Gene–gene interaction between the cystathionine β-synthase 31 base pair variable number of tandem repeats and the methylenetetrahydrofolate reductase 677C>T polymorphism on homocysteine levels and risk for neural tube defects

Abstract

Introduction: Most studies showed that mothers of children with NTD have elevated homocysteine levels pointing to a disturbed homocysteine metabolism as a risk factor for NTD. Folate lowers homocysteine levels by remethylation of homocysteine to methionine. Homocysteine can be irreversibly converted to cystathionine by the vitamin B6-dependent enzyme CBS. Recently, our group showed that a 31 bp VNTR in the CBS gene was associated with decreased CBS activity and increased tHcy levels after methionine loading in a CVD population. Aim: The aim of our study was to investigate whether this VNTR influences tHcy levels and risk for NTD. In addition, we assessed the role of vitamin B6 as an effect modifier in this possible interaction. We examined possible gene–gene interaction with the MTHFR 677C>T polymorphism. We screened genomic DNA of 88 NBD patients, 100 mothers, 88 fathers, and 505 controls for this CBS 31 bp VNTR. Results: In this study population five different alleles with 16,17, 18, 19, and 21 times the 31 bp repeat were observed that constituted 10 different genotypes. The most common 18/18 VNTR genotype was associated with higher tHcy levels compared with the 17/18 and 18/19 VNTR genotypes. Vitamin B6 levels did not influence this association. In addition, no association with risk for NTD was found. Combination of the CBS VNTR with the MTHFR 677C>T polymorphism revealed an additional increase in homocysteine levels in 18–18 individuals compared with 17–18 peers within subjects homozygous mutant for the MTHFR 677C>T polymorphism. Conclusions: The present study indicates that the number of 31 bp repeat elements in the CBS gene influences tHcy levels. This VNTR seems not to be associated with an increased risk for NTD.