Characterizing Genetic Risk at Known Prostate Cancer Susceptibility Loci in African Americans

Abstract

GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p≤0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p≤6×10⁻⁴) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry. Prostate cancer is one of the most common cancers in men and is especially frequent in men of African origin, as incidence rates in African Americans in the United States are >1.5–fold greater than rates in European Americans. In order to gain a more complete understanding of the genetic basis of inherited susceptibility to prostate cancer in men of African origin, we examined the associations at risk loci identified in men of European and Asian descent in a large African American sample of 3,425 cases of prostate cancer and 3,290 male controls. In testing 49 known risk variants, we were able to demonstrate that at least half of these variants also contribute to risk in African American men. We were able to find additional risk variants in many of the previously reported regions that better captured the pattern of risk in African American men. In addition, we verified and improved upon the evidence we previously reported that there are multiple risk variants in a region of 8q24 that are important in men of African origin.