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 are two types of genetic influences on fetal growth: 1) changes in DNA sequence (single nucleotide polymorphisms) and 2) addition of methyl groups to the DNA backbone (epigenetics). Epigenetic changes appear to be strongly influenced by the consumption of known key nutrients. The ultimate goals of this research are to understand what genetic variants and nutrients increase the risk of a baby being low birth weight and how it may be possible to reduce these risks with medical, nutritional, or pharmacological interventions. Objective: Across the entire genome, variation due to single nucleotide polymorphisms and DNA methylation will be surveyed and related to the risk of low birth weight. Additionally, variation among pregnant women in the consumption of key nutrients will be related to the patterns of DNA methylation in their newborns. Hypotheses: 1) Variation in birth weight is associated with patterns of single nucleotide polymorphism and copy number variation. 2) Variation in birth weight is associated with patterns of DNA methylation. 3) Variation in DNA methylation patterns is correlated with variation in maternal intake of nutrients involved in the pathways leading to DNA methylation. Design: DNA will be collected for 800 mother-newborn pairs and an additional 500 motherfather- newborn trios. Stringent inclusion-exclusion criteria will minimize non-genetic contributors to birth weight variation and enrich for the genetic/epigenetic component. Commercial """"""""chips"""""""" will be used to survey genome-wide patterns of single nucleotide polymorphism and DNA methylation variation. Questionnaires will be used to determine the intake of key nutrients. Statistical analyses will be performed to test the three hypotheses. Note: The only change from the original abstract is a change from 1,000 to 800 mothernewborn pairs.
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.
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