Using the Exome to Discover Genetic Determinants of Fibroids in African Americans

利用外显子组发现非裔美国人肌瘤的遗传决定因素

• 批准号: 8840292
• 负责人: Digna R Velez Edwards
• 金额: $ 7.65万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-18 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840292
• 关键词: Accounting; Adult; Affect; African American; Age; Age of Onset; Alleles; American; Benign; Body mass index; Candidate Disease Gene; Cell Culture Techniques; Characteristics; Code; Complex; Computerized Medical Record; Cultured Tumor Cells; DNA; DNA Databases; DNA Resequencing; Data; Disease; European; Feasibility Studies; Fibroid Tumor; Functional disorder; Future; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Genotype; Growth; Health; Health Care Costs; Human; Image; Incidence; Individual; Intervention; Japanese Population; Knowledge; Lead; Link; Literature; Logistic Regressions; Maps; Menopause; Menstruation; National Institute of Child Health and Human Development; Pain; Pathway interactions; Pelvic Pain; Pelvis; Phenotype; Pilot Projects; Population; Pregnancy Complications; Publishing; Race; Recording of previous events; Relative (related person); Reporting; Reproductive Health; Research; Research Priority; Resources; Risk; Role; Sample Size; Sampling; Severities; Source; Time; Tumor Tissue; Twin Studies; United States Agency for Healthcare Research and Quality; United States National Institutes of Health; Uterine Fibroids; Uterine myomectomy; Uterus; Variant; Woman; Women' s Health; Work; base; biobank; case control; cost effective; exome; genetic analysis; genetic variant; genome wide association study; inclusion criteria; meetings; novel; pressure; racial disparity; rare variant; research study; tool; trait; tumor

DESCRIPTION (provided by applicant): Uterine fibroids affect 77% of women by menopause in the U.S. and account for $2.1 billion in healthcare costs each year. Until recently, tumor tissu and cell culture studies investigating fibroid growth have been the primary sources for understanding fibroid pathophysiology. Genetic analysis provides a powerful and cost effective tool to identify etiological and causal factors, especially since a genetic predisposition to fibrods has already been shown from twin studies. As much as 69% of risk is explained by genetic factors. Racial disparities also support a role for genetics in fibroid risk. African American (AA) women have earlier age-of-onset, more numerous and larger fibroids with a greater lifetime incidence compared to European Americans (EAs). Among existing genetic analysis approaches, whole exome genotyping (WEG) is the most cost-effective and efficient compared to genome-wide association studies (GWAS) that focuses on common variants that may themselves not be causal. In this study, we will take advantage of a unique Vanderbilt resource, the BioVU DNA databank. BioVU has over 141,221 adult DNA samples linked to electronic medical records (EMR). From BioVU we have identified 3,535 AA subjects (612 cases and 2,923 controls) who meet our stringent inclusion criteria. Studies have shown that many women with fibroids are asymptomatic and without imaging as many as 51% of women may be misclassified. As a result, we have required pelvic imaging for both cases and controls. 50,000 BioVU subjects are currently being genotyped using Illumina's Exome Chip as part of an institutional initiative, including all AAs (completion summer of 2013). Our first aim is to conduc a WEG study of fibroids using AA BioVU subjects (n = 3,535) using logistic regression (common variants) and gene-based allele collapsing approaches (rare variants) to evaluate associations of SNPs with fibroids risk. Our second aim is to resequence exomes at 50X using AA BioVU extreme fibroid cases (n = 75) and controls (n = 75) to discover novel coding variants associated with fibroid risk. Extreme cases are those with youngest fibroid onset and largest number and size of fibroid. Extreme controls are the oldest subjects with no recorded history of fibroids. Aim 2 will allow us to validate variants discovered in Aim 1, as well as to identify nove variants not included on the genotyping chip. The NIH, NICHD, AHRQ, and the OWHR have made understanding the mechanisms underlying fibroid risk research priorities. This study is the largest and first whole exome experiment of fibroid among AAs. Immediate availability of samples and resources allow us to accomplish these R01 scope Aims within the budgetary and time constraints of an R03. These aims will allow us to identify novel variants associated with fibroids using two distinct approaches (WEG and exome resequencing using extreme phenotypes) and will lay the ground work for a future R01 examining rare variants associated with fibroids across racial groups. Our proposed study will fundamentally change knowledge about fibroids and lead to breakthroughs in understanding mechanisms in fibroid formation.

描述（由申请人提供）：子宫肌瘤影响美国77%的绝经妇女，每年花费21亿美元的医疗费用。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的主要来源。遗传分析提供了一种强大且成本有效的工具来确定病因和因果因素，特别是因为双胞胎研究已经显示了子宫肌瘤的遗传易感性。多达69%的风险可以用遗传因素来解释。种族差异也支持基因在子宫肌瘤风险中的作用。非裔美国人