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

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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.