Large-scale fine mapping of the HNF1B locus and prostate cancer risk.
Berndt SI., Sampson J., Yeager M., Jacobs KB., Wang Z., Hutchinson A., Chung C., Orr N., Wacholder S., Chatterjee N., Yu K., Kraft P., Feigelson HS., Thun MJ., Diver WR., Albanes D., Virtamo J., Weinstein S., Schumacher FR., Cancel-Tassin G., Cussenot O., Valeri A., Andriole GL., Crawford ED., Haiman C., Henderson B., Kolonel L., Le Marchand L., Siddiq A., Riboli E., Travis RC., Kaaks R., Isaacs W., Isaacs S., Wiley KE., Gronberg H., Wiklund F., Stattin P., Xu J., Zheng SL., Sun J., Vatten LJ., Hveem K., Njølstad I., Gerhard DS., Tucker M., Hayes RB., Hoover RN., Fraumeni JF., Hunter DJ., Thomas G., Chanock SJ.
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.