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Maternal tobacco consumption is considered as a risk factor for nonsyndromic oral clefts. However, this risk is moderate and may be modulated by genetic susceptibilities, including variants of the TGFA, TGFB3 and MSX1 developmental genes and polymorphisms of genes of the CYP (1A1, 2E1) and GST (M1, T1) families involved in metabolic pathways of tobacco smoke compounds. This French case-control study (1998-2001; 240 nonsyndromic cases, 236 controls) included a case-parent design (175 triad-families) that made it possible to distinguish the direct effect of the child's genotype and maternally mediated effects. Maternal smoking during the first trimester of pregnancy was not associated with the oral cleft risk in this population, but we observed statistically significant increased risks associated with maternal exposure to environmental tobacco smoke (ETS). No variant of any of the three developmental genes was significantly associated with oral cleft. The fetal CYP1A1*2C variant allele was associated with a statistically significant decreased risk, compared with the homozygous wild-type: relative risk = 0.48, 95% confidence interval: 0.2, 1.0. Suggestive reduced risks were also observed for the maternal CYP1A1*2C allele and the fetal CYP2E1*5 allele. The GSTM1 and GSTT1 deletions appeared to play no role. Our findings suggest some interactions, with the strongest between ETS and CYP1A1 or MSX1 and between maternal smoking and CYP2E1. We did not confirm the maternal smoking-infant GSTT1 null interaction previously reported by other investigators., (Copyright 2008 Wiley-Liss, Inc.)

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)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/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 (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 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., ((c) 2007 Wiley-Liss, Inc.)

Background: Maternal alcohol consumption has been associated with an increased risk of nonsyndromic oral clefts in some studies. Study of gene-environment interaction may provide insight into the reasons for their discrepancies observed. We focused on a polymorphism of the ADH1C gene (third gene of the class I alcohol dehydrogenase family), involved in the metabolism of ethanol and other alcohols., Methods: Data come from a French case-control study (1998-2001), which tested the association between maternal alcohol consumption during the first trimester of pregnancy and the risk of nonsyndromic oral clefts (240 cases, 236 controls). A case-parent study design looked at the association with an ADH1C polymorphism (Ile349Val site) and potential gene-environment interaction effects. A log-linear model was used to distinguish the direct effect of the child's genotype from the maternally mediated effects., Results: An increased risk of nonsyndromic oral clefts was observed for women who reported drinking alcohol during the first trimester, compared with women who did not. The mutated ADH1C allele carried by the child seemed to have a protective effect against the risk of oral clefts (RRone copy, 0.71; 95% confidence interval [CI], 0.50-1.02; RRtwo copies, 0.63; 95% CI, 0.3-1.3). The maternal genotype played a less important role than the child's, and its action remains unclear. No significant evidence of interaction effects between the ADH1C genotype and maternal alcohol consumption was observed., Conclusions: Because the ADH1C gene is involved in the metabolic pathways of many alcohols, we propose several hypotheses about the causal pathway, including ethanol oxidation activity and, more probably, retinol oxidation.

The mode of inheritance of nonsyndromic cleft lip with or without cleft palate (NSCLP) is still a matter of dispute. We performed segregation analysis on three data sets of families ascertained through an affected child with NSCLP. The first two data sets were selected in France and were pooled for a global analysis. No major gene effect could be evidenced in spite of a very large number of families (666 pedigrees including 719 nuclear families). The third data set was British and consisted of three-generation families including the offspring of probands. A major gene effect, as well as a strong residual multifactorial component, were highly significant and we could show that this evidence almost entirely came from the information on probands' offspring. We conclude that a mixture of monogenic and of multifactorial cases is probably the best explanation for the observations made in this study. Analyses performed in pedigrees with multiple cases closely related might allow reducing heterogeneity and help identifying those Mendelian sub-entities.

Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.