Date of Award:

2014

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Nutrition, Dietetics, and Food Sciences

Advisor/Chair:

Ronald G. Munger

Abstract

Orofacial clefts (OFCs) are facial malformations that happen during early pregnancy and have a complex and heterogeneous etiology, involving both genetic and environmental risk factors. This project examined the association between maternal nutrition, folaterelated biomarkers, candidate genes involved in one-carbon metabolism (OCM), and OFCs in order to achieve more comprehensive knowledge of how nutrition and genetics influence OFC risk. First, the association between maternal periconceptional multivitamin (PCMV) use, maternal dietary patterns during the periconceptional period, and OFC risk was examined. This study showed that neither PCMV use nor healthy dietary pattern score alone was individually associated with OFC risk. However, the combination of PCMV use and a higher score reflecting the ideal Dietary Approach to Stop Hypertension diet was associated with 55% reduction in the risk of isolated OFCs, evidence that the prevention of OFCs may require attention to both PCMV use and improving maternal diets. Second, the association between maternal multivitamin use, folic acid supplemental intake, and measured blood folate levels in case mothers of OFC children and control mothers was examined. Mothers who had an OFC-affected pregnancy compared with control mothers had lower mean levels of plasma folate in both multivitamin users and non-users. At levels of folic acid intake >400µg/day, the difference in plasma folate between case mothers and control mothers narrowed, evidence that higher folate intake levels may be required for mothers with a history of OFC-affected pregnancy. The ability to utilize supplement folic acid might be modified by MTHFR C677T genotype. In mothers with 677CC genotype, both case and control mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake, although case mothers’ plasma folate concentrations were always significantly lower than control mothers’ until folate supplemental intake reached 400µg. In mothers with 677CT genotype, control but not case mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake. In mothers with 677TT genotype, case but not control mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake. Lastly, variations in folate-related OCM genes were examined in association with risk of OFCs using GWAS data and the case-parent trio approach. Several genes in the OCM pathway were associated with isolated, non-syndromic OFCs with some through genetic effects alone but most through gene-environment interaction effects with maternal multivitamin supplementation during periconceptional period and maternal biomarker concentrations for OCM-related nutrients. These results emphasize the need to consider gene-environment interactions when searching for genes influencing isolated OFCs. Reduction in the prevalence of OFCs could have tremendous importance. The results of this dissertation may help identify factors important to OFCs etiology and in turn, provide valuable targets for preventive intervention. Children born with an OFC require medical care from birth until adulthood and encounter a higher mortality rate. The costs incurred from caring for children born with OFCs not only include the clinical care of many disciplines but also involve the emotional disturbance and social and employment exclusion for affected individuals. Reducing the risk of OFCs would lessen considerable financial and emotional burdens to families and societies.

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