Genetic Risk Underlying Racial Disparities in Uterine Fibroids

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.]]>
Fibroid cases are adult women with pelvic imaging confirmed fibroid. Fibroid controls are adult women with intact uteruses and pelvic imaging, where not fibroids were identified. ]]>

在美国，77%的女性在绝经前会罹患子宫肌瘤（Fibroids），每年造成的医疗支出高达21亿美元。子宫肌瘤会对生殖健康造成负面影响，引发经量过多与痛经、盆腔疼痛与压迫感、妊娠并发症，还需进行子宫肌瘤切除术（myomectomy）与子宫切除术（hysterectomy）等临床干预。直至近期，针对肌瘤生长的肿瘤组织与细胞培养研究仍是解析子宫肌瘤病理生理学的主要研究手段。遗传分析可作为识别病因与致病因子的高效且经济的工具，此前双胞胎研究已证实子宫肌瘤存在遗传易感性，约69%的发病风险可由遗传因素解释。种族差异同样佐证了遗传因素在子宫肌瘤发病风险中的作用：与白人女性相比，非裔美国女性的发病年龄更早，肌瘤数量更多、体积更大，终身发病率也更高。
本研究拟通过针对非裔美国与白人参与者开展的全基因组关联研究（genome-wide association study, GWAS），识别子宫肌瘤的发病风险遗传标记，并利用祖先差异缩小后续靶向分析的基因组区域范围。为达成这一目标，我们将依托范德堡大学独特的生物样本资源——BioVU DNA数据库（BioVU）。BioVU目前拥有超过122470名与电子病历关联的成年人样本。我们已从BioVU中筛选出2902名符合严格纳入标准的非裔美国与白人女性，用于开展子宫肌瘤的全基因组关联研究，这些受试者均接受过盆腔影像学检查。影像学数据至关重要，因为多数子宫肌瘤患者并无症状，若未借助影像学检查，研究可能会误将多达51%的女性归类错误。我们还确立了明确的对照组：即子宫完整且经盆腔影像学检查未发现子宫肌瘤的绝经后女性。此外，我们拥有一支由国内知名子宫肌瘤研究专家组成的团队，可提供超过10000份样本用于后续验证。
本研究的第一项具体目标为开展全基因组关联分析，探究常见单核苷酸多态性（single nucleotide polymorphisms, SNPs）与子宫肌瘤发病风险的关联。我们将采用病例-对照研究设计，对BioVU队列中的2902名女性（1451名子宫肌瘤病例与1451名对照）按非裔美国与白人种族进行分层分析。此外，还将开展族群混合定位分析（admixture mapping, AM），以识别感兴趣的染色体区域，优先用于后续验证。
第二项研究目标为对全基因组关联研究与族群混合定位分析所确定的染色体区域进行重测序，以发现罕见变异。
最后，在第三项研究目标中，我们将在至少3230名子宫肌瘤病例与7097名对照的独立样本中，对从第一项与第二项研究中筛选出的单核苷酸多态性进行验证。
本研究拟借助BioVU数据库已有的影像学信息与DNA样本，采用高效且经济的方法识别子宫肌瘤的遗传风险因素。本研究是目前规模最大的子宫肌瘤全基因组关联研究，也是首个针对非裔美国人群、利用新兴技术与新型统计方法开展的同类研究。本研究将从根本上改变人们对子宫肌瘤的认知，为阐明子宫肌瘤形成机制以及识别新型治疗手段奠定基础。
子宫肌瘤病例指经盆腔影像学检查确认存在子宫肌瘤的成年女性。子宫肌瘤对照指子宫完整且经盆腔影像学检查未发现子宫肌瘤的成年女性。