Gene Polymorphisms in Relation to Cancer in Black Women

黑人女性与癌症相关的基因多态性

• 批准号: 8301512
• 负责人: Julie R Palmer
• 金额: $ 58.16万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301512
• 关键词: 16q12; African American; Age; Age at Menarche; Asians; Binding Proteins; Blood specimen; Body mass index; Breast Cancer Genetics; Case-Control Studies; Cohort Studies; DNA; DNA Resequencing; Data; Department of Defense; Diet; Environmental Risk Factor; Epidemiologic Studies; Ethnic group; European; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Grant; Incidence; Intake; Lead; Malignant Neoplasms; Manuscripts; Maps; Meta-Analysis; Modeling; Mouthwash; Mutation; Nested Case-Control Study; Participant; Phenotype; Physical activity; Population; Postmenopause; Premenopause; Protein Binding; Receptor Gene; Reporting; Reproductive History; Risk; Role; Saliva; Sampling; Sampling Studies; Signal Transduction; Skin Pigmentation; Staging; Study Subject; Testing; Time; Variant; Vitamin D; Vitamin D-Binding Protein; Vitamin D2; Vitamin D3 Receptor; Woman; Women' s Health; base; cancer risk; case control; effective intervention; follow-up; gene environment interaction; genetic variant; genome wide association study; genome-wide; improved; intervention program; malignant breast neoplasm; mortality; novel; receptor

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.

描述(由申请者提供)：非裔美国人(AA)女性年轻时乳腺癌发病率较高，所有年龄段的乳腺癌死亡率均高于白人女性，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27,000名黑人妇女健康研究(BWHS)参与者那里获得了含漱口唾液的唾液样本，其中包括1,200例乳腺癌患者。我们使用乳腺癌病例和配对对照的DNA，在EA或亚洲血统人群的全基因组关联扫描(GWA)中，对一组密集的标签SNPs进行了基因分型，以确定与乳腺癌风险相关的遗传基因座。在其中两个区域，5p12和16q12，我们发现了与AA女性乳腺癌相关的新的SNP。我们还对乳腺癌的前5个SNP进行了快速复制，这些SNP来自迄今进行的唯一合作的AA GWA，从而帮助识别出一个新的SNP。在这一竞争的继续中，我们建议通过有针对性地对50名BWHS受试者胚系DNA中的5p12和16q12区域进行重新测序，以确定这些区域中的所有其他突变；然后我们将评估我们整个病例和对照中的每一种新变异与每一种新变异的相关性。我们将通过在BWHS内1200对病例对照的嵌套病例对照研究中，对阶段1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，我们将把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名对照中调查基因-环境与重要的人体测量和生殖因素的相互作用。许多再生障碍性贫血妇女缺乏维生素D。在另一个目的中，我们将在1100个发病病例和2200个匹配的对照组中检查维生素D与乳腺癌发病率的关系。事实证明，基于BMI、体力活动、纬度以及饮食和补充维生素D摄入量的维生素D预测模型在维生素D与癌症的EA研究中很有用。我们建议通过增加关于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来扩展该模型，该模型在AA女性中将是不适当的，因为皮肤色素沉着在决定维生素D水平方面起着主要作用。该预测模型将基于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样本来提高第一个尚未到达月经初潮年龄的AA GWA的能力，通过在3000名BWHS参与者的样本中对1,500个标签SNPs进行基因分型，发现与这种表型相关的变异，这些SNP在月经初潮年龄的第1阶段AA GWA中达到最高显著水平。因此，这项拟议的研究将有助于发现与AA女性乳腺癌和月经初潮年龄相关的基因变异，将首次评估AA女性中重要的潜在基因-环境相互作用，并将提供有关维生素D与AA女性乳腺癌发病率之间关系的新数据。