Searching for new risk variants in known breast cancer risk loci in Asians

描述（由申请人提供）：遗传因素在乳腺癌的病因学中起重要作用，乳腺癌是一种复杂的多因素疾病。迄今为止，全基因组关联研究（GWAS）已经发现了大约67个常见的乳腺癌风险遗传易感性位点。然而，除了少数几个位点外，所有其他位点最初都是在欧洲血统的妇女中进行的研究中确定的。在迄今为止报道的67个索引SNP中，只有大约一半可以在亚洲人中直接复制。考虑到不同种族人群的遗传结构差异，我们假设亚洲血统人群中可能存在不同的风险变异，这些变异存在于一些索引SNP未在亚洲人中复制的位点。多项研究表明，基于千人基因组计划数据的插补比基于HapMap数据的插补提供了更好的机会来识别新的风险变体，因为千人基因组计划中的数据具有更密集的SNP，特别是低等位基因频率SNP，并且样本量更大。在过去的几年中，我们使用Affysse6.0 SNP阵列对约9，400例亚洲血统的乳腺癌病例和对照进行了基因分型。我们建议使用最新的1，000个基因组计划数据作为参考，对这些样本的数据进行插补，以评估10个乳腺癌基因座，其中索引SNP在亚洲人中没有复制。有希望的SNP将在一组独立的8,400例亚洲血统的病例和对照中进一步研究。凭借强大的方法学和非常具有成本效益的研究设计，我们预计将在亚洲血统人群中的这些基因座中鉴定出新的遗传变异。这些新发现的变异可以显着提高我们对乳腺癌遗传学和生物学的理解，并可用于癌症筛查和风险评估，旨在识别高风险女性进行有针对性的乳腺癌预防。

DESCRIPTION (provided by applicant): Genetic factors play an important role in the etiology of breast cancer, a complex, multifactorial disease. To date, genome-wide association studies (GWAS) have discovered approximately 67 common genetic susceptibility loci for breast cancer risk. However, with the exception of a few loci, all others were identified initially in studies conducted among women of European ancestry. Among the 67 index SNPs reported to date, only about a half of them could be directly replicated in Asians. Given differences in genetic architecture across different ethnic populations, we hypothesize that different risk variants may exist in Asian-ancestry populations in some of the loci in which the index SNPs were not replicated in Asians. Multiple studies have showed that imputation based on the 1000 Genomes Project data provides better chance to identify novel risk variants than that based on the HapMap data since data in the 1000 Genomes Project have much denser SNPs especially low allele frequency SNPs and a larger sample size. Over the past few years, we have genotyped ~9,400 breast cancer cases and controls of Asian ancestry using Affymetrix 6.0 SNP arrays. We propose to impute data for these samples using the most recent 1,000 Genomes Project data as reference to evaluate 10 breast cancer loci in which the index SNPs were not replicated in Asians. Promising SNPs will be further investigated in an independent set of 8,400 cases and controls of Asian ancestry. With strong methodology and very cost- efficient study design, we anticipate that novel genetic variants will be identified in these loci in Asian ancestry populations. These newly-identified variants could significantly improve our understanding of breast cancer genetics and biology and could be used for cancer screening and risk assessment aimed at identifying high- risk women for targeted breast cancer prevention.