Abstract
To identify genetic susceptibility loci for nasopharyngeal carcinoma (NPC), a genome-wide association study was performed using 464,328 autosomal SNPs in 1,583 NPC affected individuals (cases) and 1,894 controls of southern Chinese descent. The top 49 SNPs from the genome-wide association study were genotyped in 3,507 cases and 3,063 controls of southern Chinese descent from Guangdong and Guangxi. The seven supportive SNPs were further confirmed by transmission disequilibrium test analysis in 279 trios from Guangdong. We identified three new susceptibility loci, TNFRSF19 on 13q12 (rs9510787, Pcombined = 1.53 × 10−9, odds ratio (OR) = 1.20), MDS1-EVI1 on 3q26 (rs6774494, Pcombined = 1.34 × 10−8, OR = 0.84) and the CDKN2A-CDKN2B gene cluster on 9p21 (rs1412829, Pcombined = 4.84 × 10−7, OR = 0.78). Furthermore, we confirmed the role of HLA by revealing independent associations at rs2860580 (Pcombined = 4.88 × 10−67, OR = 0.58), rs2894207 (Pcombined = 3.42 × 10−33, OR = 0.61) and rs28421666 (Pcombined = 2.49 × 10−18, OR = 0.67). Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of pathways related to TNFRSF19 and MDS1-EVI1 in addition to HLA molecules.
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Acknowledgements
We would like to thank all the subjects and healthy volunteers who participated in this work. We also want to thank the staffs of Bank of Tumor Resource at Sun Yat-sen University Cancer Center (SYSUCC) for help in sample storage. We also want to thank W.-Y. Meah, X. Chen, H.-B. Toh, K.-K. Heng, C.-H. Wong and D.E.K. Tan, who performed the genotyping, and R.T.H. Ong, J. Chen, K.-S. Sim and E. Tantoso for their assistance in data analysis. This work was funded by the High-Tech Research and Development Program of China (863 Plan, 2006AA02A404), the Natural Science Foundation of China (30621063, 30872929 and u0732005), the National Basic Research Program of China (973 Plan; 2004CB518604 and 2006CB910104), Beijing Science & Technology nova program (2006A54), the National Science and Technology Support Program of China (2006BAI02A11) and the Agency for Science, Technology and Research of Singapore.
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Y.-X.Z. was the overall study principal investigator who conceived the study and obtained financial support. Y.-X.Z., J.-X.B. and J.L. designed and oversaw the study. W.-H.J., B.-J.F., Q.-S.F. and L.-Z.C. initiated or participated in the recruitment of Guangdong Chinese samples and preparation of biological samples. H.Z., G.Z. and F.H. were responsible for the recruitment and sample preparation of Guangxi Chinese samples. J.-X.B. conducted sample inclusion and data management. B.-J.F. helped to impute the HLA alleles. J.-X.B. and Y.L. undertook the statistical analyses under guidance from J.L. and with help from H.-Q.L. J.-X.B. interpreted the results, drafted and synthesized the manuscript. E.T.L., T.K. and E.S.T. reviewed the manuscript and J.L. helped to revise it.
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Supplementary Text and Figures
Supplementary Note, Supplementary Tables 1–17 and Supplementary Figures 1–5 (PDF 2569 kb)
Supplementary Table 1
Summary of previous studies on the associations of HLA genes and nasopharyngeal carcinoma. (XLS 32 kb)
Supplementary Table 2
Summary of previous studies on the associations of non-MHC genes and nasopharyngeal carcinoma, based on candidate-gene approach. (XLS 34 kb)
Supplementary Table 3
Our GWAS results of the SNPs that were reported by the previously studies. (XLS 28 kb)
Supplementary Table 5
Association results of the 42 SNPs subjected to the validation analysis. (XLS 30 kb)
Supplementary Table 15
Susceptibility loci of different malignancies identified by GWAS up to March 9, 2010. (XLS 158 kb)
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Bei, JX., Li, Y., Jia, WH. et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat Genet 42, 599–603 (2010). https://doi.org/10.1038/ng.601
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DOI: https://doi.org/10.1038/ng.601
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