Abstract LB-337: Synergistic effects of twelve common genetic polymorphisms and smoking habits on absolute risk of bladder cancer
Authors: García-Closas M. , Rothman N. , Figueroa J. D. , Prokunina-Olsson L. , Han S. , Baris D. , Jacobs E. , Malats N. , Vivo I. De , Albanes D. , Purdue M. P. , Sharma S. , Fu Y. P. , Kogevinas M. , Wang Z. , Tang W. , Tardón A. , Serra C. , Carrato A. , García-Closas R. , Lloreta J. , Johnson A. , Schwenn M. , Karagas M. R. , Schned A. , Andriole G. , Grubb R. , Black A. , Gapstur S. M. , Thun M. , Diver W. R. , Weinstein S. J. , Virtamo J. , Hunter D. J. , Caporaso N. , Landi M. T. , Hutchinson A. , Burdett L. , Jacobs K. B. , Yeager M. , Fraumeni J. F. , Chanock S. J. , Silverman D. T. , Chatterjee N. 
Published: August 2012

Abstract
Smoking is the strongest established risk factor for bladder cancer and recent studies have identified multiple common susceptibility loci for this disease. Evaluation of gene-smoking interactions on absolute risk of bladder cancer could be important for understanding both the public health and biological significance of the combined effect of these factors. However, previous studies of gene-environment interactions focused on relative rather than absolute risk measures and thus did not address this important question. The aim of our analyses was to estimate absolute risk of bladder cancer in relation to smoking habits and 12 known susceptibility variants for this disease, and to evaluate if smoking risk differences (RD) vary by levels of a polygenic risk score derived from these variants, using additive tests for interaction. Analyses were based on data from 4,098 cases and 5,995 controls of European background in eight studies participating in the NCI bladder cancer genome-wide association study (GWAS). Absolute risks were estimated based on US incidence and mortality data. The main outcome measures were 30-year cumulative absolute risk of bladder cancer and RDs for males aged 50 years in relation to smoking habits and the polygenic risk score. RDs for ever compared to never smokers were significantly larger (P-additive interaction &lt; 0.05) for subjects carrying risk alleles for seven out of 12 known susceptibility variants. Polymorphisms in two detoxification enzymes, NAT2 and UGT1A6, provided the strongest evidence of additive interactions (P-additive interaction of 0.0002 and 0.0003, respectively), supporting the presence of biological interactions between smoking and these variants. The 30-year risk of bladder cancer in never, former and current smokers was 0.7%, 1.6% and 3.7%, respectively, for subjects in the bottom quartile of the polygenic risk score, compared to 2.0%, 5.1% and 8.0% for subjects in the top quartile. This translates into a significantly larger number of projected cases, which could be avoided by smoking prevention in subjects at higher compared to lower genetic risk (P-additive (2df)=4.6x10-9 for top to bottom quartile of the polygenic risk score). In conclusion, our analyses provide strong evidence for synergistic effects of smoking and known susceptibility loci for bladder cancer on the absolute risk of the disease. This indicates that targeting intense smoking prevention efforts to individuals at elevated genetic risk for bladder cancer could improve the public health impact of such efforts. However, genetic susceptibility for other smoking-related diseases, as well as practical and ethical considerations, would need to be taken into account before any recommendations could be made. (MGC, NR are Co-first authors; N.C. and DTS are Co-last authors)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-337. doi:1538-7445.AM2012-LB-337