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: 8354914
• 负责人: JEROME F STRAUSS
• 金额: $ 26.67万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354914
• 关键词: Admixture; Affect; African; African American; Alleles; American; Birth; Chromosomes; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 21; Communities; Developed Countries; Early treatment; 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; 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; 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，与单胎妊娠相关的早产率仍然很高，远远高于其他发达国家的水平。此外，早产的发生率存在显著的种族/民族差异，与欧洲裔美国人相比，非洲裔美国人的早产人数不成比例。拟议研究的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对早产起作用：1）在所有人群中都有易患早产的等位基因，可能是基因-环境相互作用的结果，这些环境因素可能在非洲裔美国人社区中更为普遍; 2）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相互作用;和3）欧洲血统的风险等位基因混合到非洲血统的基因组赋予的风险，不成比例地影响非洲裔美国人，可能再次因为环境的相互作用。我们过去的工作确定了其中两种机制的例子（1和2），下面我们的初步描述为第三种机制提供了强有力的支持（3）。本申请中提出的三个具体目标将检验上述假设，并提供急需的客观方法来鉴定导致种族/种族差异的早产基因。 具体目标1：通过对PPROM病例（胎儿/新生儿）和对照组的21号染色体基因进行外显子组测序来识别遗传变异。 具体目标二：使用传递不平衡检验（TDT），在存在关联的情况下，检测特异性目标1中识别的PPROM连锁变异。 具体目标3：通过对携带非洲血统风险等位基因的区域进行外显子组测序，确定2号和11号染色体上的遗传变异。