title: Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis.
abstract: Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case-case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort (N=469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00-1.77, P-value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60-0.94, P=0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB (CHUK, MYD88, NFKBIB, and NLRP3).
authors.affiliation: Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark.|Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.|Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark.|OPEN (Odense Patient data Explorative Network), Odense University Hospital, Odense, Denmark.
authors.forename: J
authors.identifier: 0000-0002-2718-9320
authors.initials: J
authors.lastname: Sode
authors.affiliation: National Research Centre for the Working Environment, Copenhagen, Denmark.
authors.forename: U
authors.initials: U
authors.lastname: Vogel
authors.affiliation: Department of Medicine, Viborg Regional Hospital, Viborg, Denmark.|Department of Biomedicine, University of Aarhus, Aarhus, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Bank
authors.affiliation: Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.|Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: P S
authors.initials: PS
authors.lastname: Andersen
authors.affiliation: The DANBIO Registry, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre for Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M L
authors.initials: ML
authors.lastname: Hetland
authors.affiliation: Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Locht
authors.affiliation: Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark.|Department of Clinical Biochemistry, Clinical Institute, University of Southern Denmark, Odense, Denmark.
authors.forename: N H H
authors.initials: NHH
authors.lastname: Heegaard
authors.affiliation: Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark.|OPEN (Odense Patient data Explorative Network), Odense University Hospital, Odense, Denmark.|Department of Medicine, Viborg Regional Hospital, Viborg, Denmark.|Molecular Diagnostic and Clinical Research Unit, Hospital of Southern Jutland, Aabenraa, Denmark.
authors.forename: V
authors.initials: V
authors.lastname: Andersen
mesh_terms: D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D005819:Genetic Markers; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases