Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12

Abstract

We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 x 10(-9) for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.

Figure 1. A schematic view of genetic association between SNPs at 17q12 and prostate cancer risk in two study populations

(a) Combined allele tests for 64 SNPs at 17q12 and prostate cancer risk among a total of 4,456 prostate cancer cases and 2,357 controls from a population-based case-control study in CAPS and JHH. Two separate clusters of prostate cancer associated SNPs were found (red dotted boxes). (b) Inferred haplotype blocks of these 64 SNPs were estimated from the control subjects in CAPS and JHH using the Haploview computer program. These two loci were in different haplotype blocks. (c) Recombination hotspot estimated using 18 consecutive SNPs (bounded by rs4430796 at the first locus and rs11649743 at the second locus) among control subjects of CAPS and JHH using SequenceLDhot software. Strong evidence for a recombination hotspot between the two loci was found (green dotted box). (d) Genomic view at 17q12 where the only gene (HNF1B) in this region is shown.