Gene Polymorphisms in Relation to Cancer in Black Women

描述（由申请人提供）： 非裔美国人（AA）妇女在年轻时患乳腺癌的发病率较高，在所有年龄段的乳腺癌死亡率均高于白色妇女，但在遗传病因学方面研究不足。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，我们成功地从大约27，000名黑人妇女健康研究（BWHS）参与者中获得了漱口水唾液样本，其中包括1，200例乳腺癌病例。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一组密集tagSNPs进行基因分型。在其中两个区域，5 p12和16 q12，我们发现了与AA女性乳腺癌相关的新SNP。我们还对来自唯一一个合作的乳腺癌AA GWAS的前5个SNP进行了快速复制，从而帮助鉴定一种新的SNP。在这个竞争性的延续中，我们建议通过对50名BWHS受试者的生殖系DNA中的5 p12和16 q12区域进行靶向重测序来跟踪我们的BWHS发现，以确定该区域中的所有其他突变;然后我们将评估与我们整个病例和对照组中每个新变体的关联。我们将通过在BWHS内的1，200个病例对照对的嵌套病例对照研究中对第1阶段中具有最低p值的1，500个SNP进行基因分型，来增加协作AA GWAS发现与乳腺癌相关的变异的能力。然后，我们将联合收割机将这些发现与我们的观察数据相结合，在1,100例乳腺癌病例和2,200例对照中研究基因-环境相互作用与重要的人体测量和生殖因素。许多AA女性缺乏维生素D。在另一个目标中，我们将研究维生素D与乳腺癌发病率的关系，在1100例发病病例和2200例匹配对照中。基于BMI、体力活动、纬度和膳食和补充维生素D摄入量的维生素D预测模型已被证明在维生素D和癌症的EA研究中是有用的。我们建议扩展该模型，这将是不充分的AA妇女，因为皮肤色素沉着的主要作用，在确定维生素D水平，通过增加皮肤色素沉着基因和维生素D受体和结合蛋白基因的数据。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的功效，以通过在3000名BWHS参与者的样本中对在初潮年龄的第1阶段AA GWAS中达到最高显著性水平的1，500个tagSNP进行基因分型来发现与该表型相关的变体。因此，拟议的研究将有助于发现与AA女性的乳腺癌和初潮年龄相关的遗传变异，将对AA女性重要的潜在基因-环境相互作用进行首次评估，并将提供关于维生素D与AA女性乳腺癌发病率相关性的新数据。

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.