title: Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes. Currently, ~8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR>1.3). In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies. Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (P(comb)<5×10(-8)): NCF2 (P(comb) = 2.87×10(-11)), IKZF1 (P(comb) = 2.33×10(-9)), IRF8 (P(comb) = 1.24×10(-8)), IFIH1 (P(comb) = 1.63×10(-8)), and TYK2 (P(comb) = 3.88×10(-8)). Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE. These results increase the number of established susceptibility genes for lupus to ~30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease.
authors: Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, School of Medicine, King's College London, London, United Kingdom.
authors: Deborah S
authors: DS
authors: Cunninghame Graham
authors: David L
authors: DL
authors: Morris
authors: Tushar R
authors: TR
authors: Bhangale
authors: Lindsey A
authors: LA
authors: Criswell
authors: Ann-Christine
authors: AC
authors: Syvänen
authors: Lars
authors: L
authors: Rönnblom
authors: Timothy W
authors: TW
authors: Behrens
authors: Robert R
authors: RR
authors: Graham
authors: Timothy J
authors: TJ
authors: Vyse
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000235:genetics*; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D019255:NADPH Oxidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000235:genetics*; D000099185:Interferon Regulatory Factor-8
chemical_list: D053487:DEAD-box RNA Helicases; D051740:Ikaros Transcription Factor; D050835:Interferon Regulatory Factors; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons; D019255:NADPH Oxidases; D053634:TYK2 Kinase; D000099185:Interferon Regulatory Factor-8; C497239:IKZF1 protein, human; C527764:NCF2 protein, human; C070139:TYK2 protein, human; C452815:IFIH1 protein, human