title: The effect of folate supplementation and genotype on cardiovascular and epigenetic measures in schizophrenia subjects.
abstract: BACKGROUND
  Metabolic syndrome may be related to folate's pharmacogenetically regulated metabolism and atypical antipsychotic (AAP) exposure.
  
  
  OBJECTIVE
  We examined folate supplementation on metabolic measures, endothelial functioning (Reactive Hyperemia Index (RHI)), and global methylation in AAP-treated schizophrenia subjects meeting NCEP-ATP-III-a metabolic syndrome criteria.
  
  
  METHODS
  Subjects were given 5 mg/day open label folate for 3 months. Baseline and end point measurements included RHI, body mass index, fasting metabolic laboratory measures, C-reactive protein, homocysteine, IL-6, and leptin. Subjects were genotyped for methylenetetrahydrofolate reductase (MTHFR) 677C/T and catechol-O-methyltransferase (COMT) 158 Val/Met, as well as global DNA methylation using the LUminometric Methylation Assay (LUMA).
  
  
  RESULTS
  Thirty-five subjects (mean age 50±9 years and 70% Caucasian) were included. At end point, RHI improved by 20% (P=0.02), homocysteine decreased 14% (P=0.006), and IL-6 decreased 13% (P=0.09). At baseline, 61% met endothelial dysfunction criteria (RHI<1.67), which decreased to 27% (P=0.0006) at end point. The MTHFR 677C/C+COMT 158Met/Met group also showed significant reduction in those meeting endothelial dysfunction (83% baseline and 16% end point (P=0.001)). Global methylation levels increased after supplementation (4.3%, P<0.0001), with subjects receiving olanzapine or clozapine experiencing greater methylation changes after folate supplementation. Folate may reduce AAP-associated metabolic risks.
  
  
  CONCLUSIONS
  We report significant reductions in the number of subjects meeting endothelial dysfunction. Given that all subjects met metabolic syndrome criteria, this may prove as a useful avenue to reducing cardiovascular disease risk. MTHFR and COMT genotypes may affect response and underlying changes in DNA methylation may help to explain the mechanistic underpinnings of these findings.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Ellingrod
authors.affiliation: Department of Psychology, University of Michigan , Ann Arbor, MI, USA.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Grove
authors.affiliation: Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, MI, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Burghardt
authors.affiliation: Department of Psychiatry, University of Michigan , Ann Arbor, MI, USA.
authors.forename: Stephan F
authors.initials: SF
authors.lastname: Taylor
authors.affiliation: Department of Psychiatry, University of Michigan , Ann Arbor, MI, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Dalack