Association between MTHFR polymorphisms and frontoethmoidal encephalomeningocele and cleft lip with or without cleft palate

Abstract

Neural tube defect (NTD) and oral cleft are among the most common birth defects worldwide. In Thailand, Frontoethmoidal encephalomeningocele (FEEM) is a relatively common subtype of NTD. Two polymorphisms, the 677C→T and 1298A→C, in the gene encoding 5,10-Methylenetetrahydrofolate reductase (MTHFR) have been found to be associated with occipital and lumbosacral encephaloceles, subtypes of NTD commonly found in Caucasians. No studies have determined the association between these two polymorphisms and FEEM. In addition, associations between MTHFR polymorphisms and oral cleft are still controversy. In this study, we aim to determine the associations between the 677→T and 1298A→C polymorphisms in MTHFR and the developments of FEEM and oral cleft. We analyzed 48 families with FEEM and 162 families with oral cleft compared to 202 controls for the polymorphisms by PCR amplification followed by restriction enzyme digestion analysis. Our data show that the 677T allele frequency in Thai is 0.12 which is relatively low compared with those in other populations. The 1298C allele frequency is 0.25 among the Thai population which is comparable to those in other populations. Single locus analysis shows no association between the polymorphisms and patients with FEEM, oral cleft, or their parents. A family-based association studying using biallelic and multiallelic of Transmission disequilibrium (TDT) shows that transmission rates do not deviate significantly from equilibrium supporting results of no associations from the single locus analysis. Interestingly, we detected a statistically significant increased risk (OR = 3.67;95%CI:1.58-8.59) for the heterozygous mothers with the 677CT/1298AC genotype to have a child with oral cleft. This is consistent with the statistical significance (X² =6.969;p=0.008) for mother with C-C/T-A haplotype. In conclusion, our data show that in the Thai population, women with the 677/CT/1298AC MTHFR genotypes have a 3.67 fold of increased risk of having a child with oral cleft.