Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans

// Kyle M. Walsh 1 †, Christopher I. Amos 2 † * , Angela S. Wenzlaff 3 , Ivan P. Gorlov 4 , Jennette D. Sison 5 , Xifeng Wu 6 , Margaret R. Spitz 7 , Helen M. Hansen 5 , Emily Y. Lu 2 , Chongjuan Wei 6 , Huifeng Zhang 2 , Wei Chen 2 , Stacy M. Lloyd 8 , Marsha L. Frazier 6 , Paige M. Bracci 1 , Michael F. Seldin 9 , Margaret R. Wrensch 1,5 , Ann G. Schwartz 3* , John K. Wiencke 1,5* 1 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 2 Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 3 Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 4 Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 5 Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 6 Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX 7 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 8 Department of Health Disparities Research, University of Texas M.D. Anderson Cancer Center, Houston, TX 9 Department of Biochemistry and Molecular Medicine, University of California, Davis † denotes equal contribution * CIA, AGS and JKW co-directed this research Correspondence: John K. Wiencke, email: // Keywords : Lung cancer, nicotine dependence, African-Americans, genetic association, smoking Received : November 13, 2012, Accepted : November 14, 2012, Published : November 16, 2012 Abstract Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 x 10 -4 ). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 x 10 -5 ). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.