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

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 R 2 of 0.44 and a p -value of 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 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

Allele · Biology · Homeostatic model assessment · Insulin · Insulin resistance · Methylenetetrahydrofolate reductase · Population · Diet and metabolism studies · Folate and B Vitamins Research · Medicine · Metabolomics and Mass Spectrometry Studies · Endocrinology · Genetics · Internal Medicine

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

  Open Access•Chun-Hsin Chen, Chun‐Hsin Chen et al.•International Journal of…•2021

  Add to list

• Use and Abuse of Homa Modeling

  Tara M Wallace, J Levy et al.•Diabetes Care•2004

  Add to list

• Homeostasis model assessment

  Open Access•D R Matthews, J P Hosker et al.•Diabetologia•1985

  Add to list

• Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder

  Open Access•Davy Vancampfort, Brendon Stubbs et al.•World Psychiatry•2015

  Add to list

• A new look at the statistical model identification

  Open Access•Hirotugu Akaike•IEEE Transactions on Automatic…•1974

  Add to list