Fetal and maternalMTHFR C677Tgenotype, maternal folate intake and the risk of nonsyndromic oral clefts

Abstract

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.

Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft

“…Analyses excluding them produced similar conclusions. We have previously discussed in detail the recruitment, data collection and environmental exposure assessment strategies for this case-control study [Chevrier et al, 2005[Chevrier et al, , 2006[Chevrier et al, , 2007a. Maternal smoking during the first trimester of pregnancy was not associated with the risk of nonsyndromic oral cleft in this population.…”

“…We summed the reported duration of all ETS exposures and created a dichotomous (no; yes) variable as well as a threelevel variable (no; 7 hr/week; >7 hr/week; a cutoff point selected to place an equal number of controls in the latter two groups). Assessment of potential confounders such as maternal alcohol consumption or maternal folate intake has been previously described [Chevrier et al, 2005[Chevrier et al, , 2007a]. …”

Folate and one‐carbon metabolism gene polymorphisms and their associations with oral facial clefts

“…Genes encoding proteins that perform or support these conversions include MTHFD1, MTHFR, MTR, and MTRR. MTHFR polymorphisms are widely studied in coronary artery disease, neural tube defects, and facial clefts [selected recent publications: Bennouar et al, 2007;Chevrier et al, 2007;Munoz et al, 2007]. The folate cycle is coupled to one-carbon metabolism by the MTR-mediated conversion of homocysteine to methionine.…”

“…f Mostowska et al [2006]. g Beaty et al [2002], Blanton et al [2000], Chevrier et al [2007], Gaspar et al [2004], Grunert et al [2002], Jugessur et al [2003], Martinelli et al [2001], Mills et al [1999], Mostowska et al [2006], Nurk et al [2004], Pezzetti et al [2004], Prescott et al [2002], Shaw et al [1998], Shi et al [2004], Shotelersuk et al [2003], Tolarova et al [1998], van Rooij et al [2003, Vieira et al [2005], Zhu et al [2006]. h Verkleij-Hagoort et al [2007].…”

Reduced folate carrier 1 (RFC1) is associated with cleft of the lip only

“…Conflicting results have been published regarding the association between cleft lip and palate and MTHFR (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Lack of association between markers in RFC1 and oral clefts has been consistently reported (14)(15)(16)(17).…”