A systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia

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Abstract

Metabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene (FTO), leptin and leptin receptor genes (LEP, LEPR), methylenetetrahydrofolate reductase (MTHFR) gene and the serotonin receptor 2C gene (HTR2C). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality.

Introduction

Metabolic syndrome (MetS) is a grouping of biochemical and physiological risk factors for cardiovascular disease (CVD), including abdominal obesity, dyslipidaemia, insulin resistance and elevated blood pressure (BP) (Cornier et al., 2008). These individual components of MetS are independent risk factors for CVD as well. The presence of MetS has also been associated with other comorbidities such as the prothrombotic state, nonalcoholic fatty liver disease, proinflammatory states and reproductive disorders (Cornier et al., 2008). The incidence of MetS is significantly higher in patients with schizophrenia than in the general population (De Hert et al., 2006). Indeed, CVD has been identified as one of the leading causes of mortality among patients with schizophrenia (Yu et al., 2013). There are several definitions of MetS, however the International Diabetes Federation Task Force recently proposed revised criteria in an attempt to unify the diagnosis of MetS internationally (Alberti et al., 2009). According to this revision, MetS can be diagnosed if any three of the five criteria described below are present:

  • 1.

    Elevated waist circumference, according to population- and country-specific definitions

  • 2.

    Elevated triglycerides (TG) (≥ 150 mg/dl or 1.7 mmol/l) or pharmacological treatment for elevated TG

  • 3.

    Reduced high-density lipoprotein cholesterol (HDL-C) (< 40 mg/dl or 1.03 mmol/l in males and < 50 mg/dl or 1.29 mmol/l in females) or pharmacological treatment for reduced HDL-C.

  • 4.

    Elevated blood pressure (BP) (systolic  130 mmHg, diastolic  85 mmHg) or pharmacological treatment for hypertension.

  • 5.

    Elevated fasting glucose (≥ 100 mg/dl or 5.6 mmol/l) or pharmacological treatment for hyperglycemia

The high prevalence of MetS in patients with schizophrenia has, in part, been attributed to unhealthy lifestyle, including poor diet and sedentary behavior and smoking (Ringen et al., 2014). However, in recent years, the severe metabolic side-effects of antipsychotics (APs) have also become more apparent (Fleischhacker et al., 2008, Casey et al., 2004, Leucht et al., 2007). In particular, second-generation APs (SGA), such as Olanzapine (OLZ) and Clozapine (CLZ) are associated with metabolic abnormalities (Rummel-Kluge et al., 2010). Treatment with these drugs has been found to cause weight gain (Gunes et al., 2009, Simpson et al., 2001) and increase blood lipid and glucose levels (Smith et al., 2008). Low-potency first-generation APs (FGAs), administered to first-episode psychosis (FEP) patients, have also been associated with increased body mass index (BMI) and lipid profiles over time (Chiliza et al., 2015). While the use of APs is associated with weight gain (Bak et al., 2014), the high incidence of MetS in patients with schizophrenia cannot be solely attributed to the APs. For instance, in the twentieth century, prior to the development of AP medications, Henry Maudsley noticed an association between diabetes and schizophrenia (Maudsley, 1979). Since that time, studies have also demonstrated that AP-naïve patients exhibit increased visceral fat distribution, impaired glucose tolerance and increased insulin resistance compared with normal controls (Thakore et al., 2002, Venkatasubramanian et al., 2007, Fernandez-Egea et al., 2008). Furthermore, some studies have noted an increased prevalence of type II diabetes in the parents of individuals with non-affective psychosis and increased glucose intolerance in the siblings of patients with schizophrenia (Fernandez-Egea et al., 2009a, b), suggesting that heritable factors (genetic or epigenetic) may contribute to this increased prevalence.

A recent Danish study found that schizophrenia was associated with a type II diabetes risk allele located in the transcription factor 7-like 2 (T-cell specific, HMG-box) (TCF7L2) gene (Hansen et al., 2011), which suggests that diabetes and schizophrenia may share familial risk factors or a common genetic predisposition (Papanastasiou, 2013). Furthermore, studies have suggested that the presence of polymorphisms in certain candidate genes may result in increased susceptibility to the development of MetS with AP treatment (Gunes et al., 2009). It has, therefore, been hypothesized that the risk of developing MetS in patients with schizophrenia is influenced by an interaction between genetic polymorphisms, lifestyle factors and APs (Smith et al., 2008). The identification of polymorphisms that play a role in the development of MetS in patients with schizophrenia could facilitate the development of optimal treatment strategies (Smith et al., 2008). This systematic review focuses on 34 studies that have investigated genetic polymorphisms which may be associated with more severe metabolic derangements in these patients (Table 1, Supplementary Table S1). However, differences across studies make it difficult to ascertain the extent to which genetic polymorphisms play a role. Sources of heterogeneity include AP prescription and MetS diagnostic parameters. Sample size, ethnicity, gender, comorbidity, antidepressant use, age of onset, lifestyle and substance abuse are additional factors that may influence the role played by genetic polymorphisms in the development of MetS.

In this study, we systematically review and compare association studies of genes implicated in the development of MetS in patients with schizophrenia, in an effort to identify common variants that may contribute to the high comorbidity between MetS and schizophrenia, and which could, potentially, identify patients at increased risk for developing MetS.

Section snippets

Search strategy

Independent searches were performed during June 2014–June 2015 in three databases, namely PubMed, Web of Science and Scopus. The following search terms were used: (‘schizophrenia’ or ‘schizophrenic’ or ‘psychosis’ or ‘schizophrenia spectrum’ or ‘schizoaffective’ OR ‘delusional’) and (‘genes’ or ‘genetic’ or ‘genetic polymorphism’ or ‘gene variant’ or ‘single nucleotide polymorphism’) and (‘metabolic syndrome’ or ‘MetS’ or ‘cardiometabolic syndrome’). No filters were included.

Inclusion criteria

  • Studies published

Included studies

Database searches resulted in a total of 1905 records. Of these, 1506 duplicate records and seventeen records that were not in English were excluded. The remaining 382 records were screened and 341 records were excluded on the basis that these were either animal studies, meta-analyses or systematic reviews, conference papers, or studies that did not investigate genetic polymorphisms, MetS or schizophrenia. Forty-one full-text articles were reviewed and seven studies were excluded as they did

Discussion

This systematic review compared studies that investigated the association between genetic variants and the development of MetS in patients with schizophrenia, with the aim of identifying common variants in patients at particular risk for developing MetS. Replication across multiple studies and longitudinal study designs provided more robust evidence for variants that are truly associated with MetS (or features of MetS) in patients with schizophrenia (e.g., LEP, LEPR, HTR2C, FTO and MTHFR). For

Conclusions and future recommendations

Future studies should include larger samples, healthy control groups, FEP drug-naïve patients and longitudinal study designs with longer follow-up periods. Also, in view of the differential adipogenic and dysmetabolic effects of APs, treatment should be standardized. It is possible that certain metabolic abnormalities might only manifest after chronic and long-term (several years) exposure to APs, as shown by Reynolds et al. (2013). Where possible, information on other factors associated with

Role of funding source

No funding body agreements. See list of funders under acknowledgements.

Contributors

SS designed the study and SMM and SK performed the literature searches, collected and analyzed the data and constructed the draft manuscript. SS, SMJH, LA, RAE, SB, LvdH and LW assisted with writing and editing of manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

SMM, SK, SMJH, SB, LvdH, LW and LA declare no conflict of interests. RAE has received honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Lundbeck, Organon, Pfizer, Servier, Otsuka and Wyeth for participating in advisory boards and speaking at educational meetings, and has received research funding from Janssen, Lundbeck and AstraZeneca. SS has received pharmaceutical sponsorship from Pfizer, Astra Zeneca, Servier, and Dr. Reddy's, speaker's honoraria from Pfizer and Lundbeck, and

Acknowledgments

This work is supported by the Medical Research Council of South Africa (MRC Flagship Grant RFA-UFSP-01-2013) and the South African Research Chair in Posttraumatic Stress Disorder (SARChI UID 64811), funded by the Department of Science and Technology and the National Research Foundation.

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