title: Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes--the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes--we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.
authors.affiliation: Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Katarina
authors.initials: K
authors.lastname: Lindroos
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Wiman
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönsen
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: Bozena
authors.initials: B
authors.lastname: Möller
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Sari
authors.initials: S
authors.lastname: Koskenmies
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Widén
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
authors.forename: Heikki
authors.initials: H
authors.lastname: Julkunen
authors.forename: Helga
authors.initials: H
authors.lastname: Kristjansdottir
authors.forename: Kristjan
authors.initials: K
authors.lastname: Steinsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Alm
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005387:Finland; D005787:Gene Frequency; D008040:Genetic Linkage; D006801:Humans; D007055:Iceland; D050835:Interferon Regulatory Factors; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D013548:Sweden; D053634:TYK2 Kinase; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human