Identification of novel common breast cancer risk variants at the 6q25 locusamong Latinas
Identification of novel common breast cancer risk variants at the 6q25 locusamong Latinas
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DOI：
10.1186/s13058-018-1085-9
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发表时间：
2019-01-14
影响因子：
7.4
通讯作者：
Ziv, Elad
中科院分区：
文献类型：
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作者：
Hoffman, Joshua;Fejerman, Laura;Ziv, Elad
背景
乳腺癌是一种部分可遗传的性状，全基因组关联研究（GWAS）已经确定了180多种与乳腺癌相关的常见基因变异。我们之前在拉丁裔女性中进行了乳腺癌GWAS，并在6q25处确定了一种具有强保护作用的单核苷酸多态性（SNP），其具有保护作用的次要等位基因源自美洲原住民血统。在此，我们报告在一个扩大的拉丁裔女性样本中对6q25位点的精细定位情况。
方法
我们在2385例病例和6416例对照（她们要么是美国拉丁裔女性，要么是墨西哥女性）中进行了GWAS。我们在2412例病例和1620例对照（美国拉丁裔、墨西哥和哥伦比亚女性）中对排名靠前的SNP进行了重复验证。此外，我们在非洲、亚洲和欧洲血统的研究中验证了排名靠前的新型变异。在每个数据集中，我们使用逻辑回归模型来检验SNP与乳腺癌风险之间的关联，并使用主成分分析法或基于模型的方法从祖先信息标记推断出的遗传血统来校正遗传血统。
结果
我们在6q25位点确定了一组新的SNP，其与全基因组显著水平相关（p = 3.3×10⁻⁸ - 6.0×10⁻⁹），且与该位点先前报道的变异不存在连锁不平衡（LD）。这些SNP彼此之间处于高度连锁不平衡（r²>0.9），其中排名最靠前的SNP rs3778609与乳腺癌相关，优势比（OR）和95%置信区间（95%CI）为0.76（0.70 - 0.84）。在对拉丁美洲裔女性的重复验证中，我们也观察到了一致的效应（OR 0.88；95%CI 0.78 - 0.99；p = 0.037）。我们还对东亚人、非洲血统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应（rs3778609，OR 0.95；95%CI 0.91 - 0.97；p = 0.0017）。
结论
我们的研究进一步证明了6q25位点对乳腺癌易感性的重要性。我们的发现也凸显了在非欧洲人群中进一步寻找乳腺癌基因变异的实用性。
BackgroundBreast 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.MethodsWe performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPsin 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.ResultsWe identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p=3.3x10(-8) - 6.0x10(-9)) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r(2)>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).ConclusionOur 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.