Lack of association between leptin, leptin receptor

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http://informahealthcare.com/arp ISSN: 1381-3455 (print), 1744-4160 (electronic) Arch Physiol Biochem, Early Online: 1–6 ! 2015 Informa UK Ltd. DOI: 10.3109/13813455.2015.1024136

ORIGINAL ARTICLE

Lack of association between leptin, leptin receptor, adiponectin gene polymorphisms and epicardial adipose tissue, abdominal visceral fat volume and atherosclerotic burden in psoriasis patients

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Tiago Torres1,2, Nuno Bettencourt3, Joana Ferreira4, Cla´udia Carvalho4, Denisa Mendonc¸a5,6, Carlos Vasconcelos2,7, Manuela Selores1, and Berta Silva2,4 1

Department of Dermatology, Centro Hospitalar do Porto, Porto, Portugal, 2Unit for Multidisciplinary Investigation in Biomedicine, Instituto Cieˆncias Biome´dicas Abel Salazar, University of Porto, Portugal, 3Department of Cardiology, Centro Hospitalar Gaia/Espinho, Porto, Portugal, 4 Immunogenetics Laboratory, Instituto Cieˆncias Biome´dicas Abel Salazar, University of Porto, Portugal, 5Department of Population Studies, Instituto Cieˆncias Biome´dicas Abel Salazar, University of Porto, Portugal, 6Institute of Public Health, University of Porto, Portugal, and 7Department of Clinical Immunology, Centro Hospitalar do Porto, Porto, Portugal Abstract

Keywords

Context: Identifying psoriasis patients who present a higher risk of developing cardiovascular co-morbidities is of upmost importance. Two key adipokines, leptin and adiponectin, may play a role connecting psoriasis and its major co-morbidities. Objective: To evaluate the potential contribution of LEPrs2167270(19 G/A), LEPRrs 1137100(326 A/G) and ADIPOQrs1501299(276 G/T) gene polymorphisms in psoriasis susceptibility and their influence in epicardial adipose tissue and abdominal visceral fat volume and subclinical atherosclerosis in severe psoriasis patients. Materials and methods: One hundred severe psoriasis patients underwent clinical and laboratory evaluation, DNA genotyping and multi-detector computed tomography scan for epicardial adipose tissue, abdominal visceral fat and coronary artery calcification assessment. DNA control group was obtained from a previously anonymized biobank of 206 adult subjects without psoriasis. Results: No association was observed between the studied gene polymorphisms and psoriasis susceptibility, CAC or increased EAT or AVF volume. Discussion and conclusion: The studied polymorphisms do not seem, at least in this cohort of patients, to be a genetic risk factor for the development of atherosclerosis or increased adiposity in psoriasis.

Adiponectin, atherosclerosis, cardiovascular disease, epicardial adipose tissue, gene polymorphism, Leptin, leptin receptor, psoriasis

Introduction Leptin and adiponectin are two major adipocyte-secreted hormones with pleiotropic effects on metabolism, inflammation and insulin resistance (Gustafson, 2010; Gerdes et al., 2011). Genetic variants in genes encoding these adipokines are known to contribute to variations in their plasma levels and to the development of several cardiometabolic conditions (Comuzzie et al., 2001; Li et al., 1999). Polymorphisms in the leptin (LEP) and leptin receptor (LEPR) genes have been reported to be associated with obesity and higher leptin levels in obese individuals (Farooqi et al., 2007; Paracchini et al., 2005), while several adiponectin gene (ADIPOQ) single nucleotide polymorphisms (SNPs) have been shown to Correspondence: Tiago Torres, Servic¸o de Dermatologia, Centro Hospitalar do Porto, Edifı´cio das Consultas Externas, Ex. CICAP, Rua D. Manuel II, s/n, 4100 Porto, Portugal. Tel: +35191681829. Fax: +351226097429. E-mail: [email protected]

History Received 18 December 2014 Revised 13 February 2015 Accepted 24 February 2015 Published online 30 June 2015

influence adiponectin levels and to be associated with a higher risk for obesity, cardiovascular disease and type-2 diabetes (Comuzzie et al., 2001; Persson et al., 2010). Psoriasis is a systemic inflammatory disorder associated with several cardiometabolic co-morbidities and increased risk of cardiovascular disease (CVD) and cardiovascular mortality (Gisondi & Girolomoni, 2009; Horreau et al., 2013; Mehta et al., 2010; Reich, 2012). Also the systemic inflammation present in psoriasis may play an important role in the accelerated atherosclerosis observed in these patients (Armstrong et al., 2011). Recently psoriasis has been associated with increased epicardial adipose tissue (EAT) and abdominal visceral fat (AVF) (Balci et al., 2010; Torres et al., 2014a). The mechanism linking psoriasis, its associated co-morbidities and CVD has not yet been elucidated, but is probably related to common pathogenic mechanisms, shared genetic risk variants and environmental triggers or a combination of these factors (Davidovici et al., 2010).

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Elevated leptin levels and leptin receptor expression have been reported to be associated with psoriasis and to be positively correlated with body mass index and to contribute to CVD in psoriasis (Gerdes et al., 2011; Zhu et al., 2013). On the other hand, psoriasis has been associated with decreased plasma adiponectin levels independently of cardiometabolic risk factors (Gerdes et al., 2011; Li et al., 2014). Leptin gene polymorphisms and their association with psoriasis have not been extensively studied (Abdel Hay & Rashed, 2011; Kara et al., 2007; Karpouzis et al., 2014; Senturk et al., 2008) and the results have been contradictory, while to date, no studies have evaluated LEPR and ADIPOQ gene polymorphism in psoriasis. The most studied Leptin gene polymorphism in psoriasis has been LEP (-2548G/A). One study has detected significant differences accompanied by varying levels of leptin (Abdel Hay & Rashed, 2011), while two other studies found no statistically significant differences between patients and healthy controls (Kara et al., 2007; Senturk et al., 2008). Recently, another Leptin polymorphism (rs2060713) has been study in psoriasis and no statistically significant differences were observed between patients and controls (Karpouzis et al., 2014). The aim of this study was to evaluate the potential contribution of the LEP rs2167270 (19 G/A), LEPR rs1137100 (326A/G) and ADIPOQ rs1501299 (276 G/T) polymorphisms in psoriasis susceptibility and their influence in EAT, AVF and coronary artery calcification (CAC) in severe psoriasis patients. Methods Consecutive patients with severe plaque-type psoriasis (PASI 410% and/or disease requiring systemic therapy or phototherapy) observed at our Psoriasis Center were enrolled. Exclusion criteria included the presence of psoriatic arthritis (previous/ current signs/symptoms of joint evolvement), the presence of cardiovascular disease (as previously defined (Torres et al., 2014a), pregnancy, renal failure and the presence of other systemic inflammatory disease (lupus erythematous, rheumatoid arthritis or other spondylo-arthropathies). All subjects underwent clinical evaluation (complete medical history and physical examination), laboratory evaluation, DNA sample extraction and multi-detector computed tomography (MDCT) scan for EAT, AVF and coronary artery calcification (CAC) assessment. MCDT scan parameters and used methods have been previously described (Torres et al., 2014b). The control DNA group was obtained from a previously anonymized DNA biobank of 206 local general population controls without psoriasis. SNP genotyping was performed on the SequenomÔ massARRAY iPLEX platform (Sequenom, San Diego, CA) using multiplexed amplification followed by mass-spectrometric product separation. The study was approved by the hospital Institutional Review Board and subject’s written consent was obtained according to the declaration of Helsinki. Statistical analysis Variables were tested for normality using the KolmogorovSmirnov test. Chi-squared test or Fisher’s exact test were used as appropriate, to test group differences of proportions.

Arch Physiol Biochem, Early Online: 1–6

Within psoriasis patients the association between genotypes and alleles of the studied polymorphisms and EAT and AVF volume was tested using analysis of covariance (ANCOVA) adjusting for gender, age and AVF and gender and age respectively. The association between the presence of sub-clinical atherosclerosis (CAC 40) and the studied polymorphisms was performed using multivariable logistic regression adjusted for confounders. The level of statistical significance was set at ¼ 0.05. Statistical analyses were performed with SPSS version 21 (SPSS IBM, New York, USA).

Results A total of 100 psoriasis patients and 206 controls were enrolled. No significant differences were observed in the genotype or allele frequencies between both groups, before and after adjustment for age and sex. Concerning the influence of the LEP, LEPR and ADIPOQ polymorphisms in EAT and AFV volume, no significant differences were found. Similarly, none of the polymorphisms showed a significant association with the presence of CAC, both in the unadjusted analysis and after adjusting for age, sex and traditional cardiovascular risk factors (CVRF). Finally, when psoriasis patients were stratified according to clinical characteristics (metabolic and CVRF), analytic characteristics (lipid profile, insulin resistance, inflammation (hs-CRP)) and psoriasis clinical features (age at onset of the disease, psoriasis severity, family history), no significant differences, in the allele or genotype frequency of any the studied polymorphism were found after adjustment for age and sex. Also for leptin levels, no significant differences were found.

Discussion In the present study, no association was observed between polymorphisms of leptin (LEP rs2167270 [19G/A]), leptin receptor (LEPR rs1137100 [326A/G]) and adiponectin (ADIPOQ rs1501299 [276G/T]) genes and psoriasis susceptibility, CAC or increased EAT or AVF volume. To the best of our knowledge, studies aimed to establish the potential influence of LEP, LEPR and ADIPOQ gene polymorphisms in the EAT and AVF volume and development of subclinical atherosclerosis in patients with psoriasis have not been reported. It has been well established that the expansion of visceral adipose tissue, currently regarded as an immune and endocrine organ, is associated with a higher risk of cardiometabolic co-morbidities and CVD, due to the release of several pro-inflammatory cytokines and adipokines (Bays, 2009). AVF has been shown to be increased in psoriasis independently of waist circumference and may be a potential link between psoriasis and its metabolic comorbidities (Balci et al., 2010). Also EAT, a type of visceral adipose tissue surrounding the heart and coronary vessels that produces several proatherosclerotic and proinflammatory hormones and cytokines, including IL-6, TNF-a, leptin, and MCP-1 (Mazurek et al., 2003), has been shown to be increased in psoriasis patients and to be associated with subclinical atherosclerosis (Torres et al., 2014a), probably through its metabolic effects both at a paracrine and systemic level (Alexopoulos et al., 2010; Mazurek et al., 2003).

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DOI: 10.3109/13813455.2015.1024136

Adipokines gene polymorphisms and cardiovascular comorbidities in psoriasis patients

Psoriasis is a complex polygenic disease and several genes have been implicated in both disease susceptibility and increased risk of CV mortality (Lu et al., 2013). Recognizing genetic markers that could predict which patients are at risk of developing psoriasis-linked cardiovascular co-morbidities may permit an earlier management and ease screening strategies, leading to early, aggressive risk factors management including patient education to adopt healthy life-style behaviours, such as, smoking cessation, weight control and exercise (Torres et al., 2014b). Leptin and adiponectin are adipokines that may possibly connect psoriasis with its major co-morbidities, as they have been shown to play a role in excess adiposity, development of cardiovascular disease and in psoriasis (Gerdes et al., 2011). Leptin is predominantly synthesized and secreted by adipocytes, being implicated in the regulation of body weight by inhibiting food intake and stimulating energy expenditure and its action occurs through a leptin receptor (Gerdes et al., 2011; Tilg & Moschen, 2006). Increased levels of leptin have been associated with cardiovascular disorders and shown to be an independent predictor of coronary heart disease (Piatti et al., 2003). In psoriasis patients Leptin levels have been shown to correlate with subclinical atherosclerosis (Robati et al., 2014). Leptin also modulates both innate and adaptive immunity, playing a role in acute and chronic inflammation, via regulation of cytokine expression, acting as a modulator of T-cell activity (Stofkova, 2009). Leptin plasma levels have been reported to be increased in psoriatic patients (Chen et al., 2008) and to be associated with higher PASI scores (Aly et al., 2013). Leptin appears to contribute to Th1 immune response, increasing IL-2 secretion and proliferation, as well as increasing IFN-g production by memory T cells, and to be an inductive factor in driving Th17 cell differentiation. Moreover, it inhibits the proliferation of CD4 + FoxP3 + T regulatory cells (Deng et al., 2012; Johnston et al., 2008; Orlova & Shirshev, 2014). Leptin also increases macrophage activity and their production of IL-1b, IL-6, TNF-a and IL-12 (Johnston et al., 2008). Thus, Leptin, through promoting synthesis of Th1 and Th17 cytokines and diminished T regulatory activity may be involved in the pathogenesis of psoriasis (Deng et al., 2012; Johnston et al., 2008; Orlova & Shirshev, 2014; Wang et al., 2008). The LEP rs2167270 (19 G/A) polymorphism has never been studied before in psoriasis patients. It has been reported to be associated with obesity and higher leptin levels in obese individuals (Hager et al., 1998; Li et al., 1999). On the other hand, it has been shown that women carrying the A-allele had lower BMI and lower leptin levels than those not carrying this allele. Also variants in LEPR have been associated with obesity (Farooqi et al., 2007). LEPR rs1137100 (326A/G) have been shown to be associated with adiposity, although some studies, probably as a result of ethnic differences in allele frequencies, have not showed this association (Paracchini et al., 2005). Regarding adiponectin, it is secreted mostly by adipocytes, exerting insulin sensitizing effects and anti-inflammatory and atheroprotective actions by reducing the expression of vascular adhesion molecules (VCAM-1), inflammatory cytokines (TNF-a and IL-8) and reactive oxygen species in endothelial cells (Yamauchi et al., 2002; Gerdes et al., 2011).

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Table 1. Study population characteristics. N ¼ 100 Gender, male Age, y Metabolic characteristics Body mass index, kg/m2 Waist circumference, cm Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Cardiovascular risk factors Hypertension Diabetes Dislipidemia Tobacco use Obesity Family history of CVD Metabolic syndrome Psoriasis characteristics Psoriasis duration Family history PASI Psoriasis therapy* Topical only Ever phototherapy Ever acitretin Ever cyclosporine Ever methotrexate Ever biologic therapy Analytic characteristics Glucose, mg/dl Total cholesterol, mg/dl Triglycerides, mg/dl HDL-cholesterol, mg/dl LDL-cholesterol, mg/dl VLDL-cholesterol, mg/dl Oxidized LDL-cholesterol, mg/dl Apolipoprotein B, mg/dl Lipoprotein(a), mg/dl Complement C3, mg/dl hs-C-reactive protein, mg/dl Leptin, mg/dl HOMA Adipose tissue assessment Epicardial adipose fat tissue, ml Abdominal visceral fat, ml Subcutaneous fat, ml Atherosclerosis assessment Presence of atherosclerosis (CAC40)

64% 47.4 ± 10.87 28.6 ± 4.99 95.8 ± 12.16 133.6 ± 16.14 80.9 ± 8.87 49% 12% 43% 21% 37% 13% 32% 21.9 ± 10.97 43% 13.4 ± 7.67 16% 61% 30% 51% 33% 21% 93.3 ± 28.3 206.5 ± 39.9 107 (71.3–155) 51.5 ± 13.2 129.1 ± 38.2 22.0 (14.0–32.5) 183.4 ± 56.4 94.0 ± 24.3 22.5 (6–46.8) 127.2 ± 20.5 2.4 (1.0–4.7) 0.7 (0.4–1.6) 2.2 (1.4–3.5) 101.4 ± 55.52 136.7 ± 84.02 242.1 ± 108.85 43%

Mean ± standard deviation; Median (interquartile range). HOMA, homeostatic model assessment. CVD, cardiovascular disease. *Patient could be in more than one group.

Its levels have been found to be decreased in obesity, type 2 diabetes and coronary artery disease (Arita et al., 1999; Jansson et al., 2003; Pajvani et al., 2004). Several studies have reported decreased circulating levels of adiponectin in patients with psoriasis compared with a control group and that adiponectin concentration levels are negatively correlated with psoriasis severity (Shibata et al., 2009; Takahashi et al., 2008). Moreover, obese psoriasis patients appear to have decreased adiponectin serum levels. Adiponectin concentrations have a strong genetic component, with heritability estimated between 30% and 50% (Comuzzie et al., 2001). Polymorphisms located in the ADIPOQ gene exert high influence on adiponectin serum levels, and although there are conflicting results, the major allele G of the rs1501299 (276 G/T) has been associated with cardiovascular disease

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Arch Physiol Biochem, Early Online: 1–6

Table 2. Genotype and allele frequencies for studied polymorphisms in psoriasis and control subjects.

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Psoriasis (n ¼ 100) LEP rs2167270 (19 G/A) GG (n ¼ 39) 39.0% GA (n ¼ 50) 50.0% AA (n ¼ 11) 11.0% G (n ¼ 128) 64.0% A (n ¼ 72) 36% LEPR rs1137100 (326 A/G) AA (n ¼ 62) 62.0% AG (n ¼ 35) 35.0% GG (n ¼ 3) 3.0% A (n ¼ 159) 79.5% G (n ¼ 41) 20.5% ADIPOQ rs1501299 (276 G/T) GG (n ¼ 49) 49.0% GT (n ¼ 43) 43.0% TT (n ¼ 8) 8.0% G (n ¼ 141) 70.5% T (n ¼ 59) 29.5%

Controls (n ¼ 206)

(39) (50) (11) (128) (72)

35.0% 47.1% 18.0% 41.5% 58.5%

(72) (97) (37) (171) (241)

(62) (35) (3) (159) (41)

53.9% 42.2% 3.9% 75.0% 25.0%

(111) (87) (8) (309) (103)

(49) (43) (8) (141) (59)

53.9% 39.3% 6.8% 73.5% 26.5%

(111) (81) (14) (303) (109)

P*

OR (95% CI)y

0.286

1 1.04 (0.58–1.86) 0.52 (0.22–1.23) 1 0.79 (0.54–1.17)

0.192

0.218

1 0.72 (0.41–1.25) 1.08 (0.25–4.73) 1 0.83 (0.53–1.30)

0.737

1 1.37 (0.78–2.40) 1.64 (0.58–4.67)

0.429

1.31 (0.86–1.99)

0.401

*Unadjusted P. yAge- and sex-adjusted odds ratio.

Table 3. Influence of the studied polymorphisms in epicardial adipose tissue and abdominal visceral fat volume. EAT LEP rs2167270 (19 G/A) GG (n ¼ 39) 105.36 ± 49.18 GA (n ¼ 50) 99.58 ± 60.60 AA (n ¼ 11) 95.89 ± 56.78 G (n ¼ 128) 103.10 ± 53.59 A (n ¼ 72) 98.45 ± 58.69 LEPR rs1137100 (326 A/G) AA (n ¼ 62) 99.85 ± 53.24 AG (n ¼ 35) 105.96 ± 61.06 GG (n ¼ 3) 81.26 ± 41.27 A (n ¼ 159) 101.19 ± 54.75 G (n ¼ 41) 102.35 ± 58.46 ADIPOQ rs1501299 (276 G/T) GG (n ¼ 49) 106.17 ± 53.60 GT (n ¼ 43) 95.10 ± 58.27 TT (n ¼ 8) 101.59 ± 56.46 G (n ¼ 141) 103.07 ± 54.87 T (n ¼ 59) 97.51 ± 56.87

P*

AVF

Py

0.712

155.25 ± 89.67 123.64 ± 74.40 130.10 ± 99.83 142.90 ± 84.78 125.61 ± 81.46

0.633

128.82 ± 73.38 154.26 ± 100.97 93.99 ± 42.54 134.42 ± 80.40 145.44 ± 96.50

0.292

153.17 ± 87.64 119.03 ± 72.58 130.53 ± 108.12 142.76 ± 84.24 122.15 ± 81.63

0.200

0.592

0.750 0.840

0.688 0.429

0.500

0.367

0.268

*Age-, sex- and AVF-adjusted P. yAge- and sex-adjusted P. EAT, epicardial adipose tissue; AVF, abdominal visceral fat.

(Qi, 2006), while the minor allele T was associated with a reduced frequency of CV disease, possible due to different effect on adiponectin levels (Menzaghi et al., 2007; Qi et al., 2005). The chronic inflammatory status associated with psoriasis seems to be responsible for accelerated atherosclerosis and higher risk of CVD. Nevertheless, in the present study, none of the studied gene polymorphisms showed a significant association with coronary artery calcification. Atherosclerosis is a polygenic disease and a single gene variable may not be enough to explain the development of the atherosclerotic disease, since the subtle nature of the genetic effects of a single locus polymorphism are prone to be masked by confounding factors. Naturally, large-scale genetic screening is required to analyse the epigenetic effects of inflammatory

genes on cardiovascular events and mortality in psoriasis patients. Interestingly, in similar studies conducted in rheumatoid arthritis patients, using different surrogate markers of subclinical atherosclerosis, comparable results were found. However, excess adiposity was not evaluated (Garcı´aBermu´dez et al., 2011; Rodrı´guez-Rodrı´guez et al., 2011). Strengths of this study include the detailed clinical, laboratory and imaging characterization of all psoriasis patients. The imaging method used to assess EAT and AVF is, along with MRI, the gold standard to measure EAT, also enabling AVF quantification, the most reliable marker of excess adiposity. Additionally, a very sensitive and specific non-invasive measure of subclinical atherosclerosis was used. The homogenous patient sample is also a strength of the

DOI: 10.3109/13813455.2015.1024136

Adipokines gene polymorphisms and cardiovascular comorbidities in psoriasis patients

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Table 4. Influence of studied polymorphism in coronary artery calcification.

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CAC ¼ 0 LEP rs2167270 (19 G/A) GG (n ¼ 39) 38.6% (22) GA (n ¼ 50) 52.6% (30) AA (n ¼ 11) 8.8% (5) G (n ¼ 128) 64.9% (74) A (n ¼ 72) 35.1% (40) LEPR rs1137100 (326 A/G) AA (n ¼ 62) 61.4% (35) AG (n ¼ 35) 35.1% (20) GG (n ¼ 3) 3.5% (2) A (n ¼ 159) 78.9% (90) G (n ¼ 41) 21.1% (24) ADIPOQ rs1501299 (276 G/T) GG (n ¼ 49) 47.4% (27) GT (n ¼ 43) 42.1% (24) TT (n ¼ 8) 10.5% (6) G (n ¼ 141) 68.4% (78) T (n ¼ 59) 31.6% (36)

CAC40 39.5% 46.5% 14% 62.8% 37.2%

(17) (20) (6) (54) (32)

62.8% 34.9% 2.1% 80.2% 19.8%

(27) (15) (1) (69) (17)

51.2% 44.2% 4.8% 73.3% 26.7%

(22) (19) (2) (63) (23)

P*

OR (95% CI)y

0.708

1 3.12 (0.79–12.36) 9.26 (0.85–101.04) 1 1.44 (0.69–3.01)

0.768

0.941 0.861

0.677 0.532

1 0.31 (0.07–1.34) 0.26 (0.04–15.07) 1 0.42 (0.13–1.31) 1 0.61 (0.05–7.52) 1.63 (0.44–6.03) 1 1.08 (0.43–2.67)

*Unadjusted P. yOR (95% CI) Age-, sex- and traditional cardiovascular risk factors (hypertension, diabetes, dyslipidemia, tobacco use, obesity and family history of cardiovascular disease)-adjusted odds ratio.

study, as all patients had severe psoriasis and psoriatic arthritis and known CVD were exclusion criteria. However, some limitations should be addressed. Despite being the largest study focusing on genetic variants of the LEP, LEPR and ADIPOQ genes and EAT, AVF and CAC in psoriasis, this is still a relatively small single centre study. Moreover, there is a potential selection bias since it was a hospital-based study. Another limitation is the cross-sectional, observational method of the study, which prevents proving causality, serving solely for hypothesis-generation. Finally, other gene polymorphisms could have been studied, particularly LEP (-2548G/A), and only leptin serum level was measured, although no significant differences were found regarding the genotype and allele frequencies. In conclusion, the studied polymorphisms in the LEP, LEPR and ADIPOQ genes do not seem to be a genetic risk factor for the development of atherosclerosis or increased adiposity in psoriasis, neither for psoriasis susceptibility. Although studies with positive results are usually more appealing than those with negative findings (Dwan et al., 2008; Dirnagl & Lauritzen, 2010), the results presented might be useful for further research. Due to the potential role of these adipokines in the patho-physiology of psoriasis, excess adiposity and cardiovascular disease, other polymorphisms located in these genes might have an influence in the development of atherosclerosis and excess adiposity in psoriasis. The search for potential gene candidates that may influence the development of atherosclerosis and psoriasislinked co-morbidities in patients with psoriasis needs further investigation.

Acknowledgements Study sponsored by an unrestricted grant from the Portuguese Society of Dermatology and Venereology.

Declaration of interest The authors report no declarations of interest.

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