN2B-AS1 on chromosome 9 among non-Hispanic Whites. This is the major GWAS signal for clinically manifested coronary artery disease. Among African Americans, we found a suggestive association signal in the APOE gene. In conclusion, genetic susceptibility for atherosclerosis is evident, even among individuals with a substantial smoking burden. This highlights the importance of both genetics and behavioral risk factors in the susceptibility to atherosclerosis.
Author Disclosures: S.M. Lutz: None. M.H. Cho: None. G. Kinney: None. K. Pratte: None. R. Casaburi: None. E. Silverman: None. M. Budoff: None. J.E. Hokanson: None.
- © 2015 by American Heart Association, Inc.