Abstract MP82: The Effect of Nicotinic Acetylcholine Receptor Genes CHRNA3/5 on Thoracic Aortic Calcium is Mediated by Smoking
Introduction: Coronary artery calcium (CAC) and thoracic aortic calcium (TAC), markers of subclinical atherosclerosis, have been shown to strongly correlate with the amount of atheromatous plaque and subsequently predict future coronary disease events and mortality. CAC and TAC are complex heritable traits with both genetic and environmental risk factors such as cigarette smoking. We investigated the role of smoking, a key environmental risk factor, as a mediator of the genetic risk of subclinical atherosclerosis in the COPDGene study.
Hypothesis: We hypothesized that smoking will mediate a portion of the genome-wide significant SNPs with subclinical atherosclerosis as measured by TAC and CAC.
Methods: We performed genome wide genotyping of common and rare variants in COPDGene, a study of 10,192 current and former smokers with at least 10 pack-years of smoking history. CAC and TAC were measured using high dose, inspiration chest CT scans, following an established protocol in 8,739 individuals (6,150 non-Hispanic Whites and 2,589 African Americans). Mediation analysis, using the significant SNPs from the GWA of common and rare variants, was performed using R software adjusting for genetic ancestry using principal components as well as recognized risk factors (age, gender, BMI, diabetes, high blood pressure, steroid use, high cholesterol, and presence of a coronary stent). We used the log transformation of CAC plus 1 and the log transformation of TAC plus 1 as the quantitative phenotypes.
Results: There were 3 SNPs on chromosome 15q25 [CHRNA5/3] achieving genome-wide significance with TAC in non-Hispanic Whites, with the most significant result being rs951266 (p= 3.074e-8). We previously replicated 9 SNPs on chromosome 9 [CDKN2B-AS1] reaching genome-wide significance with CAC in non-Hispanic Whites. In African Americans, no genome-wide significant associations were identified. Given these findings, we tested for mediation of these genetic signals by pack-years of smoking among non-Hispanic Whites in the COPDGene study. Pack-years of smoking history was a significant mediator of CHRNA5/3 [rs951266] on TAC (p <0.001, 13% indirect effect), while smoking was not a significant mediator of CDKN2B-AS13 on CAC (p =0.58).
Conclusions: The nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/3) were significantly associated with thoracic aortic calcium in this cohort of heavy smokers. Cigarette smoking mediates this genetic risk for subclinical atherosclerosis and may offer an avenue for intervening on the genetic susceptibility to coronary artery disease.
Author Disclosures: S.M. Lutz: None. M. Cho: None. G. Kinney: None. K. Young: None. K. Pratte: None. L. Duca: None. M. Foreman: None. T. Beaty: None. E. Silverman: None. M. Budoff: None. J. Hokanson: None.
- © 2016 by American Heart Association, Inc.