Prostaglandins, Leukotrienes and Essential Fatty Acids 91 (2014) 221–225 Contents lists available at ScienceDirect Prostaglandins, Leukotrienes and Essential Fatty Acids journal homepage: www.elsevier.com/locate/plefa PPARα-L162V polymorphism is not associated with schizophrenia risk in a Croatian population S. Nadalin a, J. Giacometti b, A. Buretić-Tomljanović a,n a b Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia Department of Biotechnology, University of Rijeka, Slavka Krautzeka bb, 51000 Rijeka, Croatia art ic l e i nf o a b s t r a c t Article history: Received 28 February 2014 Received in revised form 18 June 2014 Accepted 4 July 2014 Disturbances of lipid and glucose metabolism have been repeatedly reported in schizophrenia. A functional L162V polymorphism in peroxisome proliferator-activated receptor alpha (PPARα) gene has been extensively investigated in etiology of abnormal lipid and glucose metabolism, yet not in schizophrenia. We determined whether the schizophrenia risk was associated with L162V polymorphism and we examined the impact of L162V variant on age of onset, and data of psychopathology scores. We also hypothesized that plasma glucose and lipid concentrations in patients may be influenced by L162V polymorphism. Genotype and allele frequencies between 203 patients and 191 controls did not differ significantly. Females heterozygous for the PPARα genotype (L162V) manifested significantly lower negative symptom scores, tended toward an earlier onset, and had significantly greater triglyceride levels. The PPARα-L162V polymorphism is not associated with schizophrenia risk in Croatian population, but it impacts clinical expression of the illness and plasma lipid concentrations in female patients. & 2014 Elsevier Ltd. All rights reserved. Keywords: L162V polymorphism Peroxisome proliferator-activated receptor alpha Positive and Negative Symptom Scale Schizophrenia 1. Introduction Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that belongs to the nuclear steroid receptor superfamily [1,2]. Activated by its ligand, PPARα heterodimerizes with retinoid X receptor, and binds to peroxisome proliferator response elements in the promoter region of genes to modulate their expression [2,3]. Due to its role in regulation of the expression of genes involved in fatty acid uptake, transport, β- and ω-oxidation, and ketogenesis, PPARα represents an important mediator of lipid and glucose metabolism [2,3]. Dietary fatty acids, particularly long chain polyunsaturated fatty acids (LC-PUFAs), such as arachidonic acid (20:4n 6, ARA), eicosapentaenoic acid (20:5n 3, EPA) and docosahexaenoic acid (22:6n 3, DHA) are known to be potent natural ligands of PPARα [3,4]. Several experiments in animal models suggest that PPARα may act as an important sensor of LC-PUFA status in organism [5,6]. It has been established that under conditions of essential fatty acid deficiency PPARα can enhance LC-PUFA synthesis from precursor PUFAs, such as linolenic acid (18:2n 6, LA) and alpha linolenic acid (18:3n 3, ALA), by increasing activity of Δ6- and Δ5-desaturases and elongases [6,7]. n Corresponding author. Tel.: þ 385 51 651 182; fax: þ385 51 678 896. E-mail address: alenabt@medri.uniri.hr (A. Buretić-Tomljanović). http://dx.doi.org/10.1016/j.plefa.2014.07.003 0952-3278/& 2014 Elsevier Ltd. All rights reserved. Patients with schizophrenia have significantly increased risk of developing diabetes, dyslipidemia and obesity, while mortality from coronary artery disease is two to three times greater than in the general population [8,9]. Treatment with antipsychotic medications particularly increases abnormalities in glucose and lipid metabolism in schizophrenia [8,10]. Furthermore, PUFA deficits both in red blood cell (RBC) membranes and postmortem brain tissues have been extensively reported in schizophrenia [11–14]. Decreased RBC membrane PUFA levels in patients with schizophrenia, mainly attributed to lower contents of LA, EPA and DHA, have been previously reported in our study as well [15]. To date, only one study, performed in the Japanese population, has been investigated association between PPARα gene polymorphic variations and etiology of schizophrenia [16]. However, no association between investigated Val227Ala polymorphism of the PPARα gene and risk for schizophrenia has been reported in their study [16]. Furthermore, there are no reports of Val227Ala polymorphism in the European population [17]. The leucine 162 valine (L162V) polymorphism, caused by a C to G transversion in exon 5, is the most studied variant of the PPARα gene [4,18]. While the influence of PPAR-L162V polymorphism has been intensively studied in dyslipidemia, some measures of adiposity, risk for coronary ischemic events, and age of onset in patients with diabetes [3,18–20], the relevance of L162V polymorphic variation on lipid and glucose metabolism in patients with schizophrenia has not been investigated so far. The less common V allele, the 222 S. Nadalin et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 91 (2014) 221–225 frequency of which varies from from 2–4%, however, was found exclusively in the European population [21]. To date, several studies have reported gender specific differences in L162V genotype effect on lipid metabolism [3,22,23]. Because PPARα gene is a key regulator of glucose and lipid homeostasis, variations of this gene could possibly contribute to the etiology of schizophrenia, or may influence its clinical expression. We aimed to determine whether the risk for schizophrenia was associated with L162V polymorphism of the PPARα gene in the Croatian population, and to examine the possible impact of the L162V polymorphism on mean age of onset, and baseline psychopathology data, measured via Positive and Negative Symptom Scale (PANSS) scores, in the patient group. We further hypothesized that PPARα-L162V polymorphism may influence plasma glucose and lipid concentrations in patients with schizophrenia. 2. Patients and methods 2.1. Study participants Our study group was comprised of 203 chronically ill schizophrenia patients (111 males and 92 females), recruited from the Department of Psychiatry, Clinical Medical Centre in Rijeka, Croatia (n¼110), and Psychiatric Hospital in Rab, Croatia (n¼93), between 2007 and 2010, and 191 non-psychiatric control subjects (87 males and 104 females). Rijeka and the island of Rab belong to the same geographic area. Patients' clinical data are presented in Table 1. Diagnoses were assessed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the structured clinical interview. Age of onset was obtained from medical records and determined as the patient's age at the time at their first hospital admission due to a psychotic episode at which the diagnosis of schizophrenia was used. Evaluation of PANSS psychopathology was performed at the time of last admission, during an acute state of the illness requiring hospitalization. The investigation was carried out in accordance with the latest version of the Declaration of Helsinki. After the study's purpose and methods had been described, all participants provided written informed consent to participate in the study, which had been approved by the Ethics Committee of the School of Medicine, University of Rijeka, Croatia. The control individuals were blood donors who underwent no specific examination for psychiatric status, but declared no psychiatric records. The practice with blood donation in Croatia includes providing a written statement about health status at every session. Therefore, blood donors are representatives of healthy general population, free of chronic diseases or regular medication. 2.2. Methods 2.2.1. Genotyping Genomic DNA was extracted from whole blood using a FlexiGene DNA kit 250 (QIAGEN GmbH, Hilden, Germany) according to the manufacturer's instructions. Genotyping was performed in the Laboratory for Molecular Genetics (Department of Biology and Medical Genetics, School of Medicine, Rijeka) by polymerase chain reaction/restriction fragment length polymorphism analysis using protocol previously described [24]. 2.2.2. Biochemical measurements Venous blood samples were collected from fasting patients. Plasma was separated by centrifugation at 1100g for 10 min from blood cells and used immediately for the determinations of glucose, total cholesterol and triglycerides. The analyses were carried out in the Department of Clinical Laboratory Diagnostics of the Clinical Medical Centre Rijeka. Fasting plasma glucose levels Z7.0 mmol/l, total cholesterol levels45.0 mmol/l and triglyceride levels4 2.0 mmol/l were considered elevated for the Croatian population [25]. 2.2.3. Statistical analysis Descriptive statistics was used to calculate the mean ages and mean PANSS scores in the patient group. Genotype and allele distributions between patients and controls, as well as observed and expected genotype proportions under Hardy–Weinberg equilibrium, were compared by the χ2-test. The t-test was applied to compare the means of investigated clinical and biochemical measurements in patients with schizophrenia according to PPARα genotypes. The association between several clinical features (mean age at first hospital admission, and positive, negative, general and total PANSS scores) and PPARα genotypes, as possible predictors, was tested using multiple stepwise regression analysis, adjusted for age at PANSS assessment, and sex, in patients with schizophrenia. Table 1 Clinical and biochemical features according to PPARα genotypes. Patients (n¼ 203) Age (years) Age at first hospital admission PANSS positive symptoms score PANSS negative symptoms score PANSS general psychopathology score PANSS total score Body mass index (kg/m2) Glucose (mmol/L) Total cholesterol (mmol/L) Triglycerides (mmol/L) Males Females Males Females Males Females Males Females Males Females Males Females Males Females Males Females Males Females Males Females L162L L162V 42.8 712.3 44.6 711.7 26.1 77.7 29.0 79.1 26.8 75.5 26.1 75.1 29.3 75.9 30.0 75.8 52.1 76.8 52.9 76.9 108.2 713.3 109.0 713.1 26.8 73.8 26.9 74.5 5.7 71.2 5.7 71.0 5.4 71.5 5.8 71.0 2.1 71.2 1.5 70.7 40.17 8.8 39.17 8.8 26.5 7 5.6 22.4 7 5.0 26.2 7 4.5 28.8 7 5.7 31.7 7 6.7 24.0 7 7.6 52.8 7 8.3 53.7 7 3.6 110.7 7 18.0 106.57 9.8 25.6 7 4.8 29.2 7 5.1 5.4 7 1.1 5.8 7 0.7 4.4 7 1.4 5.4 7 1.3 1.7 7 1.2 2.4 7 1.0 t p 1.20 0.60 0.18 1.88 0.28 1.22 0.93 2.34 0.25 0.31 0.42 0.46 0.44 0.99 0.65 0.24 1.02 0.53 0.53 2.09 n. s. n. s. n. s. n. s. n. s. n. s. n. s. o 0.05 n. s. n. s. n. s. n. s. n. s. n. s. n. s. n. s. n. s. n. s. n. s. o 0.05 S. Nadalin et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 91 (2014) 221–225 We considered p o0.05 statistically significant. All statistical analyses were conducted using Statistica for Windows, version 9 (StatSoft, Inc., Tulsa, OK, USA). 223 patients. Female carriers of the V162 allele had higher triglyceride concentrations (t-test: t¼2.09, po0.05) (Table 1). 4. Discussion and conclusions 3. Results 3.1. PPARα genotypes and alleles distribution The genotype frequencies of L162V polymorphism in both patients and control individuals were consistent with Hardy– Weinberg equilibrium (Table 2). Allele frequencies were 0.956 (L162¼388) and 0.044 (V162 ¼18) in the patient group, and 0.953 (L162¼364) and 0.047 (V162¼ 18) in the control group. There were no significant differences in the frequencies of genotype and allele distributions between patients and controls (Table 2). Genotype and allele frequencies between males and females also did not show significant difference (data not shown). Based on the number of total subjects involved (203 patients and 191 controls), the statistical power of our study was 80% in detecting a 2.1-fold increase in PPARα-V162 allele frequency. 3.2. Clinical expression and biochemical measurements in relation to PPARα genotype Evidence suggests that variability in the clinical presentation of schizophrenia favors females, since women affected by the illness tend to have better premorbid functioning, a later age of onset, lower prevalence of negative symptoms and better course of illness [26–28]. However, age at first hospital admission between males and females did not reach statistical significance in our sample (data not shown). We did not find statistically significant association between mean age at first hospital admission, and investigated PPARα genotypes, although heterozygous females (L162V) tended toward an earlier onset of illness when compared to those homozygous (L162L) (22.4 75.0 vs. 29.0 79.1, respectively) (Table 1). Since severity of negative symptoms is known to increase with patient's age [29], we included mean age of our patients into predictor variables to control for the age effect in regression analysis. Multiple regression analysis detected significant correlation between PPARα genotype and negative symptoms severity in female patients (βPPARα ¼ 0.25, F¼ 4.09, p o0.05). Females heterozygous for the PPARα genotype (L162V), manifested significantly lower negative symptom scores when compared to those homozygous (L162L) (t-test: t¼ 2.34, p o0.05) (Table 1). The L162V polymorphism accounted for approximately 6% of negative symptoms variability (Multiple R2 change ¼0.06; not shown). According to the biochemical reference values for the Croatian population, plasma cholesterol and triglyceride levels were slightly elevated [25]. Furthermore, the PPARα genotype significantly contributed to the variations of plasma triglyceride levels in female Table 2 The frequency of PPARα genotypes. Genotype frequency a b c a,b,c patients (n¼ 203) controls (n¼ 191) L162L L162V χ2 p 185(91.1) 173(90.6) 18(8.9) 18(9.4) 0.04 n. s. Hardy–Weinberg: patients χ2 ¼ 0.44, p¼ 0.51; controls χ2 ¼0.47, p ¼0.49. Percentages are given in parenthesis. No significant difference between males and females in both groups. PPARα has emerged as master transcription regulator of glucose and lipid metabolism [3,10]. It is known to regulate the expression of genes involved in PUFA synthesis, fatty acid uptake, transport, oxidation, and ketogenesis [2,30]. Disturbances of lipid metabolism and PUFA deficits have been repeatedly reported in patients with schizophrenia [10,31]. Although a functional L162V polymorphism of the PPARα gene has been extensively investigated in etiology of abnormal lipid and glucose metabolism [18,22,30], to the best of our knowledge, this is the first study performed in schizophrenia subjects. Moreover, our current study was also the first to determine the association between schizophrenia and L162V polymorphism, as a possible risk factor for the illness. The results of our study showed no evidence of the statistically significant association between L162V polymorphism of the PPARα gene and elevated risk for developing schizophrenia in a Croatian population. We did not detect any differences in the L162V polymorphism allele and genotype frequencies between patients and control individuals. Distribution of the V162 allele was less frequent in both patient and control groups, when compared to L162 allele (4.4% and 4.7%, respectively), and its frequency was similar to previously reported distribution in other European populations. Unfortunately, since the L162V polymorphism has been detected only in the European population, further studies are limited [21]. However, our results argue in favor of the L162V polymorphism having modulator role in the expression of the illness in female patients. Females heterozygous for the PPARα genotype (L162V) tended an interesting trend to develop the illness at slightly younger age, and they also manifested significantly less severe negative symptoms than those homozygous (L162L). Therefore, according to our results, L162V polymorphic variant of the PPARα gene could have a possible protective effect toward negative symptoms severity in female patients with schizophrenia. It is plausible that in the PUFA deficient diet, as occurs in schizophrenia, by acting as a sensor of PUFA deprivation, PPARα induces activity of Δ6- and Δ5-desaturases and elongases to increase PUFA biosynthesis from their dietary precursors, such as LA and ALA. Moreover, functional studies have demonstrated that V162 allele has higher transcriptional activity in vitro, than L162 allele [18,22,32]. Thus, the L162V polymorphic variant could possibly modulate more efficiently the ability of PPARα to induce the activity of enzymes that act in PUFA biosynthesis. Several novel findings indicate the possible influence of PPARα genotype in response to antipsychotic medications [33,34]. In fact, the induction of PUFA biosynthesis enzymes has been attributed to the action of antipsychotic drugs as well [34,35]. One in vitro study detected that treatment with several typical and atypical antipsychotic medications up-regulate Δ6- and Δ5-desaturase mRNA expression in human cell lines [34]. Increased Δ6-desaturase mRNA expression, after chronic exposure to atypical antipsychotic medications, has also been demonstrated in recent in vivo study, performed in rats [35]. Furthermore, chronic treatment with both typical and atypical antipsychotic drugs in rats was found to significantly increase PUFA levels, in RBC membranes, as well as in brain tissue [33,35]. The observed inconsistencies regarding effects of antipsychotic treatment on membrane PUFA profile may be linked to several confounding effects of disease-related factors, such as state of illness, its duration, type of antipsychotic medication, etc. [31,36]. Recent study in Tunisian population examined 224 S. Nadalin et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 91 (2014) 221–225 RBC membranes PUFA profile in patients with schizophrenia before and after antipsychotic treatment and tested their association with psychopathology [36]. At enrollment, decreased levels of ARA and DHA were associated with higher severity of several negative symptoms, while treatment with typical antipsychotic medications over a period of 3 months, normalized PUFA levels, in parallel with improvement of psychopathology. Partial normalization of membrane PUFA levels following antipsychotic therapy (atypical 4typical) in post-mortem brain of patients with schizophrenia has also been reported by McNamara et al. [11]. However, recent meta-analysis confirmed RBC membranes PUFA deficits, in particular DHA, in patients with schizophrenia, irrespective of the type of antipsychotic medication intake [31]. In accordance with previous studies [4,20,30], the PPARα genotype affected plasma lipid concentrations in our sample as well, although significant impact has been detected only for plasma triglyceride levels in female patients (Table 1). Additionally, Tai et al. [37] reported an interesting PPARα genotype-diet interaction that may also contribute to variations in plasma lipid concentrations, possibly by modulating activity of the PPARα. In their study the presence of 162V allele in PPARα genotype was associated with greater triglycerides and apolipoprotein C-III concentrations in subjects consuming low PUFA diet, while higher PUFA intake, in 162V carriers, surprisingly, reduced their concentrations. In contrast, among subjects that were homozygotes for the 162L allele, the amount of PUFA intake, however, did not affect either triglycerides or apolipoprotein C-III concentrations. These findings suggest that 162V carriers that suffer from dyslipidemia, and especially patients with schizophrenia to whom have been prescribed atypical antipsychotics, could possibly benefit from use of dietary treatment with higher PUFA intake, or additional PUFA supplementation. Furthermore, since in our current study significantly greater plasma triglyceride levels have been detected in female carriers of the 162V allele (Table 1), it would be particularly useful to genotype females receiving antipsychotic therapy for the PPARα-L162V polymorphism and, regarding genotype, to modify diet habits/regimen for each individual. To date, a whole series of studies have reported gender specific differences in PPARα genotype effect on lipid plasma levels, response to statin treatment, and risk for developing hypertension and obesity [3,22,23], indicating a possible role of sex hormones on expression and/or PPARα activity. Furthermore, there is also evidence, based on studies performed in animal models, that PPARα expression and/or activity might be regulated by estrogen signaling pathways [2]. Estrogen binding to its membrane receptors activates extracellular receptor kinase–mitogen activated protein kinase (ERK–MAPK) and protein kinase A and they further phosphorylate and increase the activity of the PPARα. In addition, estrogen activation of ERK-MAPK pathways, increases intracellular concentration of PUFA and eicosanoids, strong natural PPARα ligands, via elevated phospholipase A2 (PLA2) and cyclooxygenase-2 (COX-2) enzyme activities. The current study has got several limitations. Relatively small sample size as well as low frequency of PPARα-V allele carriers leaves the possibility that some real effects were not detected. Furthermore, correlation analyses regarding plasma glucose and lipid concentrations were limited only to schizophrenia group. Further studies in other European populations, in whom PPARαL162V variant is present, controlling for the contribution of dietary habits and antipsychotic medications could be helpful in elucidating the relationship between PPARα-L162V polymorphism and schizophrenia. Moreover, clarifying the underlying molecular mechanisms which may associate L162V polymorphism with schizophrenia requires further experimentation as well. In conclusion, although L162V polymorphism of the PPARα gene could not be associated with an elevated risk for developing schizophrenia in our study, the investigated polymorphic variant, according to its possible protective effect toward negative symptoms severity in females with schizophrenia, might have a modifier role in clinical expression of the illness. 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