Understanding the genetic risk underlying racial disparities in uterine fibroids

描述(由研究人员提供)：在美国，子宫肌瘤影响了77%的更年期女性，每年造成21亿美元的医疗费用。子宫肌瘤对生殖健康造成负面影响，导致月经过多和疼痛，盆腔疼痛和压力，妊娠并发症，以及包括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。基因分析可以提供一种强大且经济有效的工具来确定病因和病因，特别是因为双胞胎研究已经证明了子宫肌瘤的遗传易感性。高达69%的风险是由遗传因素造成的。种族差异也支持遗传因素在肌瘤风险中的作用。与高加索人相比，非洲裔美国女性的发病年龄更早，肌瘤数量更多，体积更大，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的全基因组关联研究(GWAS)，利用祖先的差异来缩小基因组区域的范围，进行有针对性的后续分析，以确定肌瘤风险的遗传标记。为了实现这一目标，我们将利用范德比尔特独特的资源--BioVU DNA数据库。BioVU目前有超过122,470名成年人链接到电子病历。从BioVU，我们已经确定了2902名非裔美国人和高加索人，他们符合我们严格的纳入标准，可以进行子宫肌瘤的GWA检查，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女性没有症状，如果没有成像，研究可能会错误地对多达51%的女性进行分类。我们还确定了绝经后无子宫肌瘤患者的确切对照。我们有一个强大的全国知名的肌瘤研究人员团队，他们将提供10,000多个样本供复制。我们的第一个具体目标是对常见的单核苷酸多态(SNPs)和肌瘤风险之间的关联进行GWA。使用病例对照设计，我们将对来自BioVU的2,902名妇女(1,451例肌瘤病例和1,451名对照)进行GWAS检查，这些妇女按非裔美国人和高加索种族分层。还将进行二次混合作图(AM)分析，以确定优先复制的感兴趣的染色体区域。我们的第二个目标是对从GWAS和AM中识别的染色体区域进行重新测序，以发现罕见的变异。最后，在目标3中，我们将在至少3,230例肌瘤患者和7,097名对照的独立样本中复制从目标1和2中选择的SNPs。我们提出了一种有效且经济高效的方法来识别子宫肌瘤的遗传风险因素，方法是利用BioVU提供的成像信息和DNA。这项研究代表了最大的子宫肌瘤GWA，也是第一次在非裔美国人中利用新兴技术和新的统计方法进行这项研究。我们提出的研究将从根本上改变对肌瘤的认识，并为在理解肌瘤形成机制和确定新的治疗方法方面取得突破奠定基础。

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.