Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts†

The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998–2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)≤230 µg/day = ref; for CL/P, OR[230–314 µg/day] = 0.56, 95% confidence interval = 0.3–0.9, OR>314 µg/day = 0.64, 0.4–1.1; for CP, OR[230–314 µg/day] = 1.15, 0.6–2.2, OR>314 µg/day = 0.70, 0.3–1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (ORCC = ref; for CL/P, ORTT = 0.54, 0.3–1.1; for CP, ORTT = 0.33, 0.1–1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts. © 2007 Wiley-Liss, Inc.