TY - JOUR
T1 - Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus
AU - Sigurdsson, Snaevar
AU - Nordmark, Gunnel
AU - Göring, Harald H.H.
AU - Lindroos, Katarina
AU - Wiman, Ann Christin
AU - Sturfeit, Gunnar
AU - Jönsen, Andreas
AU - Rantapää-Dahlqvist, Solbritt
AU - Möller, Bozena
AU - Kere, Juha
AU - Koskenmies, Sari
AU - Widén, Elisabeth
AU - Eloranta, Maija Leena
AU - Julkunen, Heikki
AU - Kristjansdottir, Helga
AU - Steinsson, Kristjan
AU - Alm, Gunnar
AU - Rönnblom, Lars
AU - Syvänen, Ann Christine
N1 - Funding Information:
We thank Raul Figueroa and Per Lundmark (Molecular Medicine, Department of Medical Sciences, Uppsala University) for producing the tag-microarrays and for advice on the Haploview analysis, respectively; Marta Alarcón-Riquelme (Department of Genetic and Pathology, Uppsala University), for sequence information on the PDCD1 gene; and Lars Berglund (Uppsala Clinical Research Center), for performing the logistic regression analysis. Financial support for the study was provided by the Swedish Research Council and by the Knut and Alice Wallenberg Foundation (Wallenberg Consortium North) (to A.-C.S.), the Swedish Research Council, the Swedish Rheumatism Foundation, the Agnes and Mac Rudbergs Foundation, the King Gustaf V 80-Year Foundation, the Nanna Svartz Foundation, the Magnus Bergvall Foundation, the Börje Dahlin Foundation, the Brunnberg Foundation, the Astrid Karlsson Foundation, and the Uppsala University Hospital Research and Development Fund (to L.R. and G.A.)
PY - 2005/3
Y1 - 2005/3
N2 - 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.
AB - 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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U2 - 10.1086/428480
DO - 10.1086/428480
M3 - Article
C2 - 15657875
AN - SCOPUS:13844292408
VL - 76
SP - 528
EP - 537
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -