Maternal-Fetal Conflict: The Effect of Imprinted Genes on Fetal Growth

小于胎龄儿出生的个体在儿童时期面临严重的健康问题， 成人原发性高血压、心血管疾病、2型糖尿病和妊娠相关疾病 高血压和糖尿病。胎儿的生长速度受遗传因素的影响很大。的基因 是有印记的，这样从母亲或父亲遗传的等位基因在一些胎儿中不表达。 组织或胎儿发育的某些阶段是这种遗传影响的主要部分。 目的：鉴定与基因大小变异相关的8个印记基因组区域的变异， 胎龄，通过直接母体遗传效应，父母的起源（印记）效应或直接胎儿 基因型效应 假设：1）胎龄大小受父母或直接母亲遗传因素的影响。 归因于印记位点的效应。2)胎儿单核苷酸多态性（SNP）与 单个或组合的胎龄大小（单倍型）。 印记区域：胰岛素（INS）、胰岛素样生长因子2（IGF 2）、胰岛素样生长因子2受体 （IGF 2 R）、H19、生长因子受体结合蛋白10（GRB 10）、鸟嘌呤核苷酸结合蛋白、α- 刺激（GNAS）和染色体区域7 q32和11 p15。 设计：500名（非裔美国人和白人各250名）母亲-父亲-新生儿三人组将被 随机招募了不同胎龄的婴儿。严格的入选-排除标准将 最大限度地减少出生体重变化的非遗传因素，并丰富遗传成分。变异 单核苷酸多态性（SNPs）将在三人组中确定， 用于鉴定遗传因素对孕龄大小的影响的技术， 变异、印记（“起源父母”）和新生儿遗传变异。分析将控制一些 已知或潜在的胎儿大小相关因素，如性别、胎龄、母体BMI和产次。 与公共卫生的相关性：检测易生小胎的能力 在成年期也可能表现出对慢性疾病的易感性增加的人， 实施可能促进胎儿生长或改善长期妊娠的干预方法， 胎儿生长受限的后果。例如，饮食干预，改变可及性， 甲基供体在小鼠模型中显示出前景。

Individuals born small for gestational age face severe health problems as children and increased risks as adults of essential hypertension, cardiovascular disease, type 2 diabetes and pregnancy-related hypertension and diabetes. There is a substantial genetic influence on the rate of fetal growth. Genes that are imprinted such that the allele inherited from the mother or the father is not expressed in some fetal tissues or at some stages of fetal development are a major part of this genetic influence. Objective: Identify variation in 8 imprinted genomic regions that are associated with variation in size for gestational age, via direct maternal genetic effects, parent-of-origin (imprinting) effects or direct fetal genotypic effects. Hypotheses: 1) Size for gestational age is influenced by parent-of-origin or direct maternal genetic effects attributable to imprinted loci. 2) Fetal single nucleotide polymorphisms (SNPs) are associated with size for gestational age individually or in combinations (haplotypes). Imprinted regions: Insulin (INS), insulin-like growth factor 2 (IGF2), insulin-like growth factor 2 receptor (IGF2R), H19, growth factor receptor-bound protein 10 (GRB10), guanine nucleotide-binding protein, alpha- stimulating (GNAS), and chromosomal regions 7q32 and 11p15. Design: 500 (250 each of African-Americans and Caucasians) mother-father-newborn trios will be recruited randomly across the spectrum of size for gestational age. Stringent inclusion-exclusion criteria will minimize non-genetic contributors to birth weight variation and enrich for the genetic component. Variation at single nucleotide polymorphisms (SNPs) will be determined in the trios and sophisticated analytical techniques used to identify genetic influences on size for gestational age attributable to maternal genetic variation, imprinting ("parent-of-origin"), and newborn genetic variation. Analyses will control for a number of known or potential correlates of fetal size, such as gender, gestational age, maternal BMI, and parity. Relevance to Public Health: The ability to detect fetuses predisposed to being born small for gestational who may also exhibit increased predisposition to chronic illnesses in adulthood will allow for the implementation of intervention methods that may facilitate fetal growth or ameliorate the long-term consequences of fetal growth restriction. For example, dietary interventions that alter the accessibility of methyl donors have shown promise in mouse models.