Admixture Mapping of Preterm Birth Genes

早产基因的混合作图

• 批准号: 8696875
• 负责人: JEROME F STRAUSS
• 金额: $ 43.99万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696875
• 关键词: Admixture; African; African American; Alleles; American; Birth; Birth Rate; Candidate Disease Gene; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 21; Data; Developed Countries; Early Intervention; Epigenetic Process; European; Exclusion; Functional disorder; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genome; Genotype; Goals; Healthcare Systems; Incidence; Individual; Knowledge; Lead; Life Style; Link; Maps; Medical; MicroRNAs; Neonatal; Outcome; Pathologic Processes; Population; Pregnancy; Pregnancy Complications; Premature Birth; Prevention strategy; Research; Risk; Risk Factors; Sampling; Testing; Therapeutic Intervention; United States; Variant; Woman; base; cost; disability; exome sequencing; expectation; experience; fetal; gene discovery; gene environment interaction; genetic variant; health disparity; high risk; innovation; neonate; premature; preterm premature rupture of membranes; prevention clinical trial; racial and ethnic disparities; transmission process

DESCRIPTION (provided by applicant): Prematurity is one of the most significant medical issues in the United States, costing the American health care system more than 26 billion dollars annually. Moreover, there are significant racial/ethnic disparities in the incidence of preterm birth, with African American women experiencing a disproportionately higher number preterm deliveries compared to European American women. Although the basis for this disparity is likely multi- factorial, there is increasing evidence that genetic variation and gene-environment interaction contribute to the increased risk of preterm birth in African Americans. One approach to elucidate risk factors for the disparity in prematurity, and also to identify targes for therapeutic intervention, is to search for genes that are associated or linked to this outcome. Genetic markers could be used to identify subjects prospectively who might benefit from early interventions. Markers predicting prematurity could also facilitate and reduce the cost of prevention clinical trials through identification of high-risk individuals and exclusion of low ris subjects. Finally, genetic markers could refine understanding of the normal as well as pathologic processes underlying parturition, and lead to innovative medical treatments based on contributing genes. The three Specific Aims proposed in this application represent an objective approach to identifying prematurity genes that contribute to ethnic/racial disparities. The focus will be on preterm premature rupture of membranes (PPROM), the leading identifiable cause of preterm birth and a pregnancy complication that is more frequent in African-Americans. We propose to: 1) Identify loci contributing to PPROM by admixture mapping (AM). This Specific Aim is grounded in the expectation that there are genes that make significant ancestry-specific contributions to risk of PPROM. The hypothesis to be tested is that African ancestry alleles as well as European ancestry alleles admixed into an African ancestry background contribute to risk of PPROM. Stated another way, ancestry and admixture can both make contributions to prematurity. 2) Identify candidate genetic variants lying under AM peaks by exome sequencing. To identify genetic variation in the AM peaks that potentially contribute to PPROM, as well as refine the AM, we will select 50 neonate cases and 50 neonate controls, whose African ancestry is similar (70- 80%), for exome sequencing of chromosomal regions underlying confirmed AM peaks. The hypotheses to be tested are: 1) Loci in the fetal genome on chromosomes 2,8,11,19 and 21 confer increased risk for PPROM~ 2) Loci on chromosome 21 confer risk and protection for PPROM in a population-specific manner~ 3) Risk genetic loci may act through epigenetic mechanisms (microRNAs) to promote PPROM. 3) Test candidate variants for linkage and association with PPROM using the transmission disequilibrium test (TDT). The goal of this Specific Aim is to test candidate genetic variants from regions identified in the feta (neonatal) AM and exome sequencing to determine if they are in association and linkage with PPROM, conferring risk or protection.

早产是美国最重要的医疗问题之一，每年花费美国医疗保健系统超过260亿美元。 此外，在发生率方面存在显著的种族/族裔差异， 早产，与欧洲裔美国妇女相比，非洲裔美国妇女的早产人数不成比例地高。虽然这种差异的基础可能是多因素的，但越来越多的证据表明，遗传变异和基因-环境相互作用导致非裔美国人早产风险增加。 阐明早产差异的风险因素以及确定治疗干预的目标的一种方法是寻找与该结果相关或相关的基因。 遗传标记可用于前瞻性地识别可能从早期干预中受益的受试者。通过识别高危个体和排除低风险受试者，预测早产的标记物也可以促进和降低预防性临床试验的成本。 最后，遗传标记可以改善对分娩的正常和病理过程的理解，并导致基于贡献基因的创新医学治疗。本申请中提出的三个特定目的代表了鉴定导致种族/人种差异的早产基因的客观方法。 重点将放在早产胎膜早破（PPROM），这是早产的主要可识别原因，也是非洲裔美国人更常见的妊娠并发症。 我们建议：1）通过混合作图（AM）确定PPROM的基因位点。这一特定目标是基于这样的期望，即有基因对PPROM的风险有显着的祖先特异性贡献。待检验的假设是，非洲血统等位基因以及欧洲血统等位基因混合到非洲血统背景中有助于PPROM的风险。 换句话说，血统和混血儿都可能导致早产。 2)通过外显子组测序鉴定位于AM峰下的候选遗传变体。 为了鉴定AM峰中可能导致PPROM的遗传变异，以及改进AM，我们将选择50例新生儿病例和50例新生儿对照，其非洲血统相似（70- 80%），用于确认AM峰的染色体区域的外显子组测序。待检验的假设是：1）位于2、8、11、19和21号染色体上的胎儿基因组中的基因座赋予PPROM增加的风险2）位于21号染色体上的基因座以群体特异性方式赋予PPROM的风险和保护3）风险遗传基因座可能通过表观遗传机制（microRNA）起作用以促进PPROM。3)使用传递不平衡检验（TDT）检测候选变异与PPROM的连锁和关联。该特定目标的目标是测试来自在羊（新生儿）AM和外显子组测序中鉴定的区域的候选遗传变异，以确定它们是否与PPROM相关和连锁，从而赋予风险或保护。