Genetic and Metabolite Variability in One-Carbon Metabolism Applied to an Insulin Resistance Model in Patients With Schizophrenia Receiving Atypical Antipsychotics

Abstract

Background: Patients with schizophrenia are at high risk of pre-mature mortality due to cardiovascular disease (CVD). Our group has completed studies in pharmacogenomics and metabolomics that have independently identified perturbations in one-carbon metabolism as associated with risk factors for CVD in this patient population. Therefore, this study aimed to use genetic and metabolomic data to determine the relationship between folate pharmacogenomics, one-carbon metabolites, and insulin resistance as measured using the homeostatic model assessment for insulin resistance (HOMA-IR) as a marker of CVD.Methods: Participants in this pilot analysis were on a stable atypical antipsychotic regimen for at least 6 months, with no diabetes diagnosis or use of antidiabetic medications. Participant samples were genotyped for MTHFR variants rs1801131 (MTHFR A1298C) and rs1801133 (MTHFR C677T). Serum metabolite concentrations were obtained with NMR. A least squares regression model was used to predict log(HOMA-IR) values based on the following independent variables: serum glutamate, glycine, betaine, serine, and threonine concentrations, and carrier status of the variant alleles for the selected genotypes.Results: A total of 67 participants were included, with a median age of 47 years old (IQR 42–52), 39% were female, and the median BMI was 30.3 (IQR 26.3–37.1). Overall, the model demonstrated an ability to predict log(HOMA-IR) values with an adjusted R2 of 0.44 and a p-value of < 0.001. Glutamate, threonine, and carrier status of the MTHFR 1298 C or MTHFR 677 T allele were positively correlated with log(HOMA-IR), whereas glycine, serine, and betaine concentrations trended inversely with log(HOMA-IR). All factors included in this final model were considered as having a possible effect on predicting log(HOMA-IR) as measured with a p-value < 0.1.Conclusions: Presence of pharmacogenomic variants that decrease the functional capacity of the MTHFR enzyme are associated with increased risk for cardiovascular disease, as measured in this instance by log(HOMA-IR). Furthermore, serine, glycine, and betaine concentrations trended inversely with HOMA-IR, suggesting that increased presence of methyl-donating groups is associated with lower measures of insulin resistance. Ultimately, these results will need to be replicated in a significantly larger population.

Influencing factors of obesity in community patients with deficit schizophrenia: a cross-sectional study

“…It shows that fasting blood glucose and triglyceride levels are risk factors for obesity. Ward et al [ 44 ] have found that the incidence of metabolic syndrome in schizophrenia is higher than that of the normal population, which may be related to the use of atypical antipsychotics. Chen et al [ 45 – 47 ] have found that typical antipsychotics and atypical antipsychotics can also affect the glucose and lipid metabolism of patients with schizophrenia.…”

Associations of Genetic Variants of Methylenetetrahydrofolate Reductase and Serum Folate Levels with Metabolic Parameters in Patients with Schizophrenia

“…MTHFR 677T carriers in Ellingrod’s study [ 16 ] and MTHFR 1298C carriers in van Winkel’s study [ 22 ] were reported to have higher risks of metabolic syndrome. Additionally, carriers with MTHFR 677T or MTHFR 1298C allele had a higher level of insulin resistance [ 23 ]. By contrast, the MTHFR 677T allele seemed to be protective against metabolic syndrome in Roffeei’s study on Asian patients [ 17 ].…”