Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2005 Jan 20

PMID 15657875

Citations 264

Authors

Snaevar Sigurdsson

Gunnel Nordmark

Harald H H Goring

Katarina Lindroos

Ann-Christin Wiman

Gunnar Sturfelt

Andreas Jonsen

Solbritt Rantapaa-Dahlqvist

Bozena Moller

Juha Kere

Sari Koskenmies

Elisabeth Widen

Maija-Leena Eloranta

Heikki Julkunen

Helga Kristjansdottir

Kristjan Steinsson

Gunnar Alm

Lars Ronnblom

Ann-Christine Syvanen

Affiliations

Soon will be listed here.

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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References

Sanghera D, Manzi S, Bontempo F, Nestlerode C, Kamboh M . Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies. Hum Genet. 2004; 115(5):393-8. DOI: 10.1007/s00439-004-1172-0. View

Barnes B, Kellum M, Pinder K, Frisancho J, Pitha P . Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res. 2003; 63(19):6424-31. View

Namjou B, Nath S, Kilpatrick J, Kelly J, Reid J, Reichlin M . Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2). Genes Immun. 2002; 3 Suppl 1:S35-41. DOI: 10.1038/sj.gene.6363905. View

Izaguirre A, Barnes B, Amrute S, Yeow W, Megjugorac N, Dai J . Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells. J Leukoc Biol. 2003; 74(6):1125-38. DOI: 10.1189/jlb.0603255. View

Barnes B, Lubyova B, Pitha P . On the role of IRF in host defense. J Interferon Cytokine Res. 2002; 22(1):59-71. DOI: 10.1089/107999002753452665. View

Ronnblom L, Alm G . Systemic lupus erythematosus and the type I interferon system. Arthritis Res Ther. 2003; 5(2):68-75. PMC: 165035. DOI: 10.1186/ar625. View

Lovgren T, Eloranta M, Bave U, Alm G, Ronnblom L . Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum. 2004; 50(6):1861-72. DOI: 10.1002/art.20254. View

Bell P, Chaturvedi S, Gelfand C, Huang C, Kochersperger M, Kopla R . SNPstream UHT: ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques. 2002; Suppl:70-2, 74, 76-7. View

Baechler E, Batliwalla F, Karypis G, Gaffney P, Ortmann W, Espe K . Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003; 100(5):2610-5. PMC: 151388. DOI: 10.1073/pnas.0337679100. View

10.

de Veer M, Holko M, Frevel M, Walker E, Der S, Paranjape J . Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001; 69(6):912-20. View

11.

Riva A, Kohane I . A SNP-centric database for the investigation of the human genome. BMC Bioinformatics. 2004; 5:33. PMC: 395999. DOI: 10.1186/1471-2105-5-33. View

12.

Richter M, Dumenil G, Uze G, Fellous M, Pellegrini S . Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1. J Biol Chem. 1998; 273(38):24723-9. DOI: 10.1074/jbc.273.38.24723. View

13.

Deapen D, Escalante A, Weinrib L, HORWITZ D, Bachman B, Roy-Burman P . A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992; 35(3):311-8. DOI: 10.1002/art.1780350310. View

14.

Santiago-Raber M, Baccala R, Haraldsson K, Choubey D, Stewart T, Kono D . Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med. 2003; 197(6):777-88. PMC: 2193854. DOI: 10.1084/jem.20021996. View

15.

Barnes B, Moore P, Pitha P . Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J Biol Chem. 2001; 276(26):23382-90. DOI: 10.1074/jbc.M101216200. View

16.

Lindroos K, Sigurdsson S, Johansson K, Ronnblom L, Syvanen A . Multiplex SNP genotyping in pooled DNA samples by a four-colour microarray system. Nucleic Acids Res. 2002; 30(14):e70. PMC: 135771. DOI: 10.1093/nar/gnf069. View

17.

Hsu T, Chen X, Duan S, Miller R, Kwok P . Universal SNP genotyping assay with fluorescence polarization detection. Biotechniques. 2001; 31(3):560, 562, 564-8, passim. DOI: 10.2144/01313rr01. View

18.

Kaplan M . Apoptosis in systemic lupus erythematosus. Clin Immunol. 2004; 112(3):210-8. DOI: 10.1016/j.clim.2004.04.007. View

19.

Cantor R, Yuan J, Napier S, Kono N, Grossman J, Hahn B . Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23. Arthritis Rheum. 2004; 50(10):3203-10. DOI: 10.1002/art.20511. View

20.

Bave U, Alm G, Ronnblom L . The combination of apoptotic U937 cells and lupus IgG is a potent IFN-alpha inducer. J Immunol. 2000; 165(6):3519-26. DOI: 10.4049/jimmunol.165.6.3519. View