Admixture Mapping of Preterm Birth Genes

描述(申请人提供)：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，在发病率方面存在着明显的种族/族裔差异。 早产，与欧洲裔美国女性相比，非洲裔美国女性经历的早产数量不成比例地高。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，基因变异和基因-环境相互作用导致非裔美国人早产风险增加。要阐明早产儿差异的危险因素，并确定治疗干预的目标，一种方法是寻找与这一结果相关或关联的基因。 遗传标记可以用来前瞻性地确定哪些受试者可能从早期干预中受益。预测早产儿的标记物还可以通过识别高危个体和排除低RIS受试者来促进和降低预防临床试验的成本。最后，遗传标记可以完善对分娩背后的正常和病理过程的理解，并导致基于促成基因的创新医疗。本申请中提出的三个具体目标代表了一种客观的方法，以确定导致民族/种族差异的早熟基因。重点将放在早产胎膜早破(PPROM)上，这是早产的主要可识别原因，也是一种在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)识别与PPROM相关的基因座。这一特定的目标是基于这样一种期望，即存在对胎膜早破风险有显著影响的特定祖先的基因。需要检验的假设是，非洲血统等位基因和欧洲血统等位基因混合在非洲血统背景中会导致PPROM的风险。换句话说，祖先和混血儿都会导致早产。2)通过外显子组测序确定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，以及完善AM，我们将选择50例新生儿病例和50名非洲血统相似(70%-80%)的新生儿对照，对确认的AM峰下的染色体区域进行外显子组测序。需要检验的假设是：1)胎儿基因组中2，8，11，19和21号染色体上的基因座增加了PPROM的风险；2)21号染色体上的基因座以群体特异性的方式提供了PPROM的风险和保护；3)危险遗传基因座可能通过表观遗传机制(MicroRNAs)促进PPROM的发生。3)使用传递不平衡检验(TDT)测试候选变异体与PPROM的连锁和关联。这一特定目标的目的是测试来自胎儿(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作用。

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.