Abstract P151: Joint Association of 61 Snps in Seven Nicotinic Acetylcholine Receptor Genes with Renal Function In American Indians: The Strong Heart Study
Background: Smoking is an important risk factor for chronic kidney disease, a strong predictor of cardiovascular disease. Genetic variants in the nicotinic acetylcholine receptors (nAChRs) have been associated with smoking-related phenotypes, and thus could potentially affect renal function. However, existing studies primarily focused on single SNP analysis, which is less powerful than examining the joint impact of multiple SNPs on disease etiology.
Objective: To assess the joint contribution of 61 tagSNPs in the nAChRs genes to interindividual variability in renal function among 3,665 American Indians in the Strong Heart Study (SHS), the largest investigation of cardiovascular disease and its risk factors in American Indians.
Methods: Renal function was assessed using estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). We first examined the association of each SNP with renal function measurements using family-based association test, adjusting for age, sex, body mass index, waist to hip ratio, history of diabetes, systolic blood pressure, total cholesterol and triglycerides. We then conducted gene-based analysis by combining p-values of all SNPs within a gene using the truncated product method weighted by each SNP’s estimated effect size. Gene-family analysis was then performed using p-values from gene-based analysis. Multiple testing was corrected using false discovery rate (FDR).
Results: Although multiple SNPs showed nominal or marginal association with either eGFR or UACR or both, only one SNP (rs2072659 in CHRNB2) showed significant association with UACR after correction for multiple testing (p = 0.047). Gene-based analysis indicated that, after adjusting for multiple testing, two genes (CHRNB2 and CHRNB4) were significantly associated with both eGFR and UACR (both p’s < 0.027). Gene-family analysis considering all SNPs in the seven nAChRs genes revealed a significant association of the nAChRs gene family with both eGFR and UACR (both p’s<0.003). Removing the most significant SNP (i.e., rs2072659) did not change our results, suggesting that the observed association is unlikely to be driven by this SNP. We also conducted sensitivity analysis to examine the potential impact of diabetes on our findings. Results showed that, after excluding diabetic patients, the gene-family association with eGFR remained statistically significant (p = 0.023), but the association with UACR was substantially attenuated (p = 0.091).
Conclusion: Genetic polymorphisms in the nAChRs gene family jointly contribute to renal function among American Indians in the Strong Heart Study. These findings may shed light on how smoking could influence interindividual variability in renal function among American Indians who suffer from high rates of chronic kidney disease and end stage renal disease.
- © 2013 by American Heart Association, Inc.