MTHFR and risk of metabolic syndrome in patients with schizophrenia

Objective: Meta-analyses have implicated polymorphisms in MTHFR, encoding a critical enzyme in folate and homocysteine metabolism, in both schizophrenia and CVD. Method: A possible association between the C677T and A1298C polymorphisms of the MTHFR gene on the one hand, and metabolic syndrome on the other, was examined in a naturalistic cohort of 518 patients with a schizophrenia spectrum disorder screened for metabolic disturbances at the Catholic University of Louvain, Belgium. Results: MTHFR A1298C, but not C677T, was associated with the metabolic syndrome, C/C genotypes having a 2.4 times higher risk compared to A/A genotypes (95% Cl 1.25-4.76, p = 0.009). Haplotype analysis revealed similar findings, showing greater risk for metabolic syndrome associated with the 677C/1298C haplotype compared to the reference 677C/1298A haplotype (OR 1.72, 95% Cl 1.24-2.39, p = 0.001). These associations were not explained by circulating folate levels. Differences between A1298C genotype groups were considerably greater in the subsample treated with clozapine or olanzapine (OR C/C versus A/A 3.87, 95% Cl 1.51-9.96) than in subsample treated with any of the other antipsychotics (OR C/C versus A/A 1.30, 95% Cl 0.47-3.74), although this did not formally reach statistical significance in the current cross-sectional study (gene-by-group interaction chi(2) = 3.0, df =1, p = 0.08). Conclusion: These data provide evidence supporting an association between MTHFR and risk of metabolic syndrome in patients with schizophrenia. Prospective studies evaluating the course of metabolic outcomes after initiation of antipsychotic medication are needed to evaluate possible gene-by-treatment interaction more specifically.