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

VCU NIMHD 综合卓越中心（项目 1；负责人：Strauss）

• 批准号: 8655802
• 负责人: JEROME F STRAUSS
• 金额: $ 26.75万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655802
• 关键词: Admixture; Affect; African; African American; Alleles; American; Birth; Chromosomes; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 21; Communities; Developed Countries; Early Intervention; Environmental Risk Factor; European; Exclusion; Fathers; Fetus; Genes; Genetic; Genetic Markers; Genetic Variation; Genome; Genotype; Healthcare Systems; Incidence; Individual; Knowledge; Lead; Life Style; Link; Medical; Mothers; Outcome; Pathologic Processes; Play; Population; Pregnancy; Premature Birth; Prevention strategy; Research; Risk; Risk Factors; Testing; Therapeutic Intervention; Variant; Woman; Work; base; cost; exome sequencing; experience; fetal; gene discovery; gene environment interaction; genetic variant; health disparity; high risk; innovation; neonate; premature; preterm premature rupture of membranes; prevention clinical trial; racial and ethnic disparities; risk variant; transmission process

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.

在美国，与单胎怀孕相关的早产仍然很高，在其他发达国家中的比率远高于比率。此外，与欧洲人相比，非洲裔美国人的早产差异很大，非裔美国人的早产数量不成比例。拟议的研究的重点是膜早产（PPROM）早产的遗传学，这是早产的主要原因。我们假设遗传学以三种不同的方式提高了早产：1）在所有人群中，有些等位基因可能是由于基因 - 环境相互作用而易于早产，而这些环境因素在非裔美国社区中可能更为普遍。 2）有一些非洲血统的等位基因给非洲裔美国人带来更大的风险，再次可能与环境因素互动； 3）欧洲血统的混合风险等位基因对非洲血统基因组的风险等位基因对不成比例影响非洲裔美国人的风险再次，可能再次是由于环境相互作用而产生的。我们过去的工作确定了其中两种机制（1和2）的示例，我们的初步介绍为第三（3）提供了强有力的支持。本应用程序中提出的三个具体目标将检验上述假设，并为识别有助于种族/种族差异的早产基因提供了急需的客观方法。 特定目的1：通过对PPROM病例（胎儿/新生儿）和对照组的21基因染色体基因的外显子组测序来鉴定遗传变异。 特定目标2：使用传输不平衡测试（TDT）在存在关联的情况下，在特定目标1中鉴定出在特定目标1中识别的变体。 特定目标3：使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来鉴定染色体2和11的遗传变异。