Infants’ MTHFR Polymorphisms and Nonsyndromic Orofacial Clefts Susceptibility

Abstract

Nonsyndromic orofacial clefts (NSOCs) are among the most common birth defects and occur in 1 per 700 to 1000 live births worldwide, although the incidence varies with geographic origin, ethnicity, and socioeconomic status. Non-syndromic orofacial clefts can be divided into the lip only (CLO), both the lip and palate (CLP), and the palate only (CPO). Nonsyndromic orofacial clefts carry large public health burdens because of the immediate and long-term medical costs, increased overall mortality, and social impacts on patients and their families. Any disturbance from genetic background or environmental teratogenic factors during critical stages of embryonic development can lead to failure of the orofacial closure mechanism. Maternal folic acid supplementation during early pregnancy may decrease the risk of orofacial clefts. The mechanism that controls low plasma folate levels is still unknown, but one possibility is the polymorphisms in genes encoding enzymes of the folate pathway. One enzyme is methylene-tetrahydrofolate reductase (MTHFR), located at chromosome 1p36.3 and composed of 2.2 kb with 11 exons. It has 2 functional polymorphisms, C677T (rs1801133) and A1298C (rs1801131). The C677T polymorphism controls altered enzyme activity, thermolability, and mild-to-moderate hyperhomocysteinemia. The A1298C variant also decreases enzymatic activity but does not affect homocysteine plasma levels. This meta-analysis was performed, using 17 case-control studies, to determine the effects of the 2 variants on the risk of NSOC. PubMed and EMBASE databases were searched to identify articles on infants’ MTHFR C677T or A1298C polymorphisms and NSOC risk. The selected case-control studies contained detailed distributions of the infants’ MTHFR C677T or A1298C genotypes among cases and controls and reported the risk of NSOC or its subgroups. The Hardy-Weinberg equilibrium was calculated based on the genotypes among controls. For studies with subjects from different ethnic groups, data were extracted separately, with ethnicity categorized as white, Asian, and African. The difference in frequency of MTHFR C677T and A1298C polymorphisms in cases and controls was assessed by the χ2 test. The strength of the association between the polymorphisms and NSOC risk was assessed by odds ratios (ORs) with 95% confidence intervals (CIs). Eight of the 17 studies examined only C677T; the other 9 examined both variants. Eleven studies focused on CL/P, 4 on both CL/P and CPO, and 2 studies on all cases. The meta-analysis of the associations between the C677T polymorphism and the risk of NSOC included 3439 cases and 5109 controls. Among Asians, the CT heterozygote and TT homozygote resulted in elevated risks of NSOC compared with CC homozygote (OR, 1.741; 95% CI, 1.043–2.907). The frequency of MTHFR 677T allele was significantly higher in Asian cases than that in Asian controls, suggesting an increased susceptibility to NSOC (OR, 1.420; 95% CI, 1.191–1.693, for T allele vs C allele). For the A1298C polymorphism, 9 studies with 1572 cases and 2665 controls were assessed. The frequency of MTHFR 1298C allele in the case group of whites was significantly lower than that in the control group (0.271 vs 0.343, P < 0.001), suggesting a protective effect against NSOC in whites (OR, 0.711; 95% CI, 0.641–0.790). However, logistic regression revealed that MTHFR A1298C was not associated with NSOC susceptibility under any of the genetic models. Funnel plots and the Egger test did not indicate any significant publication bias. This meta-analysis provides additional evidence that MTHFR C677T and A1298C polymorphisms are involved in the development of NSOC. These results may increase the understanding of MTHFR in the etiology of NSOCs. Future well-designed studies with different ethnic populations are necessary to verify these findings.