Admixture Mapping of Preterm Birth Genes

早产基因的混合作图

• 批准号: 8906535
• 负责人: JEROME F STRAUSS
• 金额: $ 35.88万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906535
• 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 approach; 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.

描述（由申请人提供）：早产是美国最重要的医疗问题之一，每年给美国医疗保健系统造成的损失超过 260 亿美元。 此外，种族/族裔的发病率存在显着差异。 早产，与欧洲裔美国女性相比，非洲裔美国女性的早产数量要高得多。尽管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。 阐明早产差异的危险因素并确定治疗干预目标的一种方法是寻找与这一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。预测早产的标记还可以通过识别高风险个体并排除低风险受试者来促进和降低预防临床试验的成本。 最后，遗传标记可以加深对分娩背后的正常和病理过程的理解，并带来基于贡献基因的创新医学治疗。本申请中提出的三个具体目标代表了一种识别导致民族/种族差异的早产基因的客观方法。 重点将放在胎膜早破 (PPROM) 上，这是早产的主要可识别原因，也是非裔美国人中更常见的妊娠并发症。 我们建议：1）通过混合作图（AM）识别对 PPROM 做出贡献的位点。这一具体目标基于这样的预期：存在对 PPROM 风险做出显着祖先特异性贡献的基因。要检验的假设是，非洲血统等位基因以及混合到非洲血统背景中的欧洲血统等位基因都会导致 PPROM 的风险。 换句话说，血统和混血都会导致早产。 2) 通过外显子组测序识别 AM 峰下的候选遗传变异。 为了确定 AM 峰中可能导致 PPROM 的遗传变异，并完善 AM，我们将选择 50 名新生儿病例和 50 名新生儿对照（其非洲血统相似（70-80%）），对已确认 AM 峰下方的染色体区域进行外显子组测序。待检验的假设为：1) 胎儿基因组中 2、8、11、19 和 21 号染色体上的基因座会增加 PPROM 的风险~ 2) 21 号染色体上的基因座以人群特异性方式赋予 PPROM 风险和保护 ~ 3) 风险遗传位点可能通过表观遗传机制 (microRNA) 促进 PPROM。 3) 使用传递不平衡测试 (TDT) 测试候选变体与 PPROM 的链接和关联。该特定目标的目标是测试羊胎（新生儿）AM 和外显子组测序中确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。