Progress in Neuro-Psychopharmacology and Biological Psychiatry
Association of the ADRA1A gene and the severity of metabolic abnormalities in patients with schizophrenia
Highlights
► A relationship between the metabolic syndrome components and the ADRA1A gene. ► The roles of the ADRA1A, ADRA2A, ADRB3, and 5HT2A genes in metabolic syndrome. ► Emphasis of a high prevalence of metabolic syndrome among people with schizophrenia. ► Psychiatric pharmacogenetics for susceptibility to the metabolic syndrome.
Introduction
Metabolic syndrome is a clustering of several interrelated cardiovascular risk factors. The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP Adult Treatment Panel III [NCEP ATP III]) (Grundy et al., 2005) defines 5 criteria for clinical identification of metabolic syndrome, including abdominal obesity, hypertriglyceridemia, low level of high-density lipoprotein cholesterol (HDL-C), hypertension, and elevated fasting glucose level, with diagnosis requiring 3 or more components. Several studies have shown that metabolic syndrome is associated with the risk of coronary heart disease, type 2 diabetes mellitus, hypertension, cardiovascular disease, and all-cause mortality (Alberti et al., 2005, Einhorn et al., 2003, Lakka et al., 2002). The prevalence of cardiovascular disease, death from cardiovascular causes (Ryan and Thakore, 2002), and the risk of developing metabolic abnormalities (Marder et al., 2004, Suvisaari et al., 2007, Thakore, 2005) are higher in patients with schizophrenia than in the general population. This phenomenon may be associated with intrinsic metabolic deficiencies in schizophrenia (Thakore, 2005), antipsychotic medication, and with many lifestyle-related cardiovascular risk factors such as lack of exercise, poor diet habits, and smoking, among others (Silverstein et al., 2009, Vancampfort et al., 2010). On the other hand, some studies found that the accumulative number of metabolic syndrome components was associated with mortality from cardiovascular disease and coronary heart disease, and the incidence of ischemic stroke (Ford, 2004, Rodriguez-Colon et al., 2009).
Clinical observation of substantial inter-individual and population differences in weight gain in patients with schizophrenia has implicated genetic involvement. Basile et al. (2001) first tested 10 genetic polymorphisms across 9 candidate genes, including the 5-HT2C, 2A, and 1A receptor genes (HTR2C/2A/1A), the histamine H1 and H2 receptor genes (H1R/H2R), the cytochrome P450 1A2 gene (CYP1A2), the adrenergic alpha1A and beta3 receptor genes (ADRA1A/ADRB3), and the tumor necrosis factor-alpha gene (TNF-α) in 80 patients with schizophrenia (58 Caucasians, 22 African-Americans). Associations between weight gain and the ADRB3, ADRA1A, TNF-α, and HTR2C genes were identified. Many related studies on genetics were conducted thereafter, and the results of these studies are summarized below. First, the ADRA1A gene was shown to be related to obesity and other cardiovascular risk factors (Freitas et al., 2008, Gunes et al., 2009, Ochoa et al., 2004, Phares et al., 2004, Piascik and Perez, 2001). One recent study found an association between the ADRA1A gene and weight gain in 401 Taiwanese chronic schizophrenia patients exposed to antipsychotics (Liu et al., 2010). Second, a role for ADRA2A C1291G polymorphism in olanzapine- and/or clozapine-induced weight gain was reported in Korean (Park et al., 2006), Taiwanese (Wang et al., 2005), and European-American and African-American (Sickert et al., 2009) patients with schizophrenia. Third, the ADRB3 Trp64Arg polymorphism gene has been reported to be associated with obesity, features of metabolic syndrome, insulin resistance syndrome, and the early onset of diabetes mellitus (Sakane et al., 1997, Walston et al., 1995). However, a study in a Taiwanese population showed a lack of association between Trp64Arg in the ADRB3 gene and clozapine-induced weight gain (Tsai et al., 2004), and little or no influence on body weight, body mass index (BMI), or atypical antipsychotics-induced weight gain was reported in other studies (Arii et al., 1997, Masuo et al., 2005, Matsushita et al., 2003). Fourth, a study that included 164 Japanese patients with schizophrenia examined the genetic association with multiple candidate genes and identified genetic variants of the 5HT2A, HTR2C, ADRB3, and G-protein β3 subunit (GNB3) genes as genetic risk factors for olanzapine-induced weight gain (Ujike et al., 2008).
In view of these findings, we aimed to examine the roles of the ADRA1A, ADRA2A, ADRB3, and 5HT2A genes in metabolic syndrome among patients with schizophrenia. Because metabolic syndrome is a clustering of several interrelated cardiovascular risk factors, application of the concept of the accumulative number of metabolic syndrome components provides an appropriate index for the genetic study of metabolic syndrome. In this study, we tried to investigate the associations between the four candidate gene polymorphisms and the accumulative number of metabolic syndrome components.
Section snippets
Participants
Patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for schizophrenia or schizoaffective disorder were recruited for this study. Participants were excluded if they had any axis I or II disorders other than the primary diagnosis of schizophrenia or schizoaffective disorder, any neurological condition, or head trauma. A total of 232 unrelated inpatients (120 males and 112 females) with a mean age of 43.4 ± 11.6 years were
Baseline characteristics
Two hundred and thirty-two patients were available for the analysis. Among these subjects, twenty-two subjects had incomplete data on metabolic syndrome components. The model fitness test indicated no significant effect of the missing components on the overall performance (data not shown), and thus these subjects were left in the following analysis. The demographic characteristics of the participants, grouped by the accumulative number of metabolic syndrome components (≧ 3, severe form; < 3, mild
Discussion
In this study, we found a significant association between the Arg347 allele of the ADRA1A gene and the severity of metabolic abnormalities in patients with schizophrenia in an ordinal logistic regression model. As many studies have revealed that patients with schizophrenia have a higher risk of developing metabolic abnormalities and increased risks of developing type 2 diabetes mellitus, cardiovascular disease, cerebrovascular disease, and cardiovascular mortality (Marder et al., 2004,
Conclusions
In conclusion, this study showed a relationship between the accumulative number of metabolic syndrome components and the ADRA1A gene. Presence of the Arg347 allele in the ADRA1A gene is a risk factor for the increase of the accumulative number of metabolic syndrome components, which means a higher risk of having more severe metabolic abnormalities. These findings imply a potential clinical application in psychiatric pharmacogenetics that chronic schizophrenia patients with a high risk genotype
Acknowledgments
We thank the lab technicians, who devoted much time and effort to this study. The project funding was provided by a grant from the Taoyuan Mental Hospital.
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These two authors contributed equally to this work.