title: 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.
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska lnstitutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Nikamo
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska lnstitutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Stanley
authors.initials: S
authors.lastname: Cheuk
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska lnstitutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Josefin
authors.initials: J
authors.lastname: Lysell
authors.affiliation: Ingrid Asp Psoriasis Research Center, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Enerbäck
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska lnstitutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bergh
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska lnstitutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu Landén
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska lnstitutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Liv
authors.initials: L
authors.lastname: Eidsmo
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska lnstitutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: mona.stahle@ki.se.
authors.forename: Mona
authors.initials: M
authors.lastname: Ståhle
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001665:Binding Sites; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007378:Interleukins / Q000235:genetics*; D008297:Male; D011401:Promoter Regions, Genetic; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D012044:Regression Analysis; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D018336:Receptors, Aryl Hydrocarbon; D000097043:Interleukin-22