Genetic Admixture Study of Uterine Fibroids in 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疾病的主要来源。相对于白色女性，黑人女性被诊断为UL的可能性高2-3倍，在较早的年龄发生肿瘤，并且在诊断时具有更严重的疾病。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。使用来自黑人妇女健康研究（BWHS）的DNA，这是一项于1995年开始的对59，000名非洲裔美国妇女的全国性随访研究，我们建议进行全基因组测定以识别与临床相关UL相关的遗传变异。在1997年、1999年、2001年、2003年和2005年完成的后续问卷调查中，BWHS参与者报告了关于UL事件发生率和广泛的UL风险因素的数据。UL在BWHS中的验证研究表明自我报告的准确性很高（>96%）。已从26，000多名BWHS参与者中获得DNA样本，其中包括2，500起UL事件。我们建议首先使用2,500例UL病例的混合图谱来寻找与UL相关的基因，这些基因在欧洲和非洲人群中的频率差异很大。在家系中，混合作图比连锁作图更能发现中等效应基因。它比全基因组关联每个样本更便宜，但在检测不同人群的变异方面具有相似的能力。如果检测到全基因组提示性或显著性峰，将在其他病例和匹配对照中进行精细定位。如果没有检测到这样的峰值，我们将对768例UL病例和匹配对照的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差异不高的变异。由于基因-疾病关联在年轻病例和具有更高病理学（疾病严重程度的标志物）的病例中可能更强，我们将优先选择年轻的经病理学证实的病例。对照组仅限于报告近期超声检查（<5年前）的患者。将在NIEHS子宫肌瘤研究中检测与BWHS中UL相关的基因，以评估我们发现的稳健性。BWHS中的大量事件UL案例将提供高统计功效。这项研究可以以相对较低的费用进行，因为对BWHS参与者的后续行动和数据收集，包括DNA样本的收集，得到了其他赠款的支持。黑人妇女UL的高发病率是一个具有重大公共卫生意义的问题。这项拟议中的研究可能会确定导致黑人妇女中大量患病的UL遗传风险因素。公共卫生相关性：子宫平滑肌瘤（UL）或肌瘤是黑人妇女妇科疾病的主要来源，每年在美国医疗保健费用中占21亿美元以上。使用数据从黑人妇女的健康研究，一个大型的前瞻性后续研究的非洲裔美国妇女，我们建议进行全基因组检测，以确定基因，可能有助于发生临床相关的UL在黑人妇女。这项研究有很大的潜力，以帮助解释非裔美国妇女的UL发病率过高。

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.