Slone Epidemiology Center at Boston University, Department of Epidemiology, School of Public Health, 1010 Commonwealth Avenue, Boston MA 02215, USA.
Cancer Epidemiol Biomarkers Prev. 2010 May;19(5):1320-7. doi: 10.1158/1055-9965.EPI-09-1250. Epub 2010 Apr 20.
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.
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.
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).
Our results confirm the association observed in genome-wide association studies of European ancestry populations.
The results narrow the locus to a smaller linkage disequilibrium block in the LOC643714 gene.
最近的全基因组关联研究发现，位于 TOX3/LOC643714 区域的 rs3803662 单核苷酸多态性（SNP）是欧洲裔女性乳腺癌易感性的遗传变异，并在其他欧洲裔人群中得到了复制。但由 rs3803662 标记物标记的因果变异的位置仍然未知。事实上，由于 rs3803662 多态性位于 TOX3 和 LOC643714 基因座之间，因此不清楚哪个基因与乳腺癌风险有因果关系。由于非洲裔人群中的连锁不平衡块较小，因此在非洲裔人群样本中进行精细定位可能是缩小 TOX3/LOC643714 基因座中因果变异位置的有效方法。
我们在黑人妇女健康研究的乳腺癌巢式病例对照研究中评估了 TOX3/LOC643714 区域内的总共 60 个标记 SNP，该研究包括 906 例病例和 1111 例对照。
未发现 rs3803662 SNP 存在显著关联。然而，另外四个 SNP(rs3104746、rs3112562、rs3104793 和 rs8046994)，均位于 LOC643714 基因中，与乳腺癌风险相关。rs3104746 观察到的相关性最强：每个 A-rs3104746 等位基因的拷贝与乳腺癌风险增加 23%相关（比值比，1.23；95%置信区间，1.05-1.44；P=0.009）。
我们的结果证实了在欧洲裔人群的全基因组关联研究中观察到的关联。
研究结果将该基因座缩小到 LOC643714 基因中较小的连锁不平衡块。
