Elsevier

Comprehensive Psychiatry

Volume 70, October 2016, Pages 118-124
Comprehensive Psychiatry

An association between the PPARα-L162V polymorphism and nicotine dependency among patients with schizophrenia

https://doi.org/10.1016/j.comppsych.2016.07.004Get rights and content

Abstract

Objective

Patients with schizophrenia are more likely to be smokers than the general population, which makes them an interesting group with which to study the etiology of nicotine dependency. We studied the prevalence of a gene variant of peroxisome proliferator-activated receptor alpha (PPARα) in schizophrenia, together with nicotine dependency, to investigate whether the PPARα-L162V polymorphism (rs1800206) influences nicotine dependency in schizophrenia. Given evidence suggesting that smoking influences the severity of schizophrenia, together with our recent data linking the PPARα-L162V polymorphism to clinical manifestations of schizophrenia (in the Croatian population), we hypothesized that interactions between the two (smoking and the PPARα-L162V polymorphism) might contribute to disease onset and scores for the Positive and Negative Syndrome Scale. To the best of our knowledge, this is the first study to investigate the possible associations between the PPARα gene and nicotine dependency.

Patients and methods

Genotyping was performed for 267 chronically ill schizophrenia patients (males/females: 140/127) by polymerase chain reaction.

Results

A significant excess of PPARα-L162V genotypes and PPARα-162V alleles were detected among female smokers in comparison to female nonsmokers (18.2% vs. 2.0%, and 9.1% vs. 1.0%, p < 0.01, respectively). We also revealed a significant PPARα genotype–smoking interaction that predicted positive symptom severity among male patients (F = 4.43, p < 0.05). These data indicated that the PPARα-L162V heterozygous genotype, depending on smoking status, might be of relevance as either protective, or a risk factor, for the severity of positive symptoms. No interaction between the PPARα-L162V polymorphism and smoking for the time of onset of schizophrenia was detected (p > 0.05, respectively).

Conclusion

We demonstrated two significant yet weak effects. The first showed an effect of the PPARα-L162V polymorphism on the risk of nicotine dependency. The second linked the PPARα genotype–smoking interaction to positive symptoms severity among schizophrenia patients; both effects manifested in a gender-specific fashion.

Introduction

Nicotine is the principal psychoactive component in tobacco smoke. By binding to nicotinic cholinergic receptors, nicotine stimulates the activity of brain mesolimbic dopamine neurons, which are believed to mediate the reward and addiction properties of tobacco [1], [2], [3], [4], [5]. A worldwide meta-analysis identified a threefold greater rate of smoking for patients with schizophrenia than the general population, and twice the incidence of smoking compared to individuals with other psychiatric illnesses, irrespective of the type of antipsychotic medication taken [6], [7], [8]. According to the self-medication hypothesis, smoking might have a beneficial effect in schizophrenia. Smoking may decrease the severity of negative symptoms and the extrapyramidal side effects of antipsychotic medications and may also ameliorate cognitive deficits [3], [9], [10]. Animal experiments suggest that nicotine may also exert protective effects towards positive schizophrenia symptoms. For instance, it has been observed that nicotine reduces subcortical dopamine hyperactivity, which is associated with more severe positive symptoms, and decreases the ability of free radicals to generate the toxic dopamine metabolite, 6-hydroxidopamine [11], [12], [13].

The genetic hypothesis proposes that specific genes, particularly those involved in dopaminergic signaling, such as dopamine receptor D2 (DRD2), alpha7 nicotinic acetylcholine receptor (CHRNA7), and brain-derived neurotrophic factor (BDNF), might be pleiotropic, thus contributing to both nicotine dependency and schizophrenia [10], [14], [15], [16], [17]. Recently, several novel genotypes, such as the dopamine-beta-hydroxylase (DBH)-19 bp insertion/deletion, the mu opioid receptor (OPRM1)-A118G polymorphism, the interleukin-1beta (IL-1β)-511C/T polymorphism, and manganese superoxide dismutase (MnSOD)-Ala-9Val variant, have been proposed to influence the severity of nicotine dependency and/or the age of smoking initiation among schizophrenia subjects [18], [19], [20], [21].

Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that belongs to the nuclear steroid receptor superfamily [22], [23]. Once activated (by ligand binding), PPARα heterodimerizes with the retinoid X receptor, then binds to peroxisome proliferator response elements (PPRE) in promoter regions in order to modulate gene expression [23], [24]. In addition to its ability to regulate numerous physiological responses (energy balance, glucose and lipid metabolism, inflammation, etc.), PPARα might also influence conditions altered by dopamine action (including substance abuse and psychiatric disorders) via dopaminergic signaling [24], [25], [26], [27], [28]. As one of the major genes of the retinoic acid cascade, PPARα is involved in the regulation and development of the central nervous system, including dopaminergic neurons [24]. Of the many transcriptional targets of retinoic acid are genes encoding both dopamine and nicotinic cholinergic receptors [24], [28]. Novel findings suggest that PPARα may also act as a negative modulator of nicotinic cholinergic receptors on dopamine neurons [25], [26], [27]. It has been discovered that PPARα-induced phosphorylation of nicotinic cholinergic receptors suppresses the dopaminergic neurons' response to nicotine in vitro [25], [26], [27]. Moreover, there is evidence that injection of several synthetic PPARα agonists might reduce, in a dose-dependent manner, nicotine-induced self-administration and reinstatement in rats and monkeys [27].

Our recent data revealed an intriguing correlate between the most studied variant of the PPARα gene (a functional leucine 162 valine (L162V) polymorphism in exon 5 (rs1800206)) and schizophrenia patients in the Croatian population [29]. While we could identify no evidence of any association between this variant and an elevated risk of schizophrenia, we observed significantly lower negative symptom scores, a trend towards an earlier age of onset, and greater triglyceride levels, for female PPARα heterozygotes (L162V). To date, no other studies have investigated the possible relevance of the PPARα-L162V polymorphism in schizophrenia. Moreover, to the best of our knowledge, there are also no reports investigating the potential associations between PPARα gene polymorphisms and the etiology of nicotine dependency in the human population. A second polymorphism in the PPARα gene, the PPARα-Val227Ala polymorphism, which has not been detected in the European population, has been investigated in the etiology of alcohol dependency in a single study for the Japanese population, with negative results reported [24], [30].

In line with the high smoking rate in schizophrenia [6], [7], [8], and with reference to the relevance (if any) of the PPARα gene in schizophrenia and nicotine dependency [27], [28], [29], we investigated whether the risk for nicotine dependency among schizophrenic patients might be associated with the PPARα-L162V polymorphic variant. Furthermore, given evidence suggesting that smoking influences the severity of schizophrenia [31], [32], [33], we hypothesized that interaction between smoking and the PPARα-L162V polymorphism might influence either the age of schizophrenia onset, and/or PANSS psychopathology data. Gender specific differences in the effects of the PPARα-L162V polymorphism in various diseases and/or conditions [34], [35], [36], including schizophrenia [29], have been noted, as have gender–gene interactions in nicotine dependency [37], [38], [39]. Therefore we conducted analyses for male and female patients separately.

Section snippets

Study participants

Our study group comprised 267 chronically ill schizophrenia patients recruited from the Department of Psychiatry, Clinical Medical Center in Rijeka, Croatia (n = 179), and the Psychiatric Hospital in Rab, Croatia (n = 88), between 2008 and 2015. Rijeka and the island of Rab belong to the same geographic area. The patients' demographic and clinical characteristics are presented in Table 1. Diagnoses were assessed by at least two psychiatrists according to the Diagnostic and Statistical Manual of

Results

As expected, an elevated smoking rate was observed among both male and female patients, of whom approximately two-thirds were smokers (Table 1). The prevalence of nicotine dependency did not differ significantly with respect to the patients' gender (p > 0.05, respectively).

Allele and genotype frequencies for the PPARα-L162V polymorphism according to the patients' smoking status are presented in Table 2. The statistical power of our study was 80% in detecting a 2.1 fold increase in the

Discussion

Due to their high smoking rate, schizophrenia patients represent a particularly interesting group with which to study the etiology of nicotine dependence [6], [7], [8]. In the current work we investigated whether, and to what extent, the PPARα-L162V polymorphic variant, which we recently found to be associated with the clinical expression of schizophrenia [29], might influence the risk for nicotine dependency among Croatian schizophrenia patients. Furthermore, we examined whether an interaction

Acknowledgment

We are grateful to the anonymous reviewers for their helpful comments. This research was supported by grant no. 13.06.1.3.39 from the University of Rijeka, Croatia. The University had no further role in the study design, collection, analysis, or interpretation of data. Nor did the university influence the decision to submit this paper for publication.

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    These authors contributed equally to this work.

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