Genetic Admixture Study of Uterine Fibroids in African American Women

非裔美国女性子宫肌瘤的基因混合研究

• 批准号: 7996066
• 负责人: LAUREN A WISE
• 金额: $ 59.27万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996066
• 关键词: Accounting; Admixture; African; African American; Age; American; Behavior; Biological Assay; Chromosome Mapping; Collection; DNA; Data; Data Analyses; Data Collection; Data Reporting; Diagnosis; Disease; Disease Association; Environmental Risk Factor; European; Family; Fibroid Tumor; Frequencies; Genes; Genetic; Genome; Genome Scan; Genotype; Grant; Gynecologic; Health; Health Care Costs; Hysterectomy; Incidence; Infertility; Maps; Medical History; Medical Records; Menorrhagia; Methods; Morbidity - disease rate; National Institute of Environmental Health Sciences; Participant; Patient Self-Report; Pelvic Pain; Phenotype; Population; Prostate; Public Health; Questionnaires; Relative (related person); Reporting; Reproductive History; Research Personnel; Risk Factors; Sampling; Scanning; Screening procedure; Severity of illness; Source; Symptoms; Testing; Time; Ultrasonography; Uterine Fibroids; Variant; Woman; Women' s Health; aged; case control; clinically relevant; clinically significant; cost; density; follow-up; genetic resource; genetic risk factor; genetic variant; genome wide association study; genome-wide; high risk; lifestyle factors; medically underserved; prospective; reproductive; tumor; validation studies

DESCRIPTION (provided by applicant): Uterine leiomyomata (UL), or fibroids, are a major source of gynecologic morbidity among reproductive-aged women. Relative to white women, black women are 2-3 times more likely to be diagnosed with UL, develop tumors at earlier ages, and have more severe disease at the time of diagnosis. Differences in environmental risk factors and screening behaviors do not explain this racial disparity. Using DNA from the Black Women's Health Study (BWHS), a nationwide follow-up study of 59,000 African American women begun in 1995, we propose to conduct genome-wide assays to identify genetic variants associated with clinically relevant UL. On follow-up questionnaires completed in 1997, 1999, 2001, 2003, and 2005, BWHS participants have reported data on the occurrence of incident UL and on a wide range of UL risk factors. A validation study of UL in the BWHS has demonstrated high accuracy of self-report (>96%). DNA samples have been obtained from over 26,000 BWHS participants, including 2,500 incident cases of UL. We propose to first use admixture mapping of 2,500 UL cases to find genes associated with UL that differ greatly in frequency across European and African populations. Admixture mapping has more power than linkage mapping in families to find genes of moderate effect. It is less expensive per sample than whole-genome association but has similar power to detect variants that differ across populations. Fine mapping in additional cases and matched controls, will be carried out if genome-wide suggestive or significant peaks are detected. If no such peaks are detected, we will carry out a whole-genome scan for UL genes in 768 UL cases and matched controls to detect variants that are not highly differentiated in frequency between African and European populations. Because gene-disease associations may be stronger among younger cases and those with greater symptomatology (markers of disease severity), we will prioritize the selection of younger surgically-confirmed cases. The controls will be restricted to those who reported a recent ultrasound (<5 years ago). Genes associated with UL in the BWHS will be tested in the NIEHS Fibroid Study to assess the robustness of our findings. The large number of incident UL cases in the BWHS will provide high statistical power. The study can be carried out at relatively low cost because the follow-up of BWHS participants and data collection, including the collection of DNA samples, are supported by other grants. The high incidence of UL in black women is a problem of major public health importance. The proposed study may identify genetic risk factors for UL that contribute to the large excess of the disease among black women. PUBLIC HEALTH RELEVANCE: Uterine leiomyomata (UL), or fibroids, are a major source of gynecologic morbidity among black women and account for more than $2.1 billion in U.S. health care costs each year. Using data from the Black Women's Health Study, a large prospective follow-up study of African American women, we propose to carry out genome-wide assays to identify genes that might contribute to the occurrence of clinically relevant UL in black women. The proposed study has great potential to help explain the excess incidence of UL among African American women.

描述（由申请人提供）：子宫平滑肌瘤（UL）或肌瘤是育龄妇女妇科发病的主要来源。相对于白人女性，黑人女性被诊断患有 UL 的可能性高出 2-3 倍，她们患肿瘤的年龄更早，并且在诊断时患有更严重的疾病。环境风险因素和筛查行为的差异并不能解释这种种族差异。黑人女性健康研究 (BWHS) 是一项于 1995 年开始的全国性跟踪研究，对 59,000 名非裔美国女性进行了研究，我们利用该研究中的 DNA 进行全基因组检测，以识别与临床相关 UL 相关的遗传变异。在 1997 年、1999 年、2001 年、2003 年和 2005 年完成的后续调查问卷中，BWHS 参与者报告了有关 UL 事件发生和各种 UL 风险因素的数据。 BWHS 中的 UL 验证研究表明自我报告的准确性很高 (>96%)。 DNA 样本已从 26,000 多名 BWHS 参与者中获取，其中包括 2,500 例 UL 事件病例。我们建议首先使用 2,500 个 UL 病例的混合作图来寻找与 UL 相关的基因，这些基因在欧洲和非洲人群中频率差异很大。混合作图比家族中的连锁作图更能找到具有中等影响的基因。每个样本的成本比全基因组关联要便宜，但检测不同人群之间差异的变异的能力相似。如果检测到全基因组暗示或显着的峰值，将在其他病例和匹配的对照中进行精细绘图。如果没有检测到这样的峰值，我们将对 768 个 UL 病例和匹配对照中的 UL 基因进行全基因组扫描，以检测非洲和欧洲人群之间频率没有高度差异的变异。由于基因与疾病的关联在年轻病例和症状（疾病严重程度标志）较多的病例中可能更强，因此我们将优先选择年轻的手术确诊病例。对照将仅限于那些最近报告过超声检查（<5 年前）的人。 BWHS 中与 UL 相关的基因将在 NIEHS 纤维瘤研究中进行测试，以评估我们研究结果的稳健性。 BWHS 中大量的 UL 事件案例将提供较高的统计功效。这项研究可以以相对较低的成本进行，因为 BWHS 参与者的后续行动和数据收集（包括 DNA 样本的收集）得到了其他资助的支持。黑人女性 UL 的高发病率是一个具有重大公共卫生意义的问题。拟议的研究可能会确定 UL 的遗传风险因素，这些因素导致黑人女性中该疾病大量发生。公共健康相关性：子宫平滑肌瘤 (UL) 或肌瘤是黑人女性妇科发病的一个主要来源，每年在美国医疗保健费用中所占的费用超过 21 亿美元。利用黑人妇女健康研究（一项针对非裔美国妇女的大型前瞻性随访研究）的数据，我们建议进行全基因组分析，以确定可能导致黑人妇女发生临床相关 UL 的基因。这项研究很有可能有助于解释非洲裔美国女性 UL 发病率过高的原因。