Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans

• Genetic by environment (e.g., cigarettes/day, CPD) interactions for lung cancer are understudied in non-European ancestry populations.
• We analyzed interactions between nominal smoking quantity SNPs (n = 7156 discovery sample) and CPD and risk of lung cancer (n = 1078 cases, n = 822 controls).
• Six SNPs were effect modifiers of CPD for lung cancer, suggesting that the allelic dose effect is most pronounced in light smokers.Lung cancer is the leading cause of cancer death, disproportionately affecting African-Americans. Prior studies have reported specific genetic markers linked to both smoking quantity and risk of lung cancer in multiple ethnic/racial groups. Investigators analyzed associations between 28 polymorphisms and average cigarettes smoked per day (CPD) in 7156 African-American females and examined interactions between the top polymorphisms and CPD in a cohort of African-American males and females (1078 lung cancer cases and 822 health control patients). The results suggested that six polymorphisms within one genomic region increased lung cancer risk in African-Americans, which was most pronounced in light smokers.

BackgroundGenome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene–environment interactions is not well understood.MethodsWe analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case–control study of African-American females and males (1078 lung cancer cases and 822 controls).FindingsNine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10− 5). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = − 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.InterpretationThese results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.