Abstract 232: Genome-wide association study (GWAS) of total nicotine equivalents: A composite biomarker of nicotine uptake

The primary risk factor for lung cancer (second most common cancer in men and women in the U.S.) is tobacco smoking. Prior GWAS have identified variants in the CHRNA5-CHRNA3-CHRNB4 cluster (chr 15q25) to be associated with smoking. Total nicotine equivalents (TNE) measured from urine represents the sum of nicotine, cotinine, and trans-3′-hydroxycotinine and its glucuronides, as well as nicotine N-oxide, and is a biomarker of nicotine uptake and, when adjusted for cigarettes smoked per day (CPD), a biomarker of smoking intensity. In addition to smoking status, genetic variation is likely to influence smoking behavior (e.g., number of cigarettes, number of puffs, depth of inhalation) and, thus, one9s internal exposure to nicotine and tobacco carcinogens. We conducted a genome-wide association study of TNE (i.e. smoking dose) among 2,239 cancer-free, current smokers from the Multiethnic Cohort, comprised of 5 ethnic groups. TNE was measured using liquid chromatography-tandem mass spectrometry analysis in overnight or first morning urine samples. Genotyping was conducted utilizing the Illumina 1M array and the data were imputed to the 1000 Genomes reference panel, for a total of 11.9 million SNPs and indels. Linear regression models were conducted in all subjects combined and each ethnic group using the log transformed TNE measurement, adjusted for age, BMI, sex, and the first ten principle components (Model 1). A separate model additionally adjusted for log transformed cigarettes per day (Model 2). Genome-wide significant associations with TNE for Model 1 included the chr 15q25 region, specifically, intronic common SNPs in CHRNB4 (rs17487223) and CHRNA3 (rs55676755) with P=7.37x10-9 (Beta (SE) = 0.21 (0.04)) and P=2.22x10-8 (Beta (SE) = 0.19 (0.03)), respectively. Ethnic specific analyses pointed to European American, African American, and Hispanic individuals mainly contributing to the signal. Nicotinic receptors, as ligand-gated channels consist of five subunits and are the primary targets for nicotine and initiate the brain responses to smoking. Our findings with nicotine uptake confirm previous reports that these biologically plausible genes influence smoking behavior. For Model 2 in all pooled ethnicities combined, three intronic SNPs were near genome-wide significance (with lowest P=7.13x10-8 for rs55934265) in the beta-1,3-galactosyltransferase (B3GALT1) gene, Beta (SE) = -0.57 (0.10). The B3GALT1 signal was primarily driven by the African American data (N=364) with ethnic specific results at P=5.3x10-4, Beta (SE) = -0.47 (0.13). B3GALT1 is expressed exclusively in the brain and is involved in the biosynthesis of glycolipids. Next steps include constructing a genetic risk score (GRS) of TNE, and evaluating the GRS in association with lung cancer risk independent of self-reported levels of smoking. Citation Format: Linda M. Polfus, S. Lani Park, Yesha M. Patel, Sharon E. Murphy, David Conti, Christopher Haiman, Daniel O. Stram, Loic Le Marchand. Genome-wide association study (GWAS) of total nicotine equivalents: A composite biomarker of nicotine uptake [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 232.