Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus |
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Authors: | Sigurdsson Snaevar Nordmark Gunnel Göring Harald H H Lindroos Katarina Wiman Ann-Christin Sturfelt Gunnar Jönsen Andreas Rantapää-Dahlqvist Solbritt Möller Bozena Kere Juha Koskenmies Sari Widén Elisabeth Eloranta Maija-Leena Julkunen Heikki Kristjansdottir Helga Steinsson Kristjan Alm Gunnar Rönnblom Lars Syvänen Ann-Christine |
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Affiliation: | Snaevar Sigurdsson, Gunnel Nordmark, Harald H. H. Göring, Katarina Lindroos, Ann-Christin Wiman, Gunnar Sturfelt, Andreas Jönsen, Solbritt Rantapää-Dahlqvist, Bozena Möller, Juha Kere, Sari Koskenmies, Elisabeth Widén, Maija-Leena Eloranta, Heikki Julkunen, Helga Kristjansdottir, Kristjan Steinsson, Gunnar Alm, Lars Rönnblom, and Ann-Christine Syvänen |
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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. |
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