Admixture Mapping of Preterm Birth Genes

早产基因的混合作图

• 批准号: 8790255
• 负责人: JEROME F STRAUSS
• 金额: $ 8.3万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790255
• 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; Pregnancy; Pregnancy Complications; Premature Birth; Prevention strategy; Research; Risk; Risk Factors; Sampling; Testing; Therapeutic Intervention; United States; Variant; Woman; base; cost; disability; exome sequencing; expectation; experience; fetal; gene discovery; genetic variant; health disparity; innovation; neonate; premature; preterm premature rupture of membranes; prevention clinical trial; racial and ethnic disparities; transmission process

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 multifactorial, there is increasing evidence that genetic variation and geneenvironment 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 targets 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 highrisk individuals and exclusion of low risk 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 AfricanAmericans. 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 ancestryspecific 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 (7080%), 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 populationspecific 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 fetal (neonatal) AM and exome sequencing to determine if they are in association and linkage with PPROM, conferring risk or protection.

早产是美国最重要的医疗问题之一，给美国医疗保健造成了巨大损失 每年系统价值超过260亿美元。此外，种族/族裔之间存在显着差异。 早产的发生率，非裔美国女性的早产率更高 与欧洲美国女性相比，早产情况。尽管这种差异的基础可能是多因素的， 越来越多的证据表明遗传变异和基因环境 互动有助于 非裔美国人早产的风险增加。阐明造成差异的风险因素的一种方法 早产，以及确定治疗干预的目标，就是寻找相关的基因 或与此结果相关。遗传标记可用于前瞻性地识别可能受益的受试者 来自早期干预。预测早产的标记物也可以促进和降低预防成本 通过识别高风险进行临床试验 个体并排除低风险受试者。最后，遗传 标记物可以加深对分娩背后的正常和病理过程的理解，并且 导致基于贡献基因的创新医学治疗。本次会议提出的三个具体目标 应用程序代表了一种识别早产基因的客观方法，这些基因有助于种族/种族 差异。重点将放在胎膜早破 (PPROM) 上，这是可识别的主要疾病 早产的原因和非裔美国人中更常见的妊娠并发症。 我们建议 目的： 1) 通过混合作图 (AM) 识别对 PPROM 做出贡献的位点。这一具体目标的基础是 期望存在具有显着血统特异性的基因 对 PPROM 风险的贡献。这 要检验的假设是非洲祖先等位基因和欧洲祖先等位基因混合成一个 非洲血统背景会增加 PPROM 的风险。换句话说，血统和混血可以 两者都会导致早产。 2) 通过外显子组识别 AM 峰下的候选遗传变异 测序。识别 AM 峰中可能导致 PPROM 的遗传变异，以及 细化AM，我们将选择50个新生儿病例和50个新生儿对照，其非洲血统相似（7080%）， 用于对已确认的 AM 峰下方的染色体区域进行外显子组测序。假设是 测试的内容包括：1) 胎儿基因组中 2、8、11、19 和 21 号染色体上的基因座会增加 PPROM 的风险；2) 21 号染色体上的基因座在特定人群中赋予 PPROM 风险和保护 方式；3）风险遗传 位点可能通过表观遗传机制 (microRNA) 促进 PPROM。 3) 测试候选变体 使用传递不平衡测试（TDT）与 PPROM 进行链接和关联。本具体目标 目的是测试胎儿（新生儿）AM 和外显子组中确定的区域的候选遗传变异 测序以确定它们是否与 PPROM 相关联，从而赋予风险或保护。