Individuals born small for gestational age have increased risks of serious illness as newborns and throughout life, including hypertension, cardiovascular disease, type 2 diabetes and pregnancy-related hypertension and diabetes. Both traditional genetics and epigenetics play a major role in fetal growth regulation. Genes that are imprinted, meaning that either the maternally- or paternally-inherited allele is silenced in some or all tissues, have a large influence on the regulation of fetal growth. Indeed, it is thought that selection has led to the uniform pattern among imprinted genes that the paternal allele of growth- retarding loci and the maternal allele of growth-promoting loci are imprinted (silenced). One of the main mechanisms for imprinting a locus is the extensive addition of methyl groups to CpG dinucleotides on one of the parental alleles. Based on observations in model organisms, the extent of methylation of fetal DNA can be dramatically influenced by the mother's intake of nutrients involved in that metabolic pathway. The immediate goal of this research is to identify genetic (fetal, maternal, and parent-of-origin) and epigenetic influences on fetal growth. The ultimate goals are to be able to anticipate those fetuses that are predisposed to being small for gestational age and to determine how to reduce that risk with medical, nutritional, or pharmacological interventions. Objectives: In all imprinted regions of the genome, survey patterns of variation in DNA sequence (single nucleotide polymorphisms;SNPs) in 500 mother-father-newborn trios and DNA methylation in those newborns and determine the maternal intake of nutrients essential to DNA methylation during pregnancy. Hypotheses: 1) Variation in birth weight is due to a) direct maternal, b) direct fetal and/or c) parent-of- origin (imprinting) genetic effects. 2) Variation in birth weight is associated with patterns of DNA methylation in imprinted genes. 3) Variation in DNA methylation patterns is correlated with variation in maternal intake of nutrients key to that process. Design: DNA is being collected from 500 sets of mothers, fathers, and their newborns based on stringent inclusion/exclusion criteria. Both tagging SNPs and those previously associated with obesity- related traits in imprinted genomic regions will be surveyed. Across all imprinted genomic regions DNA methylation patterns will be determined in differentially methylated regions and imprinting control regions. Dietary survey instruments during pregnancy and just afterwards will be used to determine the maternal intake of nutrients vital to DNA methylation. Statistical analyses will be performed to test the three hypotheses.

Public Health Relevance

to Public Health: Understanding the genetic and nutritional basis for a fetus being predisposed to low birth weight and life-long chronic illness will reveal clinical, nutritional and/or pharmacological interventions that may promote fetal growth and reduce those risks. For example, dietary interventions that alter the accessibility of methyl donors have shown promise in mouse models.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Genetic Variation and Evolution Study Section (GVE)
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Reddy, Uma M
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University of Tennessee Health Science Center
Schools of Medicine
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