engleski

The impact of ACE gene I/D polymorphism on plasma glucose and lipid concentrations in schizophrenia patients

A functional 287 nucleotide fragment insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene, by affecting ACE levels, may influence various pleiotropic effects of ACE. The I/D polymorphism has been extensively associated with the development of the metabolic syndrome and its separate components such as diabetes mellitus and dyslipidemia in the general population (Mittal et al., 2011). Since the ACE enzyme plays an important role in the functioning of the dopamine system in the brain, the I/D polymorphism has also been investigated in schizophrenia, yet with conflicting results (Crescenti et al., 2009 ; Nadalin et al., 2012 ; Hui et al., 2014 ; Zhang et al., 2014). Schizophrenia patients have a significantly higher risk of developing diabetes, dyslipidemia and obesity and it has been determined that treatment with atypical antipsychotic medications particularly contributes to abnormalities in the glucose and lipid metabolism in those patients (Kapur and Remington, 2001). In our recent study we found no association between the I/D polymorphism and schizophrenia risk in the Croatian population, but we revealed a significant polymorphism's impact on the clinical expression of the illness (Nadalin et al., 2012). We undertook the current study to determine whether and to what extent plasma glucose and lipid concentrations in schizophrenia patients may be influenced by ACE-I/D polymorphism. Our study group consisted of 211 chronically ill schizophrenia patients (115 males, 96 females) from the Department of Psychiatry of the Clinical Medical Centre in Rijeka, Croatia (N = 110) and the Psychiatric Hospital in Rab, Croatia (N = 101), aged 43.1 ± 10.8 years, all Croatian citizens. Diagnoses were assessed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the structural clinical interview. The investigation was carried out in accordance with the latest version of the Declaration of Helsinki. The study was approved by the Ethics Committee of the School of Medicine, University of Rijeka, Croatia. All patients gave informed consent to the analysis. Allele/genotype frequencies were determined by polymerase chain reaction/restriction fragment length polymorphism in the Laboratory for Molecular Genetics (Department of Biology and Medical Genetics, School of Medicine, Rijeka). Biochemical measurements (determination of fasting plasma glucose, total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride levels) were carried out in the Department of Clinical Laboratory Diagnostics of the Clinical Medical Centre Rijeka. The difference between means of plasma glucose and lipid levels according to the ACE-I/D polymorphism was revealed by the one-way ANOVA analysis of variance (ANOVA). The association between glucose and lipid levels and ACE-I/D allele/genotype variants was tested using multiple stepwise regression analysis, adjusted for the patient's age. Considering the possible interaction of the biochemical measurements with the patient's gender, we performed separate analyses among males and females. Statistical analyses were conducted using Statistica for Windows, version 9 (StatSoft, Inc., Tulsa, OK, USA). The P values less than 0.05 (P < 0.05) were considered statistically significant. The frequencies of the genotypes DD, ID and II were 0.299 (N = 63), 0.493 (N = 104) and 0.208 (N = 44), and the frequencies of the D and I alleles were 0.545 (N = 230) and 0.455 (N = 192), respectively. We did not find significant gender differences neither in the frequencies of the genotypes DD, ID and II (males vs. females: 0.278, 0.470 and 0.252 vs. 0.323, 0.521 and 0.156) nor in the frequencies of the D and I alleles (males vs. females: 0.513 and 0.487 vs. 0.583 and 0.417) (P > 0.05). The multiple stepwise regression analysis revealed a significant association between the ACE genotype and mean plasma glucose levels in females ( = -0.60, F = 8.40, P = 0.005). Females heterozygous for the ACE genotype (ID ; N = 50) had significantly higher glucose levels when compared to those DD homozygous (N = 31) and II homozygous (N = 15) (6.1 ± 1.2 vs. 5.3 ± 0.7 and 5.4 ± 0.9 ; one-way ANOVA test: F = 3.84, P = 0.026). The ACE genotype accounted for approximately 9% of plasma glucose levels variability (R2 change = 0.09). Furthermore, the ACE-ID polymorphism affected plasma triglyceride levels in males, although its impact only approached statistical significance (multiple stepwise regression analysis:  = 0.31, F = 3.92, P = 0.055). Males carrying the D allele in the ACE genotype (DD homozygous or ID heterozygous ; N = 86) trended toward higher triglyceride levels than those II homozygous (N = 29) (2.3 ± 1.4 vs. 1.5 ± 0.8 ; one-way ANOVA test: F = 3.92, P = 0.055). This is the first report investigating the possible influence of ACE-I/D polymorphism on plasma glucose and lipid levels in schizophrenia. Our results suggest gender dependent effect of the ACE-I/D polymorphism on glucose and lipid metabolism. Thus, males carrying the D allele in their ACE genotype (DD homozygous or ID heterozygous) trended toward an elevated risk for developing dyslipidemia. Furthermore, female patients heterozygous for the ACE genotype (ID) had significantly greater risk for diabetes mellitus than those DD homozygous and II homozygous. The strength of the observed association (P = 0.005) between glucose levels in female patients and ACE genotype is strong, and, to our opinion, the ACE genotype satisfactorily described plasma glucose levels (multiple stepwise regression: R2 change = 0.09). Intriguingly, this is also the first study reporting highest plasma glucose concentrations in ACE-ID heterozygous individuals while investigating the association between ACE-I/D polymorphism and glucose levels. Previous studies revealed highest plasma glucose levels in the ACE homozygous (DD) genotype as well as in the ACE homozygous (II) genotype, in patients with the metabolic syndrome (Aguilar et al., 2007 ; Mittal et al., 2011). Moreover, Zingone et al. (1994) determined the highest glucose levels in the ACE homozygous (DD) genotype among a random sample of male subjects from the general population. Thus, our results indicate that the mechanism by which the ACE may maintain glucose homeostasis possibly differs in schizophrenia compared to other diseases and/or conditions. Further studies, considering other measurements of glucose metabolism (assessing insulin sensitivity, glucose tolerance tests, etc.), as well as monitoring the possible interaction between ACE-ID polymorphism and environmental factors (diet, smoking, antipsychotic medications) on the glucose and lipid metabolism should be conducted to replicate our findings.

angiotensin converting enzyme gene ; I/D polymorphism ; schizophrenia

nije evidentirano