Arch Dermatol Res DOI 10.1007/s00403-013-1427-5

ORIGINAL PAPER

Analysis of manganese superoxide dismutase (MnSOD Ala-9Val) and glutathione peroxidase (GPx1 Pro 198 Leu) gene polymorphisms in psoriasis Go¨knur Kalkan • Havva Yıldız Sec¸kin • ¨ zyurt • Yalc¸ın Bas¸ • I˙smail Benli • Hu¨seyin O ¨ ¨ • • Omer Ates¸ Atiye Ozdemir Gu¨nseli S¸ efika Pancar

Received: 25 June 2013 / Revised: 28 October 2013 / Accepted: 30 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013

Abstract Recent studies have suggested the involvement of increased reactive oxygen species levels and decreased antioxidant system functions in psoriasis pathogenesis. In this study, we aimed to examine to investigate possible associations between the manganese superoxide dismutase (MnSOD Ala-9Val) and glutathione peroxidase (GPx1 Pro198Leu) polymorphisms and psoriasis susceptibility and disease progression in a Turkish population. The study group consisted of 100 unrelated patients with psoriasis and 167 unrelated healthy controls. Genomic DNA was extracted from peripheral leukocytes of whole blood which were obtained from all patients and control subjects. Genotyping was performed to identify MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms by a method based on PCR amplification and detection of polymorphisms with hybridization probes labeled with fluorescent dyes. Genotype and allele frequencies were compared between patients with psoriasis and 106 healthy control subjects. There was no significant difference between the MnSOD Ala-9Val single nucleotide polymorphism (SNP) genotype

distributions and allele frequencies of the psoriasis patients and the control group (p = 0.99 and p = 0.89, respectively). There was also no significant difference between distributions of the genotype or allele frequencies of the GPx1 Pro198Leu SNP of the patient groups and control subjects (p = 0.99 and p = 0.96, respectively). Also, no significant difference was found between clinical severity of psoriasis and MnSOD Ala-9Val and GPx1 Pro198Leu polymorphism. This is the first report investigating the possible associations between the MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms and psoriasis susceptibility and disease progression in the Turkish population even if no significant difference was found between patient groups and control subjects. Further studies with large cohort on different populations and ethnicities will be able to better clarify the association. Keywords Psoriasis  MnSOD Ala-9Val  GPx1 Pro198Leu  Polymorphism

Introduction G. Kalkan (&)  H. Y. Sec¸kin  Y. Bas¸ Department of Dermatology, School of Medicine, Gaziosmanpasa University, Tokat 60100, Turkey e-mail: [email protected] ¨ zyurt I˙. Benli  H. O Department of Biochemistry, School of Medicine, Gaziosmanpasa University, Tokat, Turkey ¨ . Ates¸ O Department of Medical Biology, School of Medicine, Gaziosmanpasa University, Tokat, Turkey ¨ zdemir  G. S¸ . Pancar A. O Department of Dermatology, Tokat State Hospital, Tokat, Turkey

Psoriasis is a common chronic inflammatory skin disorder affecting 1–3 % of the world’s population. It is a T-cellmediated autoimmune disorder caused by the interaction between genetic predisposition, immunological, environmental factors [1]. Although there have been significant advances for clarifying the pathogenesis of psoriasis, the exact pathogenic mechanism of the disease is still unknown. Oxidative stress (OS) is defined as a condition of disturbance in the redox state of an organism or a disturbance in the balance between reactive oxygen species (ROS) and endogenous antioxidant defenses [37]. Since increased OS

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shows its harmful effects mostly on the cell parts, including the DNA, membrane lipids and proteins, the skin appears as a potential target for oxidative injury as such, they are seen in many dermatologic disorders, like atopic dermatitis, psoriasis and vitiligo [21, 22, 28]. OS is considered to be a new etiopathogenetic key factor in the pathogenesis of psoriasis, as studies have suggested the involvement of increased ROS levels and decreased antioxidant system functions in psoriasis pathogenesis [6, 40]. Antioxidants delay or prevent ROS-induced oxidative damage can protect the epidermis from the events that contribute to epidermal toxicity and diseases [26]. Among the antioxidant enzymes involved in oxidative stress, manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx1) play primary roles in the detoxification of ROS. MnSOD is the only mitochondrial enzyme that dismutates O2 into H2O2, and then, GPx1 neutralizes H2O2 to H2O and O2. MnSOD is localized in the mitochondria, which is a major site for ROS production, while GPx1 is localized in both the mitochondria and the cytosol. The ultimate levels of mitochondrial ROS likely depend on the activities of both MnSOD and GPx1 [4, 5]. SODs are classified into three distinct groups depending on the metal content, and MnSOD may be the most significant among them [7]. The human MnSOD gene has a single nucleotide polymorphism (SNP) at codon 16 (rs4880) that encodes for either alanine (Ala) or valine (Val) at the -9 position in the mitochondrial targeting sequence located in the long arm (6q25) of chromosome 6 [32]. The transportation of the MnSOD enzyme into the mitochondria undergoes an alteration in Ala-9Val polymorphism changing its efficacy in scavenging ROS [3]. GPx1 is the most abundant izoenzyme of identified four different GPx izoenzymes. It is a selenium-dependent enzyme that is ubiquitously expressed and protects cells against oxidative damage by reducing hydrogen peroxide and wide range of organic peroxides with reduced glutathione [4]. The GPx1 gene is located at chromosome 3p21 and is composed of two exons. A genetic polymorphism was defined which is associated with C to T substitution in the exon two of GPx1 gene encoding for either proline (Pro) or leucine (Leu) at codon 198 (rs1050450) [23]. Previous studies have shown that the GPx1 Pro198Leu polymorphism causes a decline in the activity of the enzyme [17, 31]. This polymorphism is functional in humans and impacts the response of GPx1 activity to selenium which has been shown to be related to tumor susceptibility, blood selenium levels associated with supplementation, and other health conditions [11, 17]. Consequently, genetic variations in the antioxidant gene coding for the GPxs, catalase CAT, and SOD enzymes may alter ROS detoxification and may modulate disease risk

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[18]. Even if the role of oxidative stress, and GPx and SOD enzyme status in the pathogenesis of psoriasis has been investigated, any studies related about the association of these two polymorphisms with psoriasis have not been performed yet to the best of our knowledge. Therefore, in this study, we aimed to examine to investigate possible associations between the MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms and psoriasis susceptibility and disease progression in a Turkish population.

Materials and methods Subjects The study group consisted of 100 unrelated patients with psoriasis [45 male and 55 female; mean age 42.28 ± 15.068 standard deviation (SD) years], and 167 (75 male and 92 female; mean age 42.28 ± 12.837 SD years) unrelated healthy controls with no psoriatic lesions in their personal history or on clinical examination. Patients with psoriasis were gathered from Department of Dermatology of Gaziosmanpasa University, Tokat, Turkey. Clinical and demographical data were obtained from all patients, including gender, age, and disease duration. Psoriatic patients with any topical therapy within 4 weeks, systemic drug therapy or photo chemotherapy within 3 months were excluded from this study. All participants, patients and healthy controls, were of Turkish origin, from the central region of Turkey. The healthy control patients consisted of the patients who were admitted to our dermatology clinic with other reasons: nevus examination, dermatofitos infections or warts and matched for age and gender with psoriasis patients. The protocol of this study was approved by the Local Ethics Committee of Gaziosmanpasa University Faculty of Medicine (Approval no. 11BADK-162) and all participants gave written informed consent before entering the study. Psoriasis area and severity index (PASI) The patients were diagnosed by Auspitz sign, clinical features of psoriasis like erythema, itching, thickening and scaling of skin. Disease duration of the patients ranged from 5 months to 10 years with mean range (5.4 ± 4). The clinical severity was determined according to the psoriasis area and severity index (PASI) [25]. PASI assesses four body regions, the head, trunk, upper extremities and lower extremities. For each region, the surface area involved is graded from 0 to 6 and each of three parameters (erythema, thickness and scaling of the plaques) is graded from 0 to 4. The scores from the regions were summed to give a PASI score ranging from 0 to 72. Psoriatic patients were

Arch Dermatol Res

classified into mild (11 patients; PASI up to 25), moderate (20 patients; PASI C 25) and severe (24 patients; PASI C 50).

acquisition. Finally, the fluorescence signal was plotted against temperature in real time to produce melting curves for each sample.

Genotyping

Statistical analysis

DNA isolation

Statistical analysis was performed using PEPI 3.0 (available at: http://www.usdinc.com/pepi.html) and SPSS 15.0 (SPSS Inc., Chicago, IL, USA). Normally distributed variables were evaluated with Kolmogorov–Smirnov test. Continuous variables between the two groups were compared by the two independent sample t test or Mann– Whitney U test. While categorical variables were presented as counts and percentages, continuous variables were presented as mean [standard deviation (SD)] or as median [interquartile range (IQR)]. The distribution of MnSOD Ala-9Val and GPx1 Pro198Leu gene polymorphisms between psoriasis patients and healthy controls was compared by using the v2 test. p values smaller than 0.05 were considered significant. Odds ratios (ORs) and 95 % confidence intervals (CIs) were also calculated.

Blood specimens were drawn into EDTA containing tubes and genomic DNA samples were extracted from the peripheral leukocytes of the collected venous blood by the High Pure PCR Template Preparation Kit (Roche Molecular Biochemicals, Mannheim, Germany) according to the instructions of the manufacturer. MnSOD Ala-9Val and GPx Pro198Leu genotyping To identify MnSOD Ala-9Val and GPx1 Pro198Leu SNPs, genotyping was performed using PCR amplification and polymorphisms were detected with hybridization probes labeled with fluorescent dyes (LightCycler 480 II RealTime PCR System, Roche Diagnostics, Mannheim, Germany). Target fragments of the human MnSOD and GPx1 genes were amplified with specific primers. To detect the MnSOD Ala-9Val polymorphism, we applied 10 pmol of the forward primer 50 -CAGCCTGCGTAGACGGTCCC-30 and the reverse primer 50 -CGTGGTGCTTGCTGTGGTG C-30 , and 3 pmol of the sensor probe 50 -CTCCGGCTTTG GGGTATCTG-fluorescein-30 and the anchor probe 50 -LC Red 640-GCTCCAGGCAGAAGCACAGCCTCCp-30 . To detect the GPx1 Pro198Leu polymorphism, we also used 10 pmol of the forward primer 50 -ACTTTGAGAAGTTCC TGGTG-30 and the reverse primer 50 -TTCCTCCCTCGTA GGTTTAG-30 , and 3 pmol of the sensor probe 50 -CAGAC CATTGACATCGAGCCTGACATCGAA-fluorescein-30 and the anchor probe 50-LC Red 640-TGCTGTCTCAAG GGCCCAG-p-30 . The LC FastStart Master Hybridization Probes buffer (Roche Diagnostics Inc.) was used as a reaction buffer. All primers and hybridization probes were designed and synthesized by TIB MOLBIOL (Berlin, Germany). The genotypes were identified by running a melting curve with specific Tm. Wild-type MnSOD Ala exhibits a Tm of 65 ± 0.5 °C, while wild-type GPx1 Pro yields a Tm of 66 ± 0.5 °C. The allele variant MnSOD Val exhibits a Tm of 56 ± 0.5 °C, and the allele variant GPx1 Leu exhibits a Tm of 57 ± 0.5 °C. The PCR reaction was as follows: initial denaturation at 95 °C for 10 min, followed by 20 cycles at 95 °C for 10 s, annealing at 60 °C (MnSOD) and 50 °C (GPx1) for 20 s, extension at 72 °C for 20 s. And then a melting curve was recorded by an initial increase in temperature to 95 °C, cooling the reaction mixture to 40 °C at 20 °C/s holding for 30 s and then slowly heating it to 85 °C at 0.1 °C/s with continuous

Results Baseline clinical and demographical features of the study patients with psoriasis and control group were shown in Table 1. Gender, age, disease duration, clinical severity of the disease according to the Psoriasis area and severity index (PASI) score classification were analyzed. Age and gender were not different between patient and control groups (p = 0.88 and 0.91, respectively). The genotype distributions and allele frequencies of the MnSOD Ala9Val and GPx1 Pro198Leu SNPs in patients and controls are shown in Table 2. The frequencies of Pro/Pro, Pro/Leu and Leu/Leu genotypes of GPx1 Pro198Leu polymorphism in the patients were 45, 41, and 14 %; in the controls were 45, 41, and 14 % (Table 2). Pro and Leu allele frequencies were 65 and 35 % in patient group and 65 and 35 % in control group, respectively (Table 2). There was no significant difference between the MnSOD Ala-9Val SNP genotype distributions and allele frequencies of the psoriasis patients and the control group (p = 0.99 and p = 0.89, respectively). The frequencies of Ala/Ala, Ala/Val and Val/Val genotypes of MnSOD Ala-9Val polymorphism in the patients were 17, 49, and 34 %; in the controls were 17, 49, and 34 % (Table 2). Ala and Val allele frequencies were 42 and 58 % in patient group and 41 and 59 % in control group, respectively (Table 2). There was also no significant difference between distributions of the genotype or allele frequencies of the GPx1 Pro198Leu SNP of the patient groups and control subjects (p = 0.99 and p = 0.96, respectively). There was no association between

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Arch Dermatol Res Table 1 Demographics and baseline characteristics of psoriatic patients and healthy control groups

Parameters

Study group (n = 100)

Control group (n = 167)

p value 0.88

Age (mean ± SD)

42.28 ± 15.068

42.28 ± 12.837

Male (n, %)

(45, 45)

(75, 44.9)

0.91

Duration of psoriasis (years), median (IQR)

7 (3–14.75)





Mild (PASI up to 25) median (IQR)

6.2 (4, 8–9, 0) (n = 96)





Moderate (PASI C 25) (mean ± SD)

25.8 ± 0.97 (n = 4)





PASI score classification

Table 2 Distribution of GSHPx, Mn-SOD polymorphisms in patients with psoriasis and controls

Locus GSH-Px, Mn-SOD

Control n = 167

Psoriasis patients n = 100

p

O.R (95 %CI)

GSH-Px, PRO197LEU

1.01 (0.68–1.43)

Pro/Pro

75 (45 %)

45 (45 %)

Pro/Leu

68 (41 %)

41 (41 %)

Leu/Leu

24 (14 %)

14 (14 %)

Allele Pro

218 (65 %)

131 (65 %)

Allele Leu

116 (35 %)

69 (35 %)

Ala/Ala Ala/Val

28 (17 %) 81 (49 %)

17 (17 %) 49 (49 %)

Val/Val

58 (34 %)

34 (34 %)

0.99

Allele frequency 0.96

Mn-SOD ALA9VAL

1.02 (0.69–1.40) 0.99

Allele frequency Allele Ala

137 (41 %)

83 (42 %)

Allele Val

197 (59 %)

117 (58 %)

clinical severity of psoriasis and MnSOD Ala-9Val and GPx1 Pro198Leu polymorphism. The observed and expected frequencies of the polymorphism in both patient and control group were in Hardy–Weinberg equilibrium.

Discussion In this study, we investigated the associations of MnSOD Ala-9Val and GPx1 Pro198Leu gene polymorphisms with the risk of psoriasis in the Turkish population and with the diagnosis of psoriasis in a group of Turkish patients to establish whether it is a risk factor or not for the development of psoriasis. However, we could not find statistically significant association between psoriasis patients and controls according to genotype and allele distribution of MnSOD Ala-9Val and GPx1 Pro198Leu gene polymorphisms. To the best of our knowledge, this is the first study investigating the association between psoriasis and MnSOD Ala-9Val and GPx1 Pro198Leu gene polymorphisms. We could not find any association between the

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0.89

clinical severity of psoriasis as expressed by the Psoriatic Area Severity Index score and MnSOD Ala-9Val and GPx1 Pro198Leu polymorphism. Psoriasis is a complex inflammatory multifactorial skin disease with a genetic predisposition in which keratinocyte hyperproliferation is mediated through a cytokine network. Recently, it has been suggested that increased ROS production and compromised function of antioxidant system may be involved in the pathogenesis of this disease [6, 28]. Antioxidants have been proven to be beneficial as a therapy for psoriasis because cellular signaling pathways are known to be redox sensitive and have been shown to be involved in the progress of psoriasis [40]. The signals are eventually transmitted to transcription factors, directly or through ROS which mainly play a role in the step of activation of transcription factors in keratinocytes [34]. Therond et al. demonstrated that antioxidant enzyme activities, particularly Mn-SOD and CuZn-SOD are significantly elevated in cells from psoriatic patients [35]. Kadam et al. reported a significant increase in level of MDA, nitric oxide end products and decrease in the

Arch Dermatol Res

activity of GPx, SOD catalase activity and total antioxidant status in patients with psoriasis [19]. Polkanov et al. and Yıldırım et al. found lower erythrocyte SOD and GP activities in psoriasis patients compared to controls [30, 39]. In a recently performed study, serum SOD activities were significantly decreased in psoriatic patients as compared with healthy controls. SOD activity in moderate psoriatic patients was significantly lower than in the patients presenting with mild psoriasis; whereas, severe psoriatic patients exhibited a significant decrease in SOD activity as compared to moderate psoriatic patients [12]. Decreased SOD activity might be related to epidermal hyperproliferation, because the ROS are thought to induce cell proliferation in various cell systems [24]. And also decreased SOD activity could be caused by increased superoxide anion production during the psoriatic process in the skin as well as activated peripheral neutrophils [13]. The genotype frequency of the MnSOD gene Ala–9Val SNP differs considerably with ethnicity. Patients from Turkey showed higher frequencies of the -9Ala allele and Ala/Ala genotype frequencies. MnSOD Ala/Ala genotype prevalence was found as 23.5, 37 and 11.8 %, respectively in the several studies in the Turkish population [2, 20]. In this study, the frequency of Ala/Ala was 17 %. Previous studies have suggested that the Ala allele is associated with higher activity, which results in more efficient transport of MnSOD into the mitochondria [15, 32]. Those authors assumed that this would increase the production of H2O2 which could result in ROS-induced cell damage. However, this suggestion is opposite to that of Hori et al. [16], who assumed that the Val allele is associated with a lower MnSOD content within mitochondria. Previous studies revealed that the variant -9 Ala allele associates with diseases related to oxidative stress and abnormal free radical defense mechanisms, such as exudative age-related macular degeneration, Parkinson’s disease and risk of breast, prostate and ovarian cancers [3, 7, 8, 29]. To date only one study is performed to investigate the role of MnSOD gene polymorphisms in the susceptibility to psoriatic arthritis. The genotype frequency of MnSOD 1183C/T was found as significantly higher in patients with psoriatic arthritis than in controls. MnSOD 1183C polymorphisms have been thought to be a precipitating factor for the development of psoriatic arthritis [38]. Genetic polymorphisms in GPx1 have been associated in some disorders, such as cerebral venous thrombosis, cardiovascular disease, malignant melanoma, prostate and breast cancer in which the inflammatory process is not the dominant pathogenic factor [14, 17, 23, 27, 36]. In the first study documenting the frequencies of the GPx1 Pro198Leu alleles in the Turkish population, the genotype frequencies of the GPx1 Pro198 Leu alleles in the Turkish population were found as 0.416 (CC), 0.440 (CT), and 0.144 (TT).

They have concluded that individuals with variants at the GPx1 genes may have predisposition to diseases associated with oxidant exposures [33]. Ravn-Haren et al. found that erythrocyte GPx1 activity was lower in individuals carrying the Leu allele than in individuals carrying the Pro allele [31]. However, this result is not consistent with one study, suggesting no correlation between GPx1 activity and GPx1 genotype [10]. The explanations for these inconsistent results may be that different dietary and lifestyle factors like intake of fruit and vegetables, alcohol consumption and smoking may influence GPx1 enzyme activity [9]. Besides dietary intake of selenium increases GPx1 activity and gene expression [31]. In summary, we could not find statistically significant association between MnSOD Ala-9Val and GPx1 Pro198Leu gene polymorphisms and patients with psoriasis susceptibility in the Turkish population. In this study, most of the patients with psoriasis were composed of mild psoriasis patients; we could not also find a statistically significant association between the severity of the disease and these polymorphisms. If we could be able to measure the plasma levels of antioxidants, it would be much more descriptive and we would be able to assess the functional consequence of the polymorphisms. These findings may not be generalizable to other populations, given that differences in racial and ethnic attitudes toward lifestyle may influence these results. Therefore, further studies with large cohort on different populations and ethnicities will be necessitated to better elucidate the complex psoriasis immunopathogenesis and confirm these findings. A better understanding of the pathogenesis of psoriasis will confidently recover both the diagnosis and clinical management of this disease. Analyses in conjunction with other ROS-related polymorphisms will also help to elucidate the contribution of these genes to psoriasis. Thus, our study provides a frame-work for future studies concerning the role of MnSOD Ala-9Val and GPx1 Pro198Leu gene polymorphisms in the susceptibility of complex diseases by induced free radicals in the Turkish population. Conflict of interest of interest.

The authors declare that they have no conflict

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Analysis of manganese superoxide dismutase (MnSOD Ala-9Val) and glutathione peroxidase (GPx1 Pro 198 Leu) gene polymorphisms in psoriasis.

Recent studies have suggested the involvement of increased reactive oxygen species levels and decreased antioxidant system functions in psoriasis path...
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