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. In the past we have shown that elevated homocysteine is a risk factor for NTDs, that a mutation in the methylenetetrahydrofolate reductase (MTHFR) gene 677C->T is a risk factor for NTDs, and that a small dose of folic acid (100-200 micrograms) can raise red cell folate to levels that can prevent a fifth to almost a half of NTDs. We have shown that methylenetetrahydrofolate reductase (MTHFD), an important gene in the production of purine and pyrimidine for DNA synthesis, is a risk factor for NTDs. We have shown that auto-antibodies to the folate receptor, previously considered to be an important risk factor for NTDs, are no more common in affected pregnancies than unaffected pregnancies. We have reported that women with vitamin B12 levels in the deficient or borderline range are significantly more likely to bear childrene with NTDs. We have investigated the potential mechanisms by which vitamin B12 could be related to NTD risk.The transcobalamin II receptor (TCIIR) mediates the uptake of B12 into cells.We examined common variants in TCIIR for association with NTDs first in a case control study then in a family based triad confirmatory group. Two tightly linked variants were significantly related to NTDs after correction. These variants also appeared as possible risk factors in the uncorrected triad analysis. In addition, a copy number variant and previously unreported exonic insertion-deletion polymorphisms were identified in cases. These may represent low frequency, high penetrance risk factors given their absence in normal controls. These results suggest that vitamin B12 transfer and binding may be important factors in the etiology of NTDs. Our investigation of risk factors for oral facial clefts produced new findings as well. In collaboration with a group performing the largest genome wide association study of cleft lip with or without cleft palate (CLP), we reported that risk variants are present in two genes not previously known to be associated with CLP. The genes are MAFB and ABCA4. In addition, this study confirmed the previously reported association between CLP and the 8q24 region and IRF6. MAFB is a transcription factor known to be important in development of the hindbrain, pancreas and hemopoietic system. Expression data from the mouse indicate that it plays a role in lip and palate development. ABCA4 is a member of the superfamily of transmembrane proteins. Mutations play a role in human retinopathies;ABCA4's role in clefts needs to be investigated. The large size of our cleft study population enables us to play an important role in confirming or refuting reported associations between gene variants and clefts. We recently reported analyses looking at reported associations in 12 cleft genes. Using our population of 509 patients with CLP, 383 with cleft palate only (CPO), their parents and 902 controls, we found that three of the 12 reported associations were replicated. We reported further evidence that PTCH1, SUMO1 and TGFA are associated with non-syndromic clefts. PTCH1 is an important factor in holoprosencephaly, which is sometimes associated with clefts. SUMO1 affects post-translational proteins and has been associated with oral clefts. TGFA's association with clefts in humans was controversial given both positive an negative studies. Thus, our study, which provided the large number of subjects in any investigation for 10 of the 12 genes investigated, provides valuable confirmatory evidence.
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