Genetic Variants of the IL22 Promoter Associate to Onset of Psoriasis before Puberty and Increased IL-22 Production in T Cells

Abstract

Most psoriasis susceptibility genes were identified in cohorts of mixed clinical phenotypes and the exploration of genes in clinical subtypes is scarce. IL-22 has an established role in host defense and in psoriasis skin pathology, reflecting the delicate balance between control of infection and immunopathology. In a case-control study, we compared the genetic association to IL22 in psoriasis onset in patients between 0-9 (n=207), 10-20 (n=394), and 21-40 (n=468) years with healthy controls (n=1,529). Logistic regression analysis revealed association to regulatory elements in the IL22 promoter confined to onset of psoriasis before puberty (odds ratio=1.45, P<0.0007). The associated variants contain putative binding sites for AhR, a potent inducer of IL-22 expression. In a luciferase assay, transcriptional activity of a high-risk gene variant resulted in 80% higher promoter activity (P=0.012) compared with a low-risk variant. Ex vivo stimulated T cells from peripheral blood were analyzed with flow cytometry. Children with psoriasis carrying a high-risk variant produced 1.7 times more IL-22 compared with low-risk variants (P=0.042). Our combined genetic and functional data support the notion that a genetic IL22 variant that promotes epithelial barrier defense is preferentially enriched in and may precipitate the onset of psoriasis at an early age.

Clinical Characterisation at Onset of Childhood Psoriasis – A Cross Sectional Study in Sweden

“…Previous studies from our group using puberty as cut-off indicate differences in the genetic background between pre-pubertal and pubertal children with a stronger association to HLA-C*06 in pubertal children (20,21). In contrast to the findings of Gudjonsson et al (22) a younger age of onset was not associated with more severe disease (higher PASI) in our material (see Table II).…”

“…However, most studies are retrospective and reliable information captured at onset is lacking. We have previously reported that psoriasis onset before puberty is genetically distinct from adolescent onset (20,21). The overall aim of this study was to examine whether such differences would translate into phenotypic differences and indeed, we found that depending on the age of onset, the clinical disease presentation displayed significant variations.…”

Interleukin-22: Immunobiology and Pathology

“…Polymorphisms in the IL-22 gene have been associated with psoriasis in a Japanese population (289) and a polymorphism in the promoter region of IL-22 is associated with increased production of IL-22 and increased risk of psoriasis onset in childhood (290). In addition, copy number variation of IL-22 gene exon1 was significantly associated with psoriasis severity (291).…”

Cytokines in psoriasis

“…IL-22 induces epidermal hyperplasia [77] but not keratinocyte proliferation [81]; it inhibits epidermal differentiation and, either alone or in synergy with IL-1 and IL-17, drives the induction of pro-inflammatory gene expression [77,81]. Interestingly, a genetic variant that increases activity at the IL22 promoter has been associated with childhood-onset psoriasis [82]. Thus both genetic and functional data support the view that IL-22 is another critical cytokine in the pathogenesis of psoriasis and as such is a target of drug development [8].…”