Fine-mapping and family-based association analyses of prostate cancer risk variants at Xp11.
Lu L, Sun J, Isaacs SD, Wiley KE, Smith S, Pruett K, Zhu Y, Zhang Z, Wiklund F, Grönberg H, Walsh PC, Chang BL, Zheng SL, Isaacs WB, Xu J
Two single nucleotide polymorphisms (SNP; rs5945572 and rs5945619) at Xp11 were recently implicated in two genome-wide association studies of prostate cancer. Using a family-based association test for these two SNPs in 168 families with prostate cancer, we showed in this study that the risk alleles of the two reported SNPs were overtransmitted to the affected offspring (P= 0.009 for rs5945372 and P = 0.03 for rs5945619), which suggested that the observed association in case-control studies were not driven by potential population stratification. We also did a fine-mapping study in the approximately 800 kb region at Xp11 between two independent case-control studies, including 1,527 cases and 482 controls from Johns Hopkins Hospital and 1,172 cases and 1,157 controls from the Prostate, Lung, Colon and Ovarian Cancer screening trial. The strongest association was found with SNPs in the haplotype block in which the two initial reported SNPs were located, although many SNPs in the approximately 140 kb region were highly significant in the combined allelic tests (P = 10(-5) to 10(-6)). The second strongest association was observed with SNPs in the approximately 286 kb region at another haplotype block (P = 10(-4) to 10(-5)), approximately 94 kb centromeric to the first region. The significance of SNPs in the second region decreased considerably after adjusting for SNPs at the first region, although P values remained at <0.05. Additional studies are warranted to test independent prostate cancer associations at these two regions.