DESCRIPTION (Adapted from the Applicant's Description) Orofacial clefts are among the most common birth defects in the world yet little is known about their major causes and regional differences in occurrence. In our previous studies in the Philippines we recently found biochemical evidence that poor vitamin B-6 and folic acid levels of mothers are independently associated with increased risks of clefting and that the MTHFR C677T mutation is associated with a reduced risk of clefting. We propose to elaborate these methods for studying nutrient-gene interactions and apply them in a population-based case- control study of orofacial clefts in Utah with the following specific aims: (1) Children with orofacial clefts (n = 686) will be ascertained by the state- wide Utah birth defects registry and their mothers will be recruited as case participants; (2) Children without clefts (n= 686) will be randomly selected from Utah birth certificates and their mothers wIll be recruited as control participants; (3) Data will be collected on dietary patterns, smoking, alcohol use and other exposures using telephone-based interviews and mailed questionnaires; (4) Venous blood samples will be drawn from mothers, rapidly processed, and assayed for biochemical indicators of vitamin B-6 and folate status; (5) DNA from mothers, children, and fathers will be prepared and genotyped for polymorphic genetic markers related to vitamin B-6 and folate metabolism. The following hypotheses will be addressed: (1) Poor maternal vitamin B-6 status is independently associated with increased risk of orofacial clefts; (2) Poor maternal folate status is independently associated with increased risk of orofacial clefts; (3) The MTHFR C677T allele is associated with a reduced risk of clefting. In addition the association between allelic variants of other folate- and vitamin B-6-related genetic markers and the risk of orofacial clefts will be examined; (4) The nutrients and candidate genes mentioned above interact, additively or multiplicatively, to increase the risk of orofacial clefting. Our multidisciplinary study of maternal nutrition and risk of clefting in the context of genes related to metabolic pathways may lead to a better understanding of the causes and prevention of orofacial clefts.