Methionine synthase polymorphism A2756G is associated with susceptibility for thromboembolic events and altered B vitamin/thiol metabolism

Abstract

BACKGROUND AND OBJECTIVES: Vitamin B12 dependent methionine synthase (MS) regulates de novo production of methionine from homocysteine (Hcy). Since moderate elevations in Hcy are considered vasculotoxic, we examined a common variant (A2756G-MS) of the gene coding for this enzyme as a risk for thromboembolism. DESIGN AND METHODS: We investigated A2756G-MS and folate/thiol status in 51 individuals who had experienced a thromboembolic event (TE) and 95 subjects being treated for non-thromboembolic (NTE) vascular problems. RESULTS: The prevalence of the mutant G allele was lower in TE subjects than in controls, indicating a protective role for this base substitution (OR 0.39; 95%CI 0.20-0.78; p=0.010). Consistent with an advantage conferred by this allele, heterozygotes had generally lower levels of Hcy and glutathione (GSH), and higher levels of B-vitamins than wildtypes. The OR for the wildtype having an increased risk for TE was 2.32 (95%CI 1.06-5.08). Additionally, as might be predicted, TE-wildtypes had elevated GSH levels compared to corresponding NTE-wildtypes (p=0.004) - a likely response to oxidative stress. NTE subjects showed a dramatic reduction in Hcy between wildtype and heterozygote (p=0.017), and again between recessive and heterozygote genotypes (p=0.002). The same pattern, although not significant, occurred in TE subjects. The similarity in Hcy between clinical groups for each genotype raises questions on the etiological role of Hcy in TE. The functional relationship between enzyme variant and its B12-cofactor may be of more interest, since the polymorphic site occurs near the B12-binding domain, and our results indicate wildtype-TE subjects have a much lower level of vitamin B12 than heterozygote-TE subjects (p=0.0019). This effect is attenuated in NTE subjects. INTERPRETATION AND CONCLUSIONS:. A2756G-MS may protect against a thromboembolic event. The role of Hcy remains unclear.