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

在亚洲人已知的乳腺癌风险位点中寻找新的风险变异

• 批准号: 9248748
• 负责人: Jirong Long
• 金额: $ 4.96万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248748
• 关键词: Searching; new; risk; variants; known

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.

描述（由申请人提供）：乳腺癌是一种复杂的多因素疾病，遗传因素在其病因学中发挥着重要作用。迄今为止，全基因组关联研究 (GWAS) 已发现大约 67 个常见的乳腺癌风险遗传易感位点。然而，除了少数基因座外，所有其他基因座最初都是在欧洲血统女性中进行的研究中发现的。迄今为止报道的 67 个指数 SNP 中，只有大约一半可以在亚洲人身上直接复制。考虑到不同种族人群遗传结构的差异，我们假设亚洲血统人群中的一些位点可能存在不同的风险变异，而这些位点的索引 SNP 并未在亚洲人中复制。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异，因为千人基因组计划中的数据具有更密集的 SNP，尤其是低等位基因频率的 SNP 和更大的样本量。在过去几年中，我们使用 Affymetrix 6.0 SNP 芯片对约 9,400 例亚洲血统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来估算这些样本的数据，以评估 10 个乳腺癌位点，其中索引 SNP 未在亚洲人中复制。有前景的 SNP 将在 8,400 个亚洲血统的独立病例和对照中进行进一步研究。凭借强大的方法论和极具成本效益的研究设计，我们预计将在亚洲血统人群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，从而有针对性地预防乳腺癌。