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Birth Defects Res A Clin Mol Teratol. 2014 Jan;100(1):30-5. doi: 10.1002/bdra.23199. Epub 2013 Nov 19.

MTHFR rs2274976 polymorphism is a risk marker for nonsyndromic cleft lip with or without cleft palate in the Brazilian population.

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Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil.



Polymorphisms within the MTHFR (rs2274976) and MTHFD1 (rs2236225) genes were previously associated with maternal susceptibility for having an offspring with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in the Brazilian population. However, as the genotypes of the patients with NSCL/P were not evaluated, it is not clear whether the effects are associated with maternal or offspring genotypes. The aim of this study was to evaluate the association of rs2274976 and rs2236225 in the pathogenesis of NSCL/P.


By using the TaqMan 5'-exonuclease allelic discrimination assay, the present study genotyped the rs2274976 and rs2236225 polymorphisms in 147 case-parent trios, 181 isolated samples of NSCL/P and 478 healthy controls of the Brazilian population. Transmission disequilibrium test and structured case-control analysis based on the individual ancestry proportions were performed.


The transmission disequilibrium test showed a significant overtransmission of the rs2274976 A allele (p = 0.004), but no preferential parent-of-origin transmission was detected. The structured case-control analysis supported those findings, revealing that the minor A allele of rs2274976 was significantly more frequent in NSCL/P group compared with control group (p = 0.001), yielding an odds ratio of 3.46 (95% confidence interval, 2.05-5.85). No association of rs2236225 polymorphism with NSCL/P was observed in both transmission disequilibrium test and case-control analysis.


The results of the study revealed that the presence of the rs2274976 A allele is a risk marker for the development of NSCL/P in the Brazilian population.


MTHFD1; MTHFR; folic acid; nonsyndromic cleft lip with or without cleft palate; polymorphism; susceptibility

[Indexed for MEDLINE]

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