||Blechter B, Wong JYY, Agnes Hsiung C, Hosgood HD, Yin Z, Shu XO, Zhang H, Shi J, Song L, Song M, Zheng W, Wang Z, Caporaso N, Burdette L, Yeager M, Berndt SI, Teresa Landi M, Chen CJ, Chang GC, Hsiao CF, Tsai YH, Chen KY, Huang MS, Su WC, Chen YM, Chien LH, Chen CH, Yang TY, Wang CL, Hung JY, Lin CC, Perng RP, Chen CY, Chen KC, Li YJ, Yu CJ, Chen YS, Chen YH, Tsai FY, Jie Seow W, Bassig BA, Hu W, Ji BT, Wu W, Guan P, He Q, Gao YT, Cai Q, Chow WH, Xiang YB, Lin D, Wu C, Wu YL, Shin MH, Hong YC, Matsuo K, Chen K, Pik Wong M, Lu D, Jin L, Wang JC, Seow A, Wu T, Shen H, Fraumeni JF, Yang PC, Chang IS, Zhou B, Chanock SJ, Rothman N, Chatterjee N, Lan Q
||We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10-26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10-3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.