Abstract A60: Prostate cancer susceptibility loci: Results from an admixture mapping study in African American men

There are considerable racial disparities in prostate cancer risk, with 60% more incident cases among African American (AA) men compared with European American (EA) men, and a 2.4 fold higher mortality rate in AA men than in EA men. Recently, Freedman et al. published results from a genome wide admixture mapping study of prostate cancer in 1,597 African American men which detected a susceptibility region on chromosome 8q24 (PNAS 2006;103;14068–14073). Follow-up studies using both admixture and case-control association methods have implicated four independent loci in this region associated with prostate cancer. In the current study, we performed admixture mapping in AA men from two independent case-control studies of prostate cancer. Subjects were genotyped for 1,327 ancestry informative markers across the genome, using a similar marker panel to that used by Freedman et al. Our objective was to confirm the 8q24 ancestry linkage and also identify other genomic regions with disproportionate African ancestry in AA prostate cancer cases. Multiplex genotyping was performed on the Illumina BeadStation using GoldenGate assays. 520 cases and 287 controls were eligible for inclusion in the analyses. The mean estimated individual admixture proportions were 20% European and 80%African. Admixture mapping was performed using ADMIXMAP software, adjusting for age at diagnosis. The most significant observed increase in ancestry occurred at marker rs2141360 on chromosome 7 in both the case-only and case-control analyses, where excess European ancestry was observed (case-only p=0.000004). The linkage region contains the PODXL gene, which was implicated in aggressive prostate cancer risk by Casey et al. (Hum Mol Genet 2006;15:735–741), and the variant most associated with prostate cancer was very rare in the Yoruban population. The most significant observed increase in African ancestry across the genome occurred at rs7729084 on chromosome 5q35 in the case-only analysis (p=0.002), and at marker rs12474977 in the case-control analysis (p=0.004). Note that marker rs12474977 is 646 kb centromeric to marker rs7729084, and the two markers were adjacent to each other on the panel. The marker on Chromosome 8 that was associated with the greatest excess African Ancestry in both the case-only and case-control analyses was rs4367565 (case-only and case-control p=0.02), confirming linkage to the region on chromosome 8q24 detected by Freedman et al. Overall, we were able to confirm the previous findings on 8q24, and identified additional ancestry-linked regions potentially harboring prostate cancer susceptibility loci.