Mahé E, Maccari F, Beauchet A, et al Childhood-onset psoriasis:

Cardiovascular comorbidities in childhood psoriasis

40. Mahé E, Maccari F, Beauchet A, et al Childhood-onset psoriasis:

association with future cardiovascular and metabolic comorbidities. Br

J Dermatol 2013; 169: 889-95.

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2. ARTIGOS PUBLICADOS

Influência de Polimorfismos Genéticos na IL-6 na Gordura Epicárdica e Calcificação Arterial Coronária em Doentes com Psoríase

Torres T, Bettencourt N, Ferreira J, Carvalho C, Mendonça D, Pinho-Costa P, Vasconcelos C, Selores M, Silva B.

Influence of IL-6 gene polymorphisms in epicardial adipose tissue and coronary artery calcification in psoriasis patients. Br J Dermatol. 2014

These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. Wiley-Blackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists

Accepted Date : 06-Jul-2014 Article type : Correspondence

Influence of IL-6 gene polymorphisms in epicardial adipose tissue and coronary artery calcification in psoriasis patients

Short title: IL-6 gene polymorphisms and epicardial adipose tissue in psoriasis

T. Torres1,2_{, N. Bettencourt}3_{, J. Ferreira}4_{, C. Carvalho}4_{, D. Mendonça}5_{, P. Pinho-Costa}2,6_{, C.} Vasconcelos2,7_{, M. Selores}1_{, B. Silva}2,4

1- Department of Dermatology, Centro Hospitalar do Porto, Porto, Portugal

2- Unit for Multidisciplinary Investigation in Biomedicine, Instituto Ciências Biomédicas Abel Salazar, University of Porto, Portugal

3- Department of Cardiology, Centro Hospitalar Gaia/Espinho, Porto, Portugal

4- Immunogenetics Laboratory, Instituto Ciências Biomédicas Abel Salazar, University of Porto, Portugal

5- Department of Population Studies, Instituto Ciências Biomédicas Abel Salazar, University of Porto, Portugal

6- Immunogenetics Laboratory, Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA), Porto, Portugal 7- Department of Clinical Immunology, Centro Hospitalar do Porto, Porto, Portugal

Corresponding Author: Tiago Torres

Address: Serviço de Dermatologia, Centro Hospitalar do Porto, Edifício das Consultas Externas, Ex- CICAP, Rua D. Manuel II, s/n, 4100 Porto, Portugal

E-mail: tiagotorres2002@hotmail.com

Fundings: This study was supported in part by an unrestricted grant from the Portuguese Society of Dermatology and Venereology

158

Psoriasis is currently considered a systemic inflammatory disorder associated with several comorbidities and increased risk of cardiovascular disease (CVD)1_{. Several proinflammatory} cytokines are overexpressed cutaneous and systemically and may be responsible for skin lesions but also for psoriasis-associated conditions1_{. Epicardial adipose tissue (EAT), a type of visceral fat} surrounding the heart, is now regarded as an important factor in the pathogenesis of coronary atherosclerosis and CVD, through inflammatory burden proximal to the coronary arteries, and has been shown to be increased in psoriasis patients independently of abdominal visceral fat (AVF) and to be associated with subclinical atherosclerosis2_.

IL-6 has been implicated in the pathogenesis of psoriasis1 _{but also of abdominal obesity}3_, atherosclerosisand CVD4_{. IL-6 is produced by several cells, with}_{adipose tissue accounting for up to} 30% of total circulating concentrations in healthy subjects3_{. The expression of many cytokines is} thought to be influenced by polymorphisms in their gene loci, and this may contribute to the development of psoriasis, but also excess adiposity3_{. The association between IL-6 polymorphisms} and psoriasis has been investigated5_{, as well as, with excess adiposity}3_{. Recognizing genetic markers} that could predict which patients are at risk of developing psoriasis-linked cardiovascular comorbidities may permit an earlier management, with important clinical implications6_{. This study} aimed to evaluate the potential contribution of four IL-6 genetic variants (rs1800795[-174G>C], rs1800796[-572G>C], rs2069827[-1426G>T], rs2069840[-1753C>G]) in psoriasis susceptibility and its influence in EAT and coronary artery calcification (CAC) in severe psoriasis patients.

Consecutive Portuguese, European ancestry, adult patients with severe plaque-type psoriasis (PASI>10 and/or requiring systemic therapy/phototherapy) without psoriatic arthritis, CVD, and other systemic inflammatory disease were enrolled. All subjects underwent clinical and laboratory evaluation, DNA sample extraction and multidetector computed tomography scan for EAT, AVF and CAC assessment. The scan parameters and used methods have been previously described2_{. The} Control DNA group was obtained from a previously anonymized DNA biobank of 206 adult Portuguese general population controls without psoriasis. SNP genotyping was performed on the Sequenom™massARRAY iPLEX platform. The study was approved by the hospital Institutional Review Board.

No significant differences were observed in genotype or allele frequencies between psoriasis patients and controls (table 1). Psoriasis patients homozygous for the minor G-allele of the rs2069840 polymorphism had increased EAT volume comparing to those carrying the C-allele (CC+CG) (136.05±87.20vs95.32±45.98,P=0.008) independently of age, sex and AVF(P=0.031). Analysing allele distribution, G-allele presence was associated with increased EAT volume, comparing to C-allele, independently of age, sex and AVF (110.39±65.77vs95.33±46.33, adjusted P=0.026). No significant differences were found when analysing other polymorphisms. 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 CVRF(table 2).

The present study showed that psoriasis patients carrying the minor G-allele of the IL-6 rs2069840 polymorphism had increased EAT volume independently of age, sex and AVF. This effect appeared to be enhanced in the homozygous status for the G-allele. However, none of the studied SNPs was associated with increased risk of CAC. Atherosclerosis is a polygenic disease and a single gene variable may not be enough to explain the development of atherosclerotic disease. Finally, no differences were observed in genotype or allele frequencies between psoriasis patients and controls. 2. ARTIGOS PUBLICADOS

Probably there are other factors and inflammatory pathways, rather than genetic contribution, which mainly define IL-6 levels in psoriasis patients.

More than one polymorphic site in the IL-6 gene has been suggested to influence gene transcription, both in the promoter or intron region. The rs1800795 variant is the best-studied IL-6 polymorphism, but data on its effects in psoriasis, excess adiposity and IL-6 expression has been inconsistent5,7,8_{. IL-6}

rs2069827 polymorphism has been associated with adiposity8 _{while rs2069840 variant has not yet}

been associated with any chronic inflammatory disease or excess adiposity, but has been associated both with higher and reduced IL-6 plasma levels9_{. Possibly the effect of the IL-6 polymorphisms on IL-}

6 expression and the effect of IL-6 itself may vary by situation or cell type7,8_.

The way IL-6 polymorphism influences EAT or overall adiposity is unknown, but some IL-6 genotypes may be associated with lower fasting energy expenditure providing a hypothesis for some polymorphism to influence long-term weight gain and obesity10_.

Some limitations should be addressed: the cross-sectional method of the study prevents proving causality, serving solely for hypothesis-generation; the relatively small studied population; a haplotype analysis could provide further insight than the effects of single SNPs; although, the measurement of circulating IL-6 levels may not reflect biological significance at tissue level, serum IL- 6 levels were not measured, making it impossible to conclude on the functional consequences of the IL-6 polymorphisms on the excess adiposity observed.

Although further studies in other psoriasis populations are warranted, genetic variants in the IL-6 gene may have a role in the association between psoriasis and its comorbidities and be involved in the development of increased EAT in these patients.

References

1. Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol 2010;

130:1785–96.

2. Torres T, Bettencourt N, Mendonça D, et al. Epicardial adipose tissue and coronary artery calcication in psoriasis patients. J Eur Acad Dermatol Venereol 2014 Apr 21.

3. Clement K, Boutin P, Froguel P. Genetics of obesity. Am J Pharmacogenomics 2002; 2:177–

No documento Avaliação da importância da psoriase em placas moderada a grave como factor de risco cardiovascular: estudo numa população portuguesa (páginas 153-159)