鉴定拉丁裔人群中 6q25 位点的新型常见乳腺癌风险变异。
Identification of novel common breast cancer risk variants at the 6q25 locus among Latinas.
机构信息
Department of Epidemiology and Biostatistics, Institute of Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Division of General Internal Medicine, Department of Medicine, Institute of Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, Box 0320, San Francisco, CA, 94143, USA.
出版信息
Breast Cancer Res. 2019 Jan 14;21(1):3. doi: 10.1186/s13058-018-1085-9.
BACKGROUND
Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas.
METHODS
We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach.
RESULTS
We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10 - 6.0 × 10) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017).
CONCLUSION
Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.
背景
乳腺癌是一种部分遗传性特征，全基因组关联研究（GWAS）已经确定了 180 多个与乳腺癌相关的常见遗传变异。我们之前在拉丁裔人群中进行了乳腺癌 GWAS，并在 6q25 上发现了一个强烈的保护性单核苷酸多态性（SNP），保护性的次要等位基因源自美洲原住民的祖先。在这里，我们报告了在扩大的拉丁裔样本中对 6q25 基因座的精细定位。
方法
我们在 2385 例病例和 6416 例对照中进行了 GWAS，这些病例和对照要么是美国拉丁裔，要么是墨西哥女性。我们在 2412 例美国拉丁裔、墨西哥和哥伦比亚女性病例和 1620 例对照中复制了顶级 SNP。此外，我们在非洲、亚洲和欧洲血统的研究中验证了顶级新型变体。在每个数据集，我们使用逻辑回归模型来检测 SNP 与乳腺癌风险之间的关联，并使用基于模型的方法使用主成分或遗传祖先推断的遗传祖先来校正遗传祖先。
结果
我们在 6q25 基因座发现了一组新的 SNP，与全基因组水平的显著性相关（p=3.3×10 - 6.0×10），与之前报道的该基因座的变异无连锁不平衡（LD）。这些 SNP 彼此之间高度 LD（r>0.9），其中顶级 SNP rs3778609 与乳腺癌相关，其比值比（OR）和 95%置信区间（95%CI）为 0.76（0.70-0.84）。在拉丁裔女性的复制中，我们也观察到了一致的效果（OR 0.88；95%CI 0.78-0.99；p=0.037）。我们还对东亚、非洲和欧洲血统人群中的这些 SNP 进行了荟萃分析，也观察到了一致的效果（rs3778609，OR 0.95；95%CI 0.91-0.97；p=0.0017）。
结论
我们的研究增加了关于 6q25 基因座对乳腺癌易感性重要性的证据。我们的发现还突出了在非欧洲人群中进行乳腺癌遗传变异的额外搜索的效用。
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