Polymorphisms in the TOX3/LOC643714 locus and risk of breast cancer in African-American women

Abstract

Background: The rs3803662 single nucleotide polymorphism (SNP) in the TOX3/LOC643714 region was identified as a breast cancer susceptibility genetic variant in recent genome-wide association studies of women of European ancestry and has been replicated in other populations of European ancestry. The position of the causal variant tagged by the rs3803662 marker is still unknown. In fact, because the rs3803662 polymorphism is located between the TOX3 and the LOC643714 loci, it is unclear which gene is the one causally related to the risk of breast cancer. Because linkage disequilibrium blocks are smaller in populations of African ancestry, fine-mapping in African ancestry samples might be an effective approach to narrowing the position of the causal variant(s) in the TOX3/LOC643714 locus.

Methods: We evaluated a total of 60 tagging SNPs throughout the TOX3/LOC643714 region in a nested case-control study of breast cancer within the Black Women's Health Study, which included 906 cases and 1,111 controls.

Results: No significant association was found for the rs3803662 SNP. However, four other SNPs (rs3104746, rs3112562, rs3104793, and rs8046994), all of them located in the LOC643714 gene, were associated with risk of breast cancer. The strongest association was observed for rs3104746: each copy of the A-rs3104746 allele was associated with a 23% higher risk of breast cancer (odds ratios, 1.23; 95% confidence intervals, 1.05-1.44; P=0.009).

Conclusions: Our results confirm the association observed in genome-wide association studies of European ancestry populations.

Impact: The results narrow the locus to a smaller linkage disequilibrium block in the LOC643714 gene.

Figure 1. Linkage disequilibrium (LD) structure of the TOX3/LOC643714 region in HapMap CEU and YRI populations

LD structure was assessed using linkage disequilibrium units (LDU) estimated with the SNPBrowser software (25). LDU are proportional to the decay of LD along the physical distance. Regions of constant (‘flat’) LDU represent LD blocks. Note that the big block (from 51.09 Mb to 51.18 Mb) that covers parts of the TOX3 and LOC643714 genes in HapMap CEU population and it is split into smaller blocks and gaps in the HapMapYRI population.

Figure 2. Scatterplot and LD map of the genotyped tagging SNPs along the TOX3/LOC643714 region

The four tagging SNPs associated with risk of breast cancer in the BWHS population are located in the LOC643714 locus. The position of the previously reported rs3803662 is also indicated. The dotted line indicates the threshold of significance for alpha = 0.05.