MTHFR and risk of metabolic syndrome in patients with schizophrenia

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Abstract

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% CI 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% CI 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% CI 1.51–9.96) than in subsample treated with any of the other antipsychotics (OR C/C versus A/A 1.30, 95% CI 0.47–3.74), although this did not formally reach statistical significance in the current cross-sectional study (gene-by-group interaction χ2 = 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.

Introduction

High prevalence rates of metabolic dysregulation and cardiovascular morbidity and mortality (CVD) have been consistently reported in patients with schizophrenia (De Hert et al., 2006b, van Winkel et al., 2006), with lifestyle factors and antipsychotic medication, especially clozapine and olanzapine, as likely contributing factors (De Hert et al., 2009, Newcomer, 2008, Scheen and De Hert, 2007). Patients treated with these agents, however, do not all develop weight gain or metabolic disturbances (De Hert et al., 2008), which may in part be due to differences in underlying genetic vulnerability. Given the impact of metabolic disturbances on CVD risk (Correll et al., 2006), treatment compliance (Weiden et al., 2004), clinical outcome (Lyketsos et al., 2002) and self-esteem (De Hert et al., 2006a), there is a pressing need to identify vulnerability genes for metabolic dysregulation in patients with schizophrenia.

The gene encoding for 5,10-methylenetetrahydrofolate reductase (MTHFR) represents an interesting candidate for further consideration. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, the predominant circulating form of folate. 5-Methylenetetrahydrofolate donates a methyl group to homocysteine in the generation of S-adenosylmethionine (SAM), a major source of methyl groups in the brain (Cantoni, 1953). Methyl groups are required for DNA methylation, which takes place at the carbon-5 position of cytosine in CpG dinucleotides and changes gene expression by blocking transcription factors, attracting gene-repressing molecules and altering the chromatin packaging of DNA (Jirtle and Skinner, 2007).

Two common single nucleotide polymorphisms have been described in the MTHFR gene, situated at codon 677 (C→T) and 1298 (A→C) respectively. Both polymorphisms are functional and result in diminished enzyme activity, leading to lower folate and higher homocysteine levels. Each copy of the 677T allele causes a 35% reduction of enzyme activity (Frosst et al., 1995), whereas individuals with the 1298C allele may have more moderate reductions in enzyme activity (van der Put et al., 1998). Three recent meta-analyses involving more than 25,000 patients have shown a significantly increased risk for cardiovascular disease (CVD) in persons carrying the 677T-variant (Klerk et al., 2002, Lewis et al., 2005, Wald et al., 2002). Furthermore, both MTHFR polymorphisms have been associated with schizophrenia risk in recent meta-analyses (Allen et al., 2008, Shi et al., 2008).

Nevertheless, only one preliminary report investigated the association between MTHFR polymorphisms and metabolic risk in a sample of 58 patients with schizophrenia and found an increased risk for the metabolic syndrome in patients carrying a 677T-allele (Ellingrod et al., 2008). Therefore, the current study aimed to investigate the association between the two functional polymorphisms in MTHFR and metabolic syndrome in a large, naturalistic cohort of patients with schizophrenia recruited at the Catholic University of Louvain, Belgium, where all psychotic patients are systematically screened for metabolic disturbances using a standard protocol (De Hert et al., 2006b, van Winkel et al., 2006).

Section snippets

Sample

All patients in receipt of antipsychotic medication and in treatment at the University Psychiatric Centre of the Catholic University in Louvain (Belgium) were routinely screened for the presence of metabolic abnormalities (van Winkel et al., 2006, van Winkel et al., 2008a) and asked for permission to store a blood sample for genetic analyses. This screening routine was described extensively elsewhere (De Hert et al., 2006b, van Winkel et al., 2006, van Winkel et al., 2008b). The study

Sample

The sample consisted of 518 individuals (66.4% male) with a non-affective psychotic disorder who were on average 35.0 years old (SD 11.1). They had clinical diagnoses of schizophrenia (69.3%), schizophreniform disorder (11.4%) or schizoaffective disorder (19.3%). The vast majority of the sample was White (97.3%); 1.9% was Black and 0.8% was Asian. The metabolic syndrome was present in 33.2% of the sample. Gender, level of education and age at first admission did not differ according to MTHFR

Findings

The current study found evidence that the reported schizophrenia risk polymorphism MTHFR A1298C is associated with metabolic syndrome in patients with a schizophrenia spectrum disorder. In contrast to our hypothesis, we did not find an increased risk for the metabolic syndrome in MTHFR 677T-carriers.

These findings are of considerable interest, as they may potentially help to identify patients with schizophrenia at the highest risk for developing metabolic dysregulation. Furthermore, there was a

Role of funding source

None.

Contributors

The study was designed by R van Winkel, J van Os† and M De Hert†.

O Peerbooms did the genotyping. R van Winkel wrote the first draft of the paper, B Rutten, O Peerbooms, J Peuskens, J van Os† and M De Hert† commented and contributed to the subsequent revisions.

† These authors contributed equally to the manuscript.

Conflict of interest

Dr. van Winkel has been a consultant for Eli Lilly and received honoraria from AstraZeneca, Eli Lilly and Janssen-Cilag. Dr. Rutten received honoraria from Janssen-Cilag. Dr. Peerbooms did not receive financial support or compensation from any individual or corporate entity over the past three years for research or professional service. Dr. Peuskens has acted as a consultant and co-operated in clinical trials with AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer and

Acknowledgements

We would like to thank Dr. Gunter Kenis for his help in the genotyping and Kim Sweers for her help with the data collection.

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