VCU NIMHD Comprehensive Center of Excellence (Project 1; PI: Strauss)

与单胎妊娠相关的早产在美国仍然很高，远远高于其他发达国家的比率。此外，在早产发生率方面存在明显的种族/族裔差异，与欧洲裔美国人相比，非洲裔美国人经历的早产人数不成比例。拟议的研究重点是早产胎膜早破(PPROM)的遗传学，这是早产的主要可识别原因。我们假设，遗传学以三种不同的方式导致早产：1)在所有人群中都有易导致早产的等位基因，可能是基因与环境相互作用的结果，这些环境因素可能在非裔美国人社区中更普遍；2)有非洲血统的等位基因赋予非裔美国人更大的风险，同样可能与环境因素相互作用；以及3)欧洲血统风险等位基因混合到非洲裔基因组中会带来不成比例地影响非裔美国人的风险，也可能是因为环境相互作用。我们过去的工作确定了其中两种机制(1和2)的例子，下面描述的初步情况为第三种机制(3)提供了强有力的支持。本申请中提出的三个具体目标将检验上述假设，并提供一个亟需的客观方法，以确定导致民族/种族差异的早产基因。 具体目的1：通过对胎膜早破患者(胎儿/新生儿)和对照组21号染色体基因的外显子组测序，确定其遗传变异。 具体目标2：使用传递不平衡检验(TDT)，在存在关联的情况下，测试在特定目标1中确定的PPROM连锁的变体。 具体目标3：利用被确定为携带非洲血统风险等位基因的区域的外显子组测序，识别染色体2和11上的遗传变异。

Prematurity associated with singleton pregnancies remains high in the U.S., and well above rates in other developed countries. Moreover, there are significant racial/ethnic disparities in the incidence of premature birth, with African Americans experiencing a disproportionate number of preterm births compared to European Americans. The focus of the proposed research is on the genetics of preterm premature rupture of membranes (PPROM), the leading identifiable cause of preterm birth. We hypothesize that genetics plays into the prematurity in three different ways: 1) There are alleles that predispose to preterm birth in all populations, probably as a result of gene-environment interactions, and those environmental factors may be more prevalent in African American communities; 2) There are alleles of African ancestry that confer greater risk to African Americans, again probably interacting with environmental factors; and 3) Admixture of European ancestry risk alleles into the African ancestry genome confers risk that disproportionately affects African Americans, possibly again because of environmental interactions. Our past work identified examples of two of these mechanisms (1 & 2), and our preliminary described below provides strong support for the third (3). The three Specific Aims proposed in this application will test the above-noted hypothesis and provide a much-needed objective approach to identifying prematurity genes that contribute to ethnic/racial disparities. Specific Aim 1: To identify genetic variants by exome sequencing of chromosome 21 genes from PPROM cases (fetal/neonates) and controls. Specific Aim 2: To test variants identified in Specific Aim 1 for PPROM linkage in the presence of association using the transmission disequilibrium test (TDT). Specific Aim 3: To identify genetic variants on chromosomes 2 and 11 using exome sequencing of regions identified as carrying African ancestry risk alleles.