Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate

Abstract

The 677 C-T polymorphism in the 5-10 methylenetetrahydrofolate reductase (MTHFR) gene has been associated with nonsyndromic cleft lip with or without cleft palate (CL/P) in some populations, but not others. Previous studies (ie, case-control and transmission disequilibrium tests (TDT)) in Brazilian families with CL/P have been unable to replicate this putative association. However, our group observed a lower proportion of CT heterozygotes among the mothers of CL/P probands, suggesting that the maternal genotype for this polymorphism might influence predisposition to CL/P. In order to further examine this issue, we performed a case-control study of the 677 C-T/MTHFR polymorphism in families with CL/P ascertained in two regions of Brazil: 172 from São Paulo (SP) and 252 from Ceará (CE). The control samples included 243 individuals from SP and 401 from CE. TDT was carried out in 102 patients with CL/P and their parents. No evidence of an association was observed between the 677 C-T/MTHFR polymorphism and CL/P using the case-control design, while borderline significance was obtained with the TDT (P ¼ 0.055). We have also looked for an interaction between maternal MTHFR genotypes and the propositi offspring's genotypes at two candidate susceptibility loci for CL/P, TGFA and BCL3. Interestingly, we observed an interaction between the maternal MTHFR and offspring's BCL3 genotypes (OR: 2.3; 95% CI: 1.1 -4.8; P ¼ 0.03) but not with the offspring's TGFA genotypes. Therefore, our results reinforce the idea that the maternal MTHFR genotype plays a significant role in susceptibility to CL/P, but its teratogenic effect depends on the genotype of the offspring.

Orofacial Clefts: A Worldwide Review of the Problem

“…The complex natures of the nonsyndromic clefts that are attributed to the multiple interacting genes conferring moderate effects have been proposed to provide susceptibility to orofacial clefts [59][60][61]. Studies on these syndromes have given sufficient clues to identify the genes that cause the non-syndromic clefts [62].…”

Progress toward discerning the genetics of cleft lip

“…For CL/P, evidence for this exists in the A/WySn mouse strain in which the Clf1 and Clf2 loci epistatically interact [78]. The utility of gene-gene analyses to either narrow a critical region [79] or to identify additional loci [80] has been demonstrated for other diseases.…”

Registries of cleft lip/palate cases between 2004 and 2010 in Denizli, Turkey

“…In regard to genes, in a case-control study of Brazilian families with CL/P, Gaspar et al (2004) have observed that the MTHFR 677T allele is associated with increased risk of malformation. However, Sözen et al (2009) found no association with MTHFR 677T in Venezuelan subjects.…”