Epigenetics in the Pathogenesis and Pathophysiology of Psoriasis Vulgaris

February 2014 | Volume 13 | Issue 2 | Original Article | 111 | Copyright © 2014

Ryan M. Trowbridgea and Mark R. Pittelkow MDb

aCreighton University Medical School, Omaha, NE
bMayo Clinic, Scottsdale, AZ

Abstract

Epigenetic phenomena, including DNA methylation, histone modification, and genetic regulation by miRNAs, are potentially heritable genetic regulatory changes that are not attributed to direct alterations in the DNA sequence of base pairs. They may explain the link between psoriasis risk alleles and disease development, as alleles possess various potentials to undergo epigenetic modification. Multiple genes involved in psoriasis pathogenesis demonstrate abnormal methylation patterns including those involved in epidermal differentiation and proliferation, immunity, the cell cycle, apoptosis, inflammation, and IFN-γ and TNF-α signaling. Hypoacetylation of histone H4 is observed in peripheral blood mononuclear cells of psoriatic patients, and the degree of hypoacetylation of histone H4 is inversely correlated to the PASI score. Investigators have reported both increased and decreased expression of miRNAs in patients with psoriasis, and have described and speculated a number of possible mechanisms for their roles in pathogenesis. Interestingly, the altered methylation patterns observed in psoriasis appear to be normalized by treatment with biologics directed at TNF-α inhibition. However, attempts to directly correlate epigenetic regulatory mechanisms with expression of genes observed in psoriasis have been limited thus far, and correlating miRNA expression levels to disease phenotypes can be challenging and inconsistent. Hopefully, the goal of drawing clinically relevant conclusions about the role of epigenetics in psoriasis will be aided by recent methods that enable fast and sensitive epigenomic profiling. Drugs targeting epigenetic mechanisms are currently being explored, though not for psoriasis, but specificity to pathogenetic mechanisms remains elusive. However, the amenability of cutaneous disease to topical therapies may elevate their usefulness in the treatment of this common skin disorder.

J Drugs Dermatol. 2014;13(2):111-118.

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INTRODUCTION

The role of genetics in the development of psoriasis has been recognized for more than six decades.1 Psoriasis harbors a significant heritable component that is wellestablished, and a family history of two affected parents portends a greater than 40% chance of developing the disease in the offspring.2 This risk diminishes to 14% if one parent is affected and 6% if a sibling is affected, compared to 2% when there is no family history.2 Predisposition to psoriasis is regarded as a polygenetic disorder, possessing a complex pattern of heritability with a strong HLA association.3 Currently, the psoriasis susceptibility locus 1 (PSORS1) is most strongly implicated in disease risk. PSORS1 is a roughly 300 kb interval imbedded in the 3.6 Mb major histocompatibility complex that contains HLA genes associated with psoriasis.4 HLA serotype C*06 is located within the PSORS1 interval and demonstrates the largest overall relative risk for familial psoriasis.5 HLA-C*06 and candidate genes linked to this allele are those most strongly implicated in the pathogenesis of the disease,6 yet, only approximately 10% of individuals carrying HLA-C*06 will actually manifest characteristic signs of psoriasis.7 Despite HLA-C*06 representing a validated psoriasis risk allele, it is also clear that predisposition for psoriasis is multifactorial. In addition to PSORS1, multiple other genetic loci on multiple different chromosomes have been linked to psoriasis susceptibility,8 including those containing genes that encode proteins involved in skin barrier function and innate and adaptive immunity.9

Data from twin studies supports an important genetic contribution to psoriasis, demonstrating 40% concordance amongst monozygotic twins but only 10% in dizygotic twins in one study.10 The discordance rate was also much lower in monozygotic (17%) compared to dizygotic (33%) twins.10 The lack of 100% concordance in monozygotic twins necessitates involvement of other critical factors in addition to strict genetic inheritance,11 and suggests that disease susceptibility likely involves multiple genes on different chromosomes. Furthermore, the observation that twin concordance rates vary greatly based on geography – lower in Norway12 and Australia11 compared to the United States10 and Denmark13 – raises the question of the interaction of environmental and lifestyle factors, such as ultraviolet radiation/solar exposure and diet, with various genetic predispositions. The likely role of environmental factors to promote or suppress development or activity of psoriasis is most dramatically illustrated by the development of guttate psoriasis following group A beta-hemolytic streptococcal throat infection in patients carrying the HLA-C*06 allele.14 A novel mechanism that is gaining better understanding by which the environmental and the genetic components of psoriasis may interact is through epigenetic phenomena.

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