Large-scale fine mapping of the HNF1B locus and prostate cancer risk

Sonja I. Berndt, Joshua Sampson, Meredith Yeager, Kevin B. Jacobs, Zhaoming Wang, Amy Hutchinson, Charles Chung, Nick Orr, Sholom Wacholder, Nilanjan Chatterjee, Kai Yu, Peter Kraft, Heather Spencer Feigelson, Michael J. Thun, W. Ryan Diver, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Fredrick R. Schumacher, Geraldine Cancel-tassinOlivier Cussenot, Antoine Valeri, Gerald L. Andriole, E. David Crawford, Christopher Haiman, Brian Henderson, Laurence Kolonel, Loic Le marchand, Afshan Siddiq, Elio Riboli, Ruth C. Travis, Rudolf Kaaks, William Isaacs, Sarah Isaacs, Kathleen E. Wiley, Henrik Gronberg, Fredrik Wiklund, Pär Stattin, Jianfeng Xu, S. Lilly Zheng, Jielin Sun, Lars J. Vatten, Kristian Hveem, Inger Njølstad, Daniela S. Gerhard, Margaret Tucker, Richard B. Hayes, Robert N. Hoover, Joseph F. Fraumeni, David J. Hunter, Gilles Thomas, Stephen J. Chanock

Research output: Contribution to journalArticle

Abstract

Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10 -8 with the most significant association with rs4430796 (P = 1.62 × 10 -24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r 2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10 -23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10 -8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10 -10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.

Original languageEnglish (US)
Article numberddr213
Pages (from-to)3322-3329
Number of pages8
JournalHuman molecular genetics
Volume20
Issue number16
DOIs
StatePublished - Aug 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Berndt, S. I., Sampson, J., Yeager, M., Jacobs, K. B., Wang, Z., Hutchinson, A., Chung, C., Orr, N., Wacholder, S., Chatterjee, N., Yu, K., Kraft, P., Feigelson, H. S., Thun, M. J., Diver, W. R., Albanes, D., Virtamo, J., Weinstein, S., Schumacher, F. R., ... Chanock, S. J. (2011). Large-scale fine mapping of the HNF1B locus and prostate cancer risk. Human molecular genetics, 20(16), 3322-3329. [ddr213]. https://doi.org/10.1093/hmg/ddr213