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Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma

Abstract

To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, Pmeta = 2.48 × 10−10, odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, Pmeta = 2.72 × 10−17, OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (Ptrend = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10−14).

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Figure 1: STAT4 relative expression levels according to rs7574865 genotypes in paired tumor tissues and adjacent nontumor tissues from 155 subjects with HCC who are chronic HBV carriers by quantitative RT-PCR.

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Acknowledgements

We thank all the subjects who participated in this study. We also thank Y. Shi and L. He from Bio-X Institutes of Shanghai Jiao Tong University for helping with data analysis of typical Chinese population control subjects, and L. Jin, Y. Zhong, H.-H. Wang and W.-Y. Yan from the School of Life Sciences of Fudan University and H.-B. Shu from College of Life Sciences of Wuhan University for suggestions on this study. The study is supported by the National Natural Science Foundation of China for Creative Research Groups (30024001 to L.Y.), the National Key Sci-Tech Special Project of China (2013ZX10002010 and 2008ZX10002-020 to L.Y.), the Project of the Shanghai Municipal Science and Technology Commission (to L.Y.), the National Natural Science Foundation of China (31071193 to L.Y. and 31100895 to D.-K.J.), Director Foundation of the State Key Laboratory of Genetic Engineering (to L.Y.), the Fund from X.-J. Qu and Chang-An Capital of Beijing (to L.Y.), the Fund from S.-J. Yan and Tianying S.T. Group of Jiangsu (to L.Y.), MOE Foundation of Cheung Kong Scholars Program (to J.L. and Q.Y.), an intramural research grant from Huashan Hospital, Fudan University (to J.X.) and an intramural research grant from Fudan-VARI Center for Genetic Epidemiology, Fudan University (to J.X.). This work is partly funded by the National Natural Science Foundation of China (30800946 to H.S.), Foundation for the Author of National Excellent Doctoral Dissertation (201081 to H.S.), the Program for New Century Excellent Talents in University (NCET-10-0178 to H.S.), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (to H.S.).

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Authors and Affiliations

Authors

Contributions

L.Y. and J.X. designed and directed the study. D.-K.J. carried out overall project management. D.-K.J., X.-P.M., H.-X.H., D.W., L.-S.T., B.P., T.-T.L., P. Zhou, B.W. and H.-X.G.S.-Y. managed DNA samples. S.L.Z., D.-K.J., P. Zhang, X.-P.M. and H.-X.H. did genotyping. J.S., Z.W., D.-K.J., H.Y. and Y.Y.S. conducted data analysis. W.J., D.-K.J., X.-P.M. and H.C. did functional analyses. D.-K.J., Z.W., J.X. and L.Y. summarized results. D.-K.J., J.X. and J.S. wrote the manuscript. The following authors from the various collaborating groups carried out assembly of case-control series in their respective regions and collected data and samples: G.C., J.Y. and Hongwei Zhang in Shanghai, Y. Liu, H.S., L.L. and Z.H. in Nanjing; D.L., C.W., J.C. and K.Z. in Beijing; Y.-Z.G. in Suzhou; W.-H.R. and Y.P. in Luoyang; X.-D.L. and Y.-F.Z. in Baise; G.Z., Hongxing Zhang, Y.Z. and X.G. in Fusui; and T.-Y.C. and P.-X.L. in Qidong. The following authors collected partial control subjects in their respective regions: Z.M., Y.G. and A.T. in Guangxi Province. The following authors provided genotype data of typical Chinese population control subjects: X.-J.Z., L.-D.S., X.-B.Z., Y. Li, X.-O.S., W.Z., J.-R.L., Y.X., R.S., F.L., X.L, S.T., Q.D. and J.X. The following authors collected tissue samples of HCC cases: T.-Y.C. and N.-J.W. (major part); L.-X.Q., J.F. and Y.-K.L. (minor part). L.Y., J.X., J.L., Q.Y., D.-K.J. and H.S. obtained funding for the study.

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Correspondence to Jianfeng Xu or Long Yu.

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Jiang, DK., Sun, J., Cao, G. et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma. Nat Genet 45, 72–75 (2013). https://doi.org/10.1038/ng.2483

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