FUNCTIONAL SIGNIFICANCE OF GENETIC VARIATION IN PREGNANCY

研究摘要 早产是美国母婴健康的一个主要问题。几 越来越多的证据表明，早产是一种复杂的综合征， 母体和胎儿的遗传易感性与环境背景有关，由神经内分泌介导， 免疫/炎症和血管病相关途径。我们计划项目“Gene-”的总体目标 人类Parfurif/on的环境相互作用”是为了确定人类Parfurif/on的遗传和环境决定因素， 人类妊娠期的长度/自发分娩的开始时间，并对基因、环境和 母胎相互作用可能是三个种族/民族人群早产风险的基础： 非裔美国人，西班牙裔和非西班牙裔白人。 部分借鉴项目一为确定受影响程度和基本人口而进行的研究 在调节哺乳动物细胞活性的关键候选基因中，母胎DNA序列变异的结构 母体-胎盘-胎儿内分泌轴，并在项目II中建立基因型-表型关系模型， 确定母亲和胎儿基因型和环境的哪些组合与测量相关 在三个种族/民族群体中的每一个中的内分泌生理学和临床结果，项目III的目标 是确定母体和胎儿特异性DNA序列变异的功能意义的三个关键 候选基因在人类怀孕方面的动态压力和分娩相关 生理过程。该项目将描述母体和胎儿的体内功能意义， 对分娩和应激反应（促肾上腺皮质激素释放激素）至关重要的基因的基因型 (CRH)、糖皮质激素受体（GR）、CRH受体1型（CRHR））的个体差异， 人类妊娠期应激暴露的病理生理反应。 具体目的是：1）确定母胎DNA序列的功能意义 在人类怀孕的生物应激反应的动态变化;和2）以确定是否 母体和胎儿DNA序列变异对生物应激个体差异的功能影响 人类妊娠的反应性受到环境的调节，重点是种族/民族。 该项目将在加州大学欧文分校进行，并将利用可用性 240名不同种族的孕妇及其胎儿/婴儿的受试者池， 正在进行的NIH资助的妊娠期心理生理应激反应研究（HD-33506，P. Wadhwa，PI）。 确定母亲和胎儿遗传变异的功能后果的关键 分娩和压力相关的基因将推进这些导致早产的关键途径的知识。 出生在这一生理途径中的多个相互作用的基因和蛋白质的模式将被阐明。 这些研究还可以确定潜在的治疗靶点，以降低对环境和社会的敏感性。 高风险人群的压力，特别是在怀孕期间。这项工作将取得进展，并具有重要意义。 对日益认识到需要根据患者的情况为患者量身定制个性化治疗的影响， 个体DNA变异和背景。

ABSTRACT OF RESEARCH PLAN Premature birth represents a major problem in maternal and child health in the United States. Several converging lines of evidence suggest that premature birth is a complex syndrome involving the interplay of maternal as well as fetal genetic predispositions with environmental contexts, mediated by neuroendocrine, immune/inflammatory and vasculopathy-related pathways. The broad goal of our Program Project "Gene- Environment Interactions in Human Parfurif/on" is to identify the genetic and environmental determinants of the length of human gestation/timing of onset of spontaneous parturition, and to model the gene, environment and maternal-fetal interactions that may underlie the risk of premature birth among three racial/ethnic populations: African-Americans, Hispanics and nonHispanic Whites. Building, in part, on studies conducted in Project I to ascertain the extent and underlying population structure of maternal-fetal DNA sequence variation in key candidate genes that regulate the activity of the maternal-placental-fetal endocrine axis, and in Project II to model genotype-phenotype relationships to determine which combinations of maternal and fetal genotypes and environments are associated with measures of endocrine physiology and clinical outcome in each of the three racial/ethnic groups, the goal of Project III Is to determine the functional significance of specific maternal and fetal DNA sequence variations in three key candidate genes in human pregnancy with respect to the dynamics of stress- and parturition-related physiological processes. This project will characterize the in vivo functional significance of maternal and fetal genotypes in genes that are central to parturition as well as the stress response (corticotrophin-releasing hormone (CRH), glucocorticoid receptor (GR), CRH receptor-type 1 (CRHR,)) with respect to individual differences in pathophysiological responses to stress exposure in human pregnancy. The SPECIFIC AIMS are: 1) To determine the functional significance of maternal and fetal DNA sequence variations in the dynamics of biological stress responsivity in human pregnancy; and 2) To determine whether the functional effects of maternal and fetal DNA sequence variations on individual differences in biological stress responsivity in human pregnancy are moderated by context, with an emphasis on race/ethnicity. The project will be conducted at the University of California, Irvine, and will capitalize on the availability of a subject pool of 240 ethnically-diverse pregnant women and their fetuses/infants who are participants in an on-going, NIH-funded study of psychophysiological stress reactivity in pregnancy (HD-33506, P. Wadhwa, PI). The determination of the functional consequences of maternal and fetal genetic variation in key parturition- and stress-related genes will advance knowledge of these critical pathways leading to premature birth. The pattern of the multiple interacting genes and proteins in this physiological pathway will be elucidated. These studies may also identify potential therapeutic targets to reduce sensitivity to environmental and social stress in at-risk individuals, and specifically during pregnancy. This work will advance and have important implications for the growing awareness of the need to tailor individual treatment to individual patients based on individual DNA variations and contexts.