Gene Polymorphisms in Relation to Cancer in Black Women

描述（由申请人提供）：非裔美国人（AA）女性在年轻时的乳腺癌发病率和所有年龄段的乳腺癌死亡率都高于白人女性，但在遗传病因方面研究不足。乳腺癌遗传学的流行病学研究主要集中在欧洲血统（EA）人群。在目前的资助下，我们成功地从约27,000名黑人妇女健康研究（BWHS）参与者中获得了漱口时的唾液样本，其中包括1,200名乳腺癌病例。我们使用来自乳腺癌病例和匹配对照的DNA，对EA或亚洲血统人群的全基因组关联扫描（GWAS）中与乳腺癌风险相关的遗传位点的密集标记snp进行基因分型。在其中两个区域5p12和16q12中，我们发现了与AA女性乳腺癌相关的新snp。我们还对迄今为止唯一的乳腺癌合作AA GWAS的前5个SNP进行了快速复制，从而帮助鉴定了一个新的SNP。在这一竞争的延续中，我们建议通过对50名BWHS受试者的种系DNA中的5p12和16q12区域进行靶向重测序来跟踪我们的BWHS发现，以确定该区域的所有其他突变；然后，我们将在我们的整个病例和对照集中评估与每个新变体的关联。我们将在BWHS内1200对病例对照的巢式病例对照研究中，通过对1期最低p值的1500个snp进行基因分型，提高协作AA GWAS发现与乳腺癌相关变异的能力。然后，我们将这些发现与我们的观察数据结合起来，在1100例乳腺癌病例和2200例对照中调查基因-环境与重要人体测量和生殖因素的相互作用。许多AA女性缺乏维生素D。另一个目的是，我们将在1100例乳腺癌病例和2200例对照病例中研究维生素D与乳腺癌发病率的关系。一个基于身体质量指数、身体活动、纬度、饮食和补充维生素D摄入量的维生素D预测模型在维生素D和癌症的EA研究中被证明是有用的。由于皮肤色素沉着在决定维生素D水平中起主要作用，我们建议通过添加皮肤色素沉着基因和维生素D受体及结合蛋白基因的数据来扩展该模型，该模型在AA女性中并不适用。该预测模型将基于来自BWHS参与者的520份血液样本进行开发和验证。在我们的最终目标中，我们将使用BWHS样本来提高初潮年龄的第一个AA GWAS的能力，通过对3000名BWHS参与者的样本进行基因分型，发现与该表型相关的变异，其中1500个标签snp在初潮年龄的1期AA GWAS中达到了最高的显著性水平。因此，本研究将有助于发现AA女性中与乳腺癌和月经初潮年龄相关的遗传变异，将首次评估AA女性中重要的潜在基因-环境相互作用，并将为维生素D与AA女性乳腺癌发病率之间的关系提供新的数据。

DESCRIPTION (provided by applicant): African American (AA) women have a higher incidence of breast cancer at young ages and higher mortality from breast cancer at all ages than white women, but are understudied with regard to the genetic etiology. Epidemiologic studies of the genetics of breast cancer have largely focused on European ancestry (EA) populations. Under the current grant, we successfully obtained mouthwash-swish saliva samples from ~27,000 Black Women's Health Study (BWHS) participants, including 1,200 breast cancer cases. We used DNA from breast cancer cases and matched controls to genotype a dense set of tagSNPs for genetic loci that had been associated with breast cancer risk in genome-wide association scans (GWAS) of EA or Asian ancestry populations. In two of those regions, 5p12 and 16q12, we identified new SNPs associated with breast cancer in AA women. We also carried out fast-track replication of the top 5 SNPs from the only collaborative AA GWAS of breast cancer yet conducted, thus helping to identify a novel SNP. In this competing continuation, we propose to follow up our BWHS findings by targeted resequencing of the 5p12 and 16q12 regions in germline DNA from 50 BWHS subjects to identify all other mutations in the regions; we will then assess associations with each of the new variants in our entire set of cases and controls. We will increase the power of the collaborative AA GWAS to discover variants associated with breast cancer by genotyping the 1,500 SNPs with lowest p-values in Stage 1 in a nested case-control study of 1,200 case-control pairs within the BWHS. We will then combine these findings with our observational data to investigate gene-environment interactions with important anthropometric and reproductive factors in 1,100 incident breast cancer cases and 2,200 controls. Many AA women are vitamin D deficient. In another aim, we will examine the relation of vitamin D to incidence of breast cancer in the 1100 incident cases and their 2200 matched controls. A prediction model for vitamin D based on BMI, physical activity, latitude and dietary and supplemental vitamin D intake has proved useful in EA studies of vitamin D and cancer. We propose to extend the model, which would be inadequate in AA women because of the major role of skin pigmentation in determining vitamin D levels, by adding data on skin pigmentation genes and vitamin D receptor and binding protein genes. The prediction model will be developed and validated based on 520 blood samples from BWHS participants. In our final aim, we will use BWHS samples to improve power of the first yet AA GWAS of age at menarche to discover variants associated with this phenotype by genotyping in a sample of 3000 BWHS participants the 1,500 tagSNPs that achieved the highest significance levels in a Stage 1 AA GWAS of age at menarche. Thus, the proposed study will aid discovery of genetic variants associated with breast cancer and age at menarche in AA women, will carry out the first assessment of important potential gene-environment interactions in AA women, and will provide novel data on the association of vitamin D with breast cancer incidence in AA women. PUBLIC HEALTH RELEVANCE: Breast cancer incidence is disproportionately high among young African American women compared with other ethnic groups, and breast cancer mortality is highest in African Americans at all ages. The proposed study seeks to identify genetic factors that are causally related to breast cancer risk in African Americans and to study the interactions of these genetic factors with environmental factors. Findings may lead to more effective intervention programs and better treatments.