Evidence of gene-gene interactions between MTHFD1 and MTHFR in relation to anterior encephalocele susceptibility in Northeast India.

BACKGROUND

Anterior encephalocele (AE) is a rare congenital anomaly of the central nervous system which is thought to be associated with genetic defects in folate metabolism.

METHODS

This case-control study investigated the interactions of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)-1958G>A (rs2236225) and the methylenetetrahydrofolate reductase (MTHFR) - 677C>T (rs1801133) and 1298A>C (rs1801131) polymorphisms with the risk of AE in the Northeast Indian population. A total of 40 AE cases and 80 controls were investigated using polymerase chain reaction-restriction fragment length polymorphism technique.

RESULTS

MTHFR 1298CC was significantly associated with AE risk (odds ratio [OR] 4.21; p = 0.01). The MTHFR haplotypes 677C-1298C/677T-1298A (OR, 2.50) and 677T-1298C (OR, 2.86) conferred risk in a progressive manner (χ = 9.82; p < 0.01). MTHFD1 1958G>A was not associated with disease susceptibility. Children with the rs2236225 GA and the rs1801131 CC genotypes were at an increased risk as compared to the reference genotype of rs2236225 GG and rs1801131 AA (OR, 14.4; p = 0.02). Children with the rs2236225 GG and rs1801133 CT genotypes were also at an elevated risk (OR, 4.76; p = 0.01). The MTHFD1 polymorphism together with the MTHFR haplotypes elevated risk in a progressive manner (χ = 6.29; p = 0.01).

CONCLUSION

The data support our hypothesis of gene-gene interaction between MTHFD1 and MTHFR and the risk of AE. Together with the MTHFR haplotypes, MTHFD1 elevates risk in a progressive manner. The minor allelic frequencies of the MTHFD1 1958G>A and MTHFR 1298A>C in our populations were similar to those reported from Southeast Asian population, suggesting a possible explanation for the prevalence of this malformation in these regions. Birth Defects Research 109:432-444, 2017. © 2017 Wiley Periodicals, Inc.