Understanding the genetic risk underlying racial disparities in uterine fibroids

描述（由研究者提供）：在美国，纤维瘤影响77%的绝经期妇女，每年造成21亿美元的医疗费用。肌瘤对生殖健康产生负面影响，导致月经量大和疼痛，盆腔疼痛和压力，妊娠并发症，以及包括子宫肌瘤切除术和子宫切除术在内的干预措施。直到最近，研究肌瘤生长的肿瘤组织和细胞培养研究一直是了解肌瘤病理生理学的主要来源。遗传分析可以提供一个强大的和具有成本效益的工具，以确定病因和因果因素，特别是因为子宫肌瘤的遗传易感性已经从双胞胎研究中记录下来。高达69%的风险由遗传因素解释。种族差异也支持遗传学与纤维瘤风险的作用。与白人相比，非裔美国妇女的发病年龄更早，肌瘤数量更多，更大，终生发病率更高。我们建议通过对非裔美国人和高加索人参与者进行全基因组关联研究（GWAS），确定肌瘤风险的遗传标记，利用祖先差异缩小基因组区域，以便进行有针对性的随访分析。为了实现这一目标，我们将利用独特的范德比尔特资源，BioVU DNA数据库。BioVU目前有超过122，470名成年人与电子医疗记录相关联。从BioVU，我们已经确定了2，902名符合我们严格的入选标准的非洲裔美国人和白人受试者，以进行肌瘤的GWAS，包括盆腔成像。可用的成像是至关重要的，因为许多患有子宫肌瘤的妇女是无症状的，没有成像，研究可能会错误分类多达51%的妇女。我们还定义了明确的控制谁达到更年期无肌瘤。我们有一个强大的全国知名的纤维瘤研究人员谁将提供超过10,000个样本进行复制。我们的第一个具体目标是进行一个GWAS的常见单核苷酸多态性（SNP）和子宫肌瘤风险之间的关联。采用病例对照设计，我们将对来自BioVU的2，902名女性（1，451名纤维瘤病例和1，451名对照）进行GWAS，按非裔美国人和高加索人种分层。还将进行二次混合物图谱（AM）分析，以确定感兴趣的染色体区域，从而优先进行复制。我们的第二个目标是对从GWAS和AM中鉴定出的染色体区域进行重测序，以发现罕见的变体。最后，在目标3中，我们将在至少3，230例纤维瘤病例和7，097例对照的独立样本中复制从目标1和2中选择的SNP。我们提出了一种有效且具有成本效益的方法，通过利用BioVU提供的成像信息和DNA来识别肌瘤的遗传风险因素。这项研究代表了子宫肌瘤最大的GWAS，也是非洲裔美国人利用新兴技术和新的统计方法进行这项研究的第一项研究。我们提出的研究将从根本上改变有关肌瘤的知识，并为理解肌瘤形成机制和确定新的治疗方法的突破奠定基础。

DESCRIPTION (provided by investigator): Fibroids affect 77% of women by onset of menopause in the U.S. and account for $2.1 billion in healthcare costs each year. Fibroids negatively impact reproductive health causing heavy and painful menses, pelvic pain and pressure, pregnancy complications, and interventions including myomectomy and hysterectomy. Until recently, tumor tissue and cell culture studies investigating fibroid growth have been the primary sources for understanding fibroid pathophysiology. Genetic analysis can provide a powerful and cost effective tool to identify etiological and causal factors, especially since a genetic predisposition to fibroids has already been documented from twin studies. As much as 69% of risk is explained by genetic factors. Racial disparities also support a role for genetics with fibroid risk. African American women have earlier age of onset, more numerous and larger fibroids with a greater lifetime incidence compared to Caucasians. We propose to identify genetic markers for risk of fibroids through a genome-wide association study (GWAS) of African American and Caucasian participants, leveraging ancestral differences to narrow down genomic regions for targeted follow- up analyses. To accomplish this we will take advantage of a unique Vanderbilt resource, the BioVU DNA databank. BioVU currently has over 122,470 adults linked to electronic medical records. From BioVU we have already identified 2,902 African American and Caucasian subjects who meet our stringent inclusion criteria to conduct a GWAS of fibroids, including pelvic imaging. Available imaging is critical, because many women with fibroids are asymptomatic and without imaging, studies may misclassify as many as 51% of women. We have also defined definitive controls who reached menopause without fibroids. We have a strong group of nationally known fibroid researchers who will provide over 10,000 samples for replication. Our first Specific Aim is to conduct a GWAS for association between common single nucleotide polymorphisms (SNPs) and fibroid risk. Using a case-control design we will perform a GWAS in 2,902 (1,451 fibroid cases and 1,451 controls) women from BioVU stratified by African American and Caucasian race. Secondary admixture mapping (AM) analyses will also be performed to identify chromosomal regions of interest to prioritize for replication. Our second Aim is to resequence chromosome regions identified from GWAS and AM to discover rare variants. Finally, in Aim 3 we will replicate SNPs selected from Aim 1 and 2 in independent samples of at least 3,230 fibroid cases and 7,097 controls. We propose an efficient and cost-effective approach to identify genetic risk factors for fibroids, by taking advantage of imaging information and DNA available through BioVU. This study represents the largest GWAS of uterine fibroids and the first among African Americans leveraging emerging technologies and new statistical approaches to conduct this study. Our proposed study will fundamentally change knowledge about fibroids and lay the ground work for breakthroughs in understanding mechanisms of fibroid formation and in identifying novel therapeutic approaches.