Abstract
Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Data-driven translational prostate cancer research: from biomarker discovery to clinical decision
Journal of Translational Medicine Open Access 07 March 2020
-
HNF1B-mediated repression of SLUG is suppressed by EZH2 in aggressive prostate cancer
Oncogene Open Access 21 October 2019
-
Identification of intermediate-sized deletions and inference of their impact on gene expression in a human population
Genome Medicine Open Access 24 July 2019
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).
Amundadottir, L.T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).
Gudmundsson, J. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39, 631–637 (2007).
Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007).
Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645–649 (2007).
Eeles, R.A. et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat. Genet. 40, 316–321 (2008).
Gudmundsson, J. et al. Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer. Nat. Genet. 40, 281–283 (2008).
Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).
Eeles, R.A. et al. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat. Genet. 41, 1116–1121 (2009).
Gudmundsson, J. et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat. Genet. 41, 1122–1126 (2009).
Yeager, M. et al. Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat. Genet. 41, 1055–1057 (2009).
Kote-Jarai, Z. et al. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat. Genet. 43, 785–791 (2011).
Takata, R. et al. Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nat. Genet. 42, 751–754 (2010).
Akamatsu, S. et al. Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese. Nat. Genet. 44, 426–429 (2012).
Haiman, C.A. et al. Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21. Nat. Genet. 43, 570–573 (2011).
Patterson, N., Price, A.L. & Reich, D. Population structure and eigen analysis. PLoS Genet. 2, e190 (2006).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Zheng, W. et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat. Genet. 41, 324–328 (2009).
Zhang, X.J. et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat. Genet. 41, 205–210 (2009).
Yang, T.P. et al. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 26, 2474–2476 (2010).
Dimas, A.S. et al. Common regulatory variation impacts gene expression in a cell type–dependent manner. Science 325, 1246–1250 (2009).
Nica, A.C. et al. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 7, e1002003 (2011).
Torkar, M. et al. Arrangement of the ILT gene cluster: a common null allele of the ILT6 gene results from a 6.7-kbp deletion. Eur. J. Immunol. 30, 3655–3662 (2000).
Hirayasu, K. et al. Evidence for natural selection on leukocyte immunoglobulin-like receptors for HLA class I in Northeast Asians. Am. J. Hum. Genet. 82, 1075–1083 (2008).
Borges, L., Hsu, M.L., Fanger, N., Kubin, M. & Cosman, D. A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J. Immunol. 159, 5192–5196 (1997).
De Marzo, A.M. et al. Inflammation in prostate carcinogenesis. Nat. Rev. Cancer 7, 256–269 (2007).
Liu, F. et al. Systematic confirmation study of reported prostate cancer risk–associated single nucleotide polymorphisms in Chinese men. Cancer Sci. 102, 1916–1920 (2011).
Wang, M. et al. Replication and cumulative effects of GWAS-identified genetic variations for prostate cancer in Asians: a case-control study in the ChinaPCa consortium. Carcinogenesis 33, 356–360 (2012).
Zheng, S.L. et al. Cumulative association of five genetic variants with prostate cancer. N. Engl. J. Med. 358, 910–919 (2008).
Hirayasu, K. et al. Long-term persistence of both functional and non-functional alleles at the leukocyte immunoglobulin-like receptor A3 (LILRA3) locus suggests balancing selection. Hum. Genet. 119, 436–443 (2006).
Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
Acknowledgements
We thank all of the subjects included in this study. This work was partially funded by the National Key Basic Research Program grant 973 (2012CB518300 to Y.S and 2012CB518301 to J.X.), the Key Project of the National Natural Science Foundation of China (81130047 to J.X.), intramural grants from the Fudan University Thousand Talents Program and Huashan Hospital (to J.X.), the US National Institutes of Health (NCI CA129684 to J.X.), the National Natural Science Foundation of China (30945204 to Z.M and 30973009 to D.Y.), the Ministry of Health Special Research Fund for Public Interests (201002007 to L.J.) and the National Science & Technology Pillar Program (2011BAI09B00 to L.J.).
Author information
Authors and Affiliations
Contributions
Y.S., J.X. and Z.M. directed the study, obtained financial support and were responsible for study design, interpretation of results and manuscript writing. D.Y., M.W., F.L. and C.X. recruited study subjects and managed respective project. G.J. performed statistical analyses, summarized results and drafted the manuscript. X.W., Q.S., Z.C., Z.T., J.Q., F.Z., Zhong Wang (affiliation 20), Y.F., D.H., Q. Wei, J. Guo, D.W., Xin Gao, J. Yuan, Gongxian Wang, Y. Xu, Guozeng Wang, H. Yao, P.D., Y.J., M.S., J. Yang, J.O.-Y., H.J., Y. Zhu, S.R., Z.Z., C.Y., Xu Gao, B.D., Z.H., Y.Y., Q. Wu, H.C., P.P., Y. Zheng, X. Zheng, Y. Xiang, J. Gong, R.N. and X.L. recruited subjects and prepared samples. J.L., X.-O.S., W.Z. and X. Zhang provided the allele frequency data from their GWAS populations. H. Yu, Zhong Wang (affiliation 4), S.T., J.F., Jishan Sun and W.L. performed statistical and bioinformatics analyses and carried out experiments. F.W. and H.G. provided samples and information from CAPS. A.H., J.R., Q.D., H.S., L.J., R.S., D.L., Jielin Sun and S.L.Z. coordinated the project. All of the authors reviewed, approved and contributed to the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Tables 1–11 and Supplementary Figures 1–7 (PDF 598 kb)
Rights and permissions
About this article
Cite this article
Xu, J., Mo, Z., Ye, D. et al. Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4. Nat Genet 44, 1231–1235 (2012). https://doi.org/10.1038/ng.2424
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.2424
This article is cited by
-
Inherited risk assessment and its clinical utility for predicting prostate cancer from diagnostic prostate biopsies
Prostate Cancer and Prostatic Diseases (2022)
-
Characterization of LILRB3 and LILRA6 allelic variants in the Japanese population
Journal of Human Genetics (2021)
-
Epidemiology and genomics of prostate cancer in Asian men
Nature Reviews Urology (2021)
-
Data-driven translational prostate cancer research: from biomarker discovery to clinical decision
Journal of Translational Medicine (2020)
-
HNF1B-mediated repression of SLUG is suppressed by EZH2 in aggressive prostate cancer
Oncogene (2020)
