The Epidemiology Branch is conducting a number of birth defect studies in collaboration with the Health Research Board and Trinity College, Dublin, Ireland. The main objective of these studies is to determine the relationship between folate and birth defects. The birth defects studied to date are neural tube defects (NTDs), oral clefts, congenital heart defects, Down syndrome and omphalocele. These studies focus on biochemical factors in the area of folate metabolism, and on genetic mutations in folate related genes associated with birth defects. Recent work has expanded to include the biochemical pathways related to birth defects. On going work is examining pathways in healthy young students of Irish genetic background (the Trinity Student Study) with several goals. These include identifying genetic factors using genome wide association study data that influence these pathways and defining how environmental influences such as smoking, alcohol and the use of supplements change the biochemical milieu. Neural tube defects (NTDs) are common birth defects (1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. We have been testing genetic variants for association with NTD for a long time including examining the biological importance of genetic variants. Dr. Anne Parle-McDermott led our group in a recent investigation of the biological importance of a dihydrofolate reductase (DHFR) variant. This investigation was important because DHFR is a key enzyme in the absorption of folic acid. This investigation showed that an insertion/deletion in the DHFR gene does not interfere with folic acid absorption. We have measured tryptophan (Trp) pathway chemical concentrations in the over 2500 student volunteers in the Trinity Student Study. Trp is affected by numerous chronic diseases; however, little information is available regarding normal concentrations of Trp metabolites or how life style factors influence them. We demonstrated that gender is an important factor in interpreting Trp pathway metabolites. Moreover, use of oral contraceptives, alcohol consumption and use of vitamin B6 containing supplements also had a significant effect on Trp metabolites. These findings have now been published. Another important result of our investigation of B vitamins has been the discovery that a genetic variant in HIBCH is responsible for some of the unexplained variation in serum methylmalonic acid (MMA) measurement. It has long been known that MMA is not always an accurate measure of vitamin B12 status. Our study shows this genetic variant, not related to actual vitamin B12 status, affects the concentration of cobalamin in the blood. Both Dr. Ruzong Fan and Dr. Aiyi Liu, research statisticians on our project, have used our work and data to identify important statistical research questions. Their major area is looking for more efficient and powerful methods to identify true associations in genome-wide investigations. This work has produced several important papers noted in the bibliography. These will be discussed by Dr. Fan and Dr. Liu in their reports.
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