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Folate and Clefts of the Lip and Palate—A U.K.-Based Case-Control Study: Part II: Biochemical and Genetic Analysis

Objective: To investigate associations between nonsyndromic oral clefts and biochemical measures of folate status and the MTHFR C677T variant in the United Kingdom, where there has been no folic acid fortification program. Method: Dietary details were obtained from the mothers of 112 cases of cleft lip with or without cleft palate (CL±P), 78 cleft palate only (CP) cases, and 248 unaffected infants. Infant and parental MTHFR C677T genotype was determined. Red blood cell (RBC) and serum folate and homocysteine levels were assessed in 12-month postpartum blood samples from a subset of mothers. The data were analyzed by logistic and log-linear regression methods. Results: There was an inverse association between CL±P and maternal MTHFR CT (odds ratio [OR]  =  0.5, 95% confidence interval [CI]  =  0.31–0.95) and TT (OR  =  0.6, 95% CI  =  0.21–1.50) genotypes, with similar risk estimates for CP. There was no clear association with infant MTHFR genotype. Higher levels of maternal postpartum RBC and serum folate were associated with a lower risk for CL±P and an increased risk for CP. Higher levels of serum homocysteine were associated with a slightly increased risk for both CL±P and CP. Conclusion: While the inverse relation between the mother's having the MTHFR C677T variant and both CL±P and CP suggests perturbation of maternal folate metabolism is of etiological importance, contrasting relations between maternal postpartum levels of RBC and serum folate by type of cleft are difficult to explain.