Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta‐Analysis

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism.

Evaluation of C677T Polymorphism of the Methylenetetrahydrofolate Reductase (MTHFR) Gene in various Neurological Disorders

“…In our study, a positive association was observed between MTHFR C677T variant allele and autism risk. Our observation supports the meta-analysis data reported by Pu et al [47]. Another study by Mohammad et al [23] of the MTHFR C677T polymorphism in Indian patients with specific neurological pathologies has indicated that there was significant association with children associated with Autism.…”

- A Prospective Study of Nutrition Education and Oral Nutritional Supplementation in Patients with Alzheimer’s Disease

“…Results of several recent studies, including the prospective study by Surin et al [8] are encouraging, but it is too early to say that universal periconceptional use of folic can reduce the incidence of ASD resulting from abnormal folate-methionine metabolism. Some very recent epigenetic studies in monozygotic twins provide support for potential role of DNA methylation via a high maternal folic acid intake in ASD [19,20]. Specifically, findings by Wong and colleagues [20] are provocative and provide support for a potential role of DNA methylation via a high maternal folic acid intake in ASD and ASD-related traits.…”

MTHFR rs1801133 Gene Polymorphism and Autism Susceptibility

“…DNA methylation defects are associated with ASDs, and MTHFR and its role in folate metabolism may contribute to epigenetic mechanisms that modify complex gene expression causing autism [26]. The association of SHANK3, methionine synthase (rs1805087) and contactin-associated-like 2 (CNTNAP2) gene polymorphism in a population in northern Iran has been demonstrated [27][28][29].…”