Genetic Variants Modifying the Risk of Lung Cancer and Its Subtypes: A Comprehensive Meta-analysis and a Case-control Study

Abstract Association studies on lung cancer have often yielded conflicting and inconclusive results. We performed a comprehensive meta-analysis to dissect the precise effects of the candidate variants. We searched for association studies on lung cancer from the Indian subcontinent. Cochran’s Q-test assessed heterogeneity. Both overall and histotype-stratified meta-analysis was done using fixed-effect and random-effects models. Smoking status stratified subgroup analysis and effect modification tests were done. An associated variant with significant heterogeneity was genotyped in an eastern Indian population to investigate the contribution of potential confounders followed by a comprehensive meta-analysis across world populations. Significant heterogeneity was observed for the 8 variants. Both fixed-effect and random-effects meta-analysis of 24 variants showed FDR-corrected associations of rs3547/ XRCC1 and rs1048943/ CYP1A1 with lung cancer along with 5 nominal associations. del1/ GSTT1 , rs4646903/ CYP1A1 , and rs10488943/ CYP1A1 were associated with adenocarcinoma, squamous cell carcinoma, and both, respectively. rs4646903/ CYP1A1 was associated with lung cancer among smokers with significant effect modification by smoking. rs10488943/ CYP1A1 was associated with lung adenocarcinoma in the East Indian case-control study. rs1048943/ CYP1A1 was associated with lung cancer across world populations. Our work confirms the risk loci for lung cancer and its subtypes in the context of smoking and other aetiological factors, which could aid in personalised treatment.