Admixture Mapping of Preterm Birth Genes

早产基因的混合作图

基本信息

批准号：
9093819
负责人：
JEROME F STRAUSS
金额：
$ 25.82万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9093819
关键词：
Admixture African African American Alleles American Birth Birth Rate Candidate Disease Gene Chromosomes, Human, Pair 2 Chromosomes, Human, Pair 21 Data Developed Countries Early Intervention Epigenetic Process European Exclusion Functional disorder Genes Genetic Genetic Markers Genetic Risk Genetic Variation Genome Genotype Goals Healthcare Systems Incidence Individual Knowledge Lead Life Style Link Maps Medical MicroRNAs Neonatal Outcome Pathologic Processes Population Pregnancy Pregnancy Complications Premature Birth Prevention strategy Research Risk Risk Factors Sampling Testing Therapeutic Intervention United States Variant Woman admixture mapping base cost disability exome sequencing expectation experience fetal gene discovery gene environment interaction genetic approach genetic variant health disparity high risk innovation neonate premature preterm premature rupture of membranes prevention clinical trial racial and ethnic disparities transmission process

项目摘要

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.

描述（由申请人提供）：早产是美国最重要的医疗问题之一，每年耗资超过260亿美元的美国医疗保健系统。此外，发生的种族/种族差异很大早产，与欧美妇女相比，非洲裔美国妇女的早产数量要高得多。尽管这种差异的基础可能是多阶乘，但越来越多的证据表明，遗传变异和基因 - 环境相互作用有助于非洲裔美国人早产的风险增加。一种阐明早产差异的风险因素的方法，以及确定治疗干预的损坏的方法，是搜索与该结果相关或相关的基因。遗传标记可用于前瞻性地识别可能从早期干预中受益的受试者。预测早产性的标志物还可以通过鉴定高风险个体和排除低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的正常和病理过程的了解，并基于促进基因进行创新的医疗治疗。本应用程序中提出的三个特定目的代表了识别有助于种族/种族差异的过早基因的客观方法。重点将放在早产膜（PPROM）的早产，这是对非洲裔美国人更频繁的早产原因和妊娠并发症的主要识别原因。我们建议：1）识别通过混合图（AM）对PPR的贡献的基因座。这一特定目标是基于预期的，即有一些基因对PPROM风险做出了重要的特定祖先贡献。要检验的假设是，非洲血统等位基因以及欧洲血统等位基因被混合到非洲血统背景中，这导致了PPROM的风险。换句话说，祖先和混合都可以为早产做出贡献。 2）通过外显子组测序确定位于AM峰下的候选遗传变异。为了确定可能有助于PPROM的AM峰的遗传变异，并改进了AM，我们将选择50例新生儿病例和50例新生儿对照，其非洲血统相似（70-80％），用于对基础染色体区域的外显子组测序。要检验的假设是：1）染色体上的胎儿基因组中的基因座2,8,11,19和21赋予PPROM 〜2）在21号染色体上增加风险的风险增加，以人口特异性的方式赋予PPROM的风险和保护PPROM的风险〜3）风险遗传基因遗传学可以通过表格机制来促进ppromss（MicroRONNAS），以促进Prproms（MicroRONNAS）。 3）使用传输不平衡测试（TDT）测试候选变体，并与PPR链接并与PPROM关联。该特定目的的目的是测试来自Feta（新生儿）AM和外显子组测序区域的候选遗传变异，以确定它们是否与PPROM相关并链接，并赋予风险或保护。