Admixture Mapping of Preterm Birth Genes

早产基因的混合作图

• 批准号: 8790255
• 负责人: JEROME F STRAUSS
• 金额: $ 8.3万
• 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/8790255
• 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; 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; genetic variant; health disparity; innovation; neonate; premature; preterm premature rupture of membranes; prevention clinical trial; racial and ethnic disparities; transmission process

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 multifactorial, there is increasing evidence that genetic variation and geneenvironment 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 targets 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 highrisk individuals and exclusion of low risk 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 AfricanAmericans. 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 ancestryspecific 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 (7080%), 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 populationspecific 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 fetal (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，花费了美国的医疗保健 系统每年超过260亿美元。此外，在种族和族裔方面存在着重大的差异。 早产的发生率，非洲裔美国妇女经历了不成比例的高数字 与欧美女性相比，早产。虽然这种差异的基础可能是多因素的， 越来越多的证据表明，遗传变异和基因环境 相互作用有助于 非裔美国人早产的风险增加。一种方法来阐明风险因素的差异， 早产，并确定治疗干预的目标，是寻找相关的基因， 或与这一结果有关。遗传标记可用于前瞻性地识别可能受益的受试者 早期干预。预测早产的标记物也可以促进和减少预防费用 临床试验通过识别高风险 个体和排除低风险受试者。最后，基因 标记物可以改善对分娩的正常和病理过程的理解， 导致基于贡献基因的创新医学治疗。这三个具体目标， 应用程序代表了一种客观的方法，以确定早产基因，有助于种族/种族 差距。重点将是早产胎膜早破（PPROM），主要可识别的 早产和妊娠并发症的原因，这是更常见的非洲裔美国人。 我们提出 1）通过混合作图（AM）鉴定导致PPROM的基因座。这一具体目标的基础是 期望有基因使重要的祖先特异性 增加PPROM风险。的 要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成一个 非洲血统背景有助于PPROM的风险。换句话说，祖先和混合物可以 两者都对早产有贡献。2)通过外显子组识别位于AM峰下的候选遗传变体 测序确定AM峰中可能导致PPROM的遗传变异，以及 我们将选择50例新生儿病例和50例新生儿对照，他们的非洲血统相似（70 - 80%）， 用于确定AM峰的染色体区域的外显子组测序。假设是 测试的是：1）染色体2、8、11、19和21上的胎儿基因组中的基因座赋予PPROM增加的风险2） 21号染色体上的基因座在特定人群中赋予PPROM的风险和保护作用 3）遗传风险 基因座可以通过表观遗传机制（microRNA）起作用以促进PPROM。3)测试候选变体 使用传递不平衡检验（TDT）与PPROM的连锁和关联。本具体目标 目的是测试来自胎儿（新生儿）AM和外显子组中鉴定的区域的候选遗传变异 测序以确定它们是否与PPROM相关和连锁，从而赋予风险或保护。