Admixture Mapping of Preterm Birth Genes

早产是美国最重要的医疗问题之一，耗费了美国人的医疗保健 系统每年超过260亿美元。此外，在这一地区存在着显著的种族/民族差距。 早产的发生率，非洲裔美国妇女经历的人数不成比例地高 早产与欧美妇女相比。尽管这种差异的基础可能是多因素的， 越来越多的证据表明，遗传变异和遗传环境 互动有助于 非洲裔美国人早产风险增加。一种解释性别差异的危险因素的方法 早产，也是为了确定治疗干预的目标，就是寻找与早产相关的基因 或与这一结果有关。遗传标记可以用来确定可能受益的受试者。 来自早期的干预。预测早产的标志物也可以促进和降低预防成本。 通过识别高风险进行临床试验 个人和排除低风险受试者。最后，基因 标记物可以加深对分娩背后的正常和病理过程的理解，以及 引领基于贡献基因的创新医疗。本报告提出的三个具体目标 应用程序代表了一种识别导致人种/种族的早熟基因的客观方法 差距。重点将放在早产儿胎膜早破(PPROM)上，这是可识别的主要 早产和妊娠并发症的原因，这种并发症在非裔美国人中更常见。 我们建议 目的：1)通过混合作图(AM)识别PPROM的基因座。这一具体目标植根于 期望有显著的祖先特有的基因 对胎膜早破风险的贡献。这个 有待检验的假设是，非洲血统等位基因以及欧洲血统等位基因混合到一个 非洲血统与胎膜早破风险相关。换句话说，祖先和混血儿可以 两者都是导致早产的原因。2)利用外显子组鉴定AM峰下的候选遗传变异 测序。确定AM峰值中可能导致胎膜早破的遗传变异，以及 精炼AM，选择非洲血统相似的新生儿病例和对照组各50例(7080%)， 对确认的AM峰下的染色体区域进行外显子组测序。假设是 测试结果如下：1)胎儿基因组中位于第2、8、11、19和21号染色体上的基因座增加了患PPROM的风险。 21号染色体上的基因座在特定人群中为胎膜早破提供风险和保护 方式；3)风险遗传 基因座可能通过表观遗传机制(MicroRNAs)促进PPROM。3)测试候选变量 使用传输不平衡检验(TDT)与PPROM进行链接和关联。这一特定的目标 目的是测试在胎儿(新生儿)AM和外显子组中确定的区域的候选遗传变异 测序以确定它们是否与PPROM相关联和联系，赋予风险或保护。

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.