Abstract
Reports of genetic association of polymorphisms with lung cancer in the Indian subcontinent are often conflicting. To summarise and replicate published evidence for association with lung cancer and its subgroups. We performed a meta-analysis of candidate associations on lung cancer, its histological subtypes and smoking status in the Indian subcontinent following PRISMA guidelines. Multiple testing corrections were done by the Benjamini–Hochberg method through assessment of significance at a false discovery rate of 10%. We genotyped and investigated rs1048943/CYP1A1 in a case–control sample from eastern India, followed by its global meta-analysis using a similar protocol. Meta-analysis of 18 variants of 11 genes reported in 39 studies (7630 cases and 8169 controls) showed significant association of rs1048943/CYP1A1 [2.07(1.49–2.87)] and rs4646903/CYP1A1 [1.48(1.93–1.95)] with overall lung cancer risk at 10% FDR, while nominal association (p < 0.05) was observed for del1/GSTT1, del2/GSTM1, rs1695/GSTP1 and rs17037102/ DKK2. Subtype analysis showed a significant association of del1/GSTT1 with adenocarcinoma, rs4646903/CYP1A1 with squamous carcinoma, and rs1048943/CYP1A1 with both. Association of rs4646903/CYP1A1 in smokers and effect modification by meta-regression analysis was observed. Genotyping of rs1048943/CYP1A1 that presented significant heterogeneity (p < 0.1) revealed an association with adenocarcinoma among eastern Indian smokers, while a global meta-analysis in 10458 cases and 10871 controls showed association with lung cancer and its subgroups. This study identified the susceptibility loci for lung cancer and its covariate-subgroups.
Highlights
We found a nominal association of rs1048943/CYP1A1 with lung Adenocarcinoma (ADC) among smokers in the dominant (GG + GA vs AA: OR = 1.99; 95% CI = 1.10–3.63; p = 0.024) effect model (Supplementary Information, Table S5)
We have performed an age-adjusted analysis restricted in males only, which showed a significant association of rs1048943 (CYP1A1) with lung Adenocarcinoma (OR = 2.97, 95% CI = 1.35–6.69, p = 0.007) among smokers (Supplementary Information, Table S5)
GWAS data mining revealed no significant association of rs1048943/CYP1A1 with lung cancer, it showed a significant association of the CYP1A1 gene with hypertension and habitual coffee consumption
Summary
We have performed an age-adjusted analysis restricted in males only, which showed a significant association of rs1048943 (CYP1A1) with lung Adenocarcinoma (OR = 2.97, 95% CI = 1.35–6.69, p = 0.007) among smokers (Supplementary Information, Table S5). In the FE meta-analysis, we found a nominal association of rs1048943 with overall lung cancer risk (AG + GG vs AA: OR = 1.21, 95% CI = 1.04–1.41, p = 0.01, Q2 = 1.74, pHet = 0.08, I2 = 42.67%) (Supplementary Information, Table S7 and Fig. S10).
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