1. ¹Human Genome Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
2. ²Hospital Menino Jesus, São Paulo, Brazil
3. ³Department of Plastic Surgery, Faculty of Medicine, University of São Paulo, Brazil
4. ⁴Genetics Program, Boston University School of Medicine, Boston, MA, US

Correspondence: MR Passos Bueno, Rua do Matão, 277, Departamento de Biologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil. CEP: 05508-900, Tel: +55 11 3091 9910; Fax: +55 11 3091 7419; E-mail: passos@ib.usp.br

Received 3 December 2003; Revised 27 January 2004; Accepted 11 February 2004; Published online 31 March 2004.

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=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=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.