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

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Abstract

To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS)1 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.

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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).

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Acknowledgements

This work is funded by the China National High-Tech Research and Development Program Grant (2009AA022705) and partly funded by the National Key Basic Research Program Grant (2011CB503805) and the National Natural Science Foundation of China (30730080, 30972541 and 30901233), Jiangsu Natural Science Foundation (BK2011028), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (11KJA330001), the US National Institutes of Health Grant (U19 CA148127) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors thank all the study subjects, research staff and students who participated in this work.

Author information

H.S. directed the study, obtained financial support and was responsible for study design, interpretation of results and manuscript writing. J. Dong and Z.H. performed overall project management, along with C. Wu, and drafted the initial manuscript. J. Dong, Z.H., Z.L., J. Dai and R.Z. performed statistical analyses. D. Lin, T.W., Y. Shi, D. Lu, L.J., B.Z., J.L. and K.C. directed each participating study and jointly organized this study. M.C., C. Wang, Y.J., S.C., Z.Q., J.G. and C.S. were responsible for sample processing and managed the genotyping data. H.M., G.J., Z.P., Y.C., Y. Shu and L.X. were responsible for subject recruitment and sample preparation of the Nanjing samples. C. Wu, D.Y., X.L. and W.T. were responsible for subject recruitment and sample preparation of the Beijing samples. H.G., Q.D., L.L. and P.X. were responsible for subject recruitment and sample preparation of the Wuhan samples. X.Z., J.W., G.Z., H.C., B.H. and C.B. were responsible for subject recruitment and sample preparation of the Shanghai samples. Z.Y., W.W., P.G., Y.Z., H. Zhang and Y.Y. were responsible for subject recruitment and sample preparation of the Shenyang samples. L.Y. was responsible for subject recruitment and sample preparation of the Guangzhou samples. H. Zheng was responsible for subject recruitment and sample preparation of the Tianjin samples. C.I.A. was responsible for the scientific editing. F.C. oversaw the statistical analyses process. All authors approved the final manuscript.

Correspondence to Hongbing Shen.

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