title: Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus.
abstract: Lupus erythematosus (LE) is a heterogeneous disease ranging from skin-restricted manifestations to a progressive multisystem disease. The specific skin lesions include chronic cutaneous, subacute cutaneous and acute cutaneous LE. Both genetic and environmental factors are involved in the development of LE. However, reports on the genetic background of cutaneous lupus erythematosus (CLE) forms, namely discoid (DLE) and subacute cutaneous lupus erythematosus (SCLE), are sparse. We investigated whether the known systemic LE (SLE) susceptibility genes also predispose to CLE. Altogether, 219 Finnish patients with DLE or SCLE and 356 healthy controls were recruited. Single nucleotide polymorphisms tagging reported risk genes were genotyped. Tyrosine kinase 2 (TYK2) rs2304256 was associated with increased risk of DLE (P = 0.012, OR = 1.47, 95% CI = 1.01-1.98). Expression of TYK2 was demonstrated by immunohistochemistry in macrophage-like cells and neutrophils and interferon regulatory factor 5 (IRF5) in macrophage- and fibroblast-like cells of DLE, SCLE and SLE skin. IRF5 rs10954213 showed association with DLE (P = 0.017, OR = 1.40, 95% CI = 1.06-1.86) and SCLE (P = 0.022, OR = 1.87, 95% CI = 1.09-3.21). A haplotype of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) showed association with DLE (P = 0.0065, OR = 2.51, 95% CI = 1.25-5.04). Our results show that the TYK2, IRF5 and CTLA4 genes previously associated with SLE also confer risk for DLE and SCLE, suggesting that different LE subphenotypes may share pathogenetic pathways.
authors.affiliation: Department of Dermatology, Institute of Clinical Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Järvinen
authors.forename: Anna
authors.initials: A
authors.lastname: Hellquist
authors.forename: Sari
authors.initials: S
authors.lastname: Koskenmies
authors.forename: Elisabet
authors.initials: E
authors.lastname: Einarsdottir
authors.forename: Lotta L E
authors.initials: LL
authors.lastname: Koskinen
authors.forename: Leila
authors.initials: L
authors.lastname: Jeskanen
authors.forename: Linda
authors.initials: L
authors.lastname: Berglind
authors.forename: Jaana
authors.initials: J
authors.lastname: Panelius
authors.forename: Taina
authors.initials: T
authors.lastname: Hasan
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Ulpu
authors.initials: U
authors.lastname: Saarialho-Kere
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008179:Lupus Erythematosus, Discoid / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D053634:TYK2 Kinase / Q000235:genetics*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D053634:TYK2 Kinase; C070139:TYK2 protein, human