Abstract P296: Joint Impact of 61 Genetic Variants in Seven Nicotinic Acetylcholine Receptor Genes on Subclinical Atherosclerosis in American Indians: A Pathway-based Analysis

Abstract

Background: Atherosclerosis is a complex disease resulting from the joint effects of multiple genetic variants. Cigarette smoking is a strong risk factor for atherosclerotic cardiovascular disease (CVD). Nicotine, the major active component of cigarette smoke, influences CVD by binding to nicotinic acetylcholine receptors (nAChRs). Genetic variants in nAChRs may therefore contribute to atherosclerosis. While each single variant may have only a minor effect, the joint contribution of multiple SNPs to atherosclerosis may be larger. Objective: To investigate the joint impact of 61 SNPs in seven nAChRs genes on subclinical atherosclerosis using a pathway-based approach. Methods: We genotyped 61 tagSNPs in seven nAChRs genes (CHRNA3-A6, CHRNB2-B4) in 3,665 American Indians recruited by the Strong Heart Family Study from Oklahoma (OK), Arizona (AZ) and North/ South Dakota (DK). Subclinical atherosclerosis was assessed by carotid intima-media thickness (cIMT) and carotid plaque score using ultrasound. We performed a pathway-based analysis to evaluate the joint impact of these 61 SNPs on cIMT and plaque score, separately, adjusting for classical cardiovascular risk factors including age, sex, body mass index (BMI), cigarette smoking status (current, former vs. never), alcohol intake (current, former vs. never), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), blood pressure, diabetes, levels of physical activity, fibrinogen, and renal function (assessed by estimated glomerular filtration rate). To avoid population substructure, all statistical analyses were stratified by study center (OK, AZ, and DK). Multiple testing was adjusted using Bonferroni correction. Results: Prevalence of smokers (current plus former) was highest in participants from DK (66%), followed by OK (58%) and AZ (51%). Compared to never smokers, smokers had significantly larger cIMT (0.647mm vs. 0.681mm, P<0.0001) and plaque score (0.568 vs. 0.793, P<0.0001). Among the 61 SNPs examined, only seven SNPs showed significant individual association with cIMT or plaque score in OK after Bonferroni correction. However, a pathway analysis indicates that the nAChRs pathway as a whole in consideration of the joint effects of all 61 SNPs was significantly associated with both cIMT and plaque score in participants from OK and AZ (all p’s<0.001), but not DK. Conclusion: Genetic variants in the nAChRs pathway jointly contribute to subclinical atherosclerosis in American Indians. Though the mechanism linking the nAChRs genetic pathway to subclinical atherosclerosis is unclear, our results may provide valuable information for behavioral and/or molecular strategies for reducing cardiovascular risk in American Indians.