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

描述（由申请人提供）：出生时小于胎龄的个体在儿童时面临严重的健康问题，成年后患原发性高血压、心血管疾病、2型糖尿病和妊娠相关高血压和糖尿病的风险增加。胎儿的生长速度受遗传因素的影响很大。这种遗传影响的主要部分是基因印记，使得从母亲或父亲遗传的等位基因在某些胎儿组织或胎儿发育的某些阶段不表达。目的：通过直接母体遗传效应、母体（印记）效应或直接胎儿基因型效应，鉴定与胎龄大小变化相关的8个印记基因组区域的变异。假设：1）胎龄的大小是由父母的起源或直接母亲的遗传效应归因于印记基因座的影响。2)胎儿单核苷酸多态性（SNPs）与胎龄的大小单独或组合（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。设计图：将在胎龄范围内随机招募500名（非裔美国人和白人各250名）母亲-父亲-新生儿三人组。严格的纳入-排除标准将最大限度地减少非遗传因素对出生体重变化的影响，并丰富遗传成分。将在三人组中确定单核苷酸多态性（SNP）的变化，并使用复杂的分析技术来确定对胎龄大小的遗传影响，这些遗传影响可归因于母体遗传变异、印记（“起源父母”）和新生儿遗传变异。分析将控制一些已知的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：能够检测出易于出生时小于妊娠期的胎儿，这些胎儿也可能在成年后表现出对慢性疾病的易感性增加，这将允许实施可能促进胎儿生长或改善胎儿生长受限的长期后果的干预方法。例如，改变甲基供体可及性的饮食干预在小鼠模型中显示出希望。

DESCRIPTION (provided by applicant): 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.