Association analyses identify multiple new lung cancer susceptibility loci and their interactions with smoking in the Chinese population

Abstract

To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS) of lung cancer in the Chinese population in an extended validation sample size of 7,436 individuals with lung cancer (cases) and 7,483 controls. We found genome-wide significant (P < 5.0 × 10(-8)) evidence for three additional lung cancer susceptibility loci at 10p14 (rs1663689, close to GATA3, P = 2.84 × 10(-10)), 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60 × 10(-9)) and 20q13.2 (rs4809957 in CYP24A1, P = 1.20 × 10(-8)). We also found consistent associations for rs247008 at 5q31.1 (IL3-CSF2-P4HA2, P = 7.68 × 10(-8)) and rs9439519 at 1p36.32 (AJAP1-NPHP4, P = 3.65 × 10(-6)). Four of these loci showed evidence for interactions with smoking dose (P = 1.72 × 10(-10), P = 5.07 × 10(-3), P = 6.77 × 10(-3) and P = 4.49 × 10(-2) for rs2895680, rs4809957, rs247008 and rs9439519, respectively). These results advance our understanding of lung cancer susceptibility and highlight potential pathways that integrate genetic variants and smoking in the development of lung cancer.

Figure 1

Regional plots of the five identified marker SNPs (rs1663689 at 10p14, rs2895680 at 5q32, rs4809957 at 20q13.2, rs247008 at 5q31.1 and rs9439519 at 1p36.32). Results (−log₁₀ P) are shown for SNPs in the region flanking 1,000 kb on either side of the marker SNPs. The marker SNPs are shown in purple, and the r² values for the other SNPs are indicated in different colors. The genes within the region of interest are annotated, with arrows indicating the direction of transcription.