title: A genetic risk score composed of rheumatoid arthritis risk alleles, HLA-DRB1 haplotypes, and response to TNFi therapy - results from a Swedish cohort study.
abstract: To prevent debilitating and irreversible joint damage, rheumatoid arthritis (RA) is often treated with tumor necrosis factor inhibitor (TNFi), but many patients do not respond to this costly therapy. Few predictors for response are known, and it has been proposed that genetic factors which influence the development of RA may also influence disease severity and response to therapy. Several previous studies have attempted to confirm this but results remain inconclusive. We expand on previous studies by including more RA risk alleles, and maximize power by combining them into a genetic risk score.
  
  
  
  We linked genotyped RA patients from the Epidemiological Investigation of Rheumatoid Arthritis study to the Swedish Rheumatology Quality Register, identifying patients who started a TNFi as their first biological disease-modifying anti-rheumatic drug, with a return visit within 2-8 months after treatment start (N = 867). We calculated risk scores from 76 established RA risk SNPs, and four HLA-DRB1 amino acid positions, and tested whether risk scores or individual genetic risk factors could predict the European League Against Rheumatism (EULAR) response.
  
  
  
  We found no association between any of the risk scores or HLA-DRB1 haplotypes and EULAR response, neither overall nor stratified by anti-citrullinated protein/peptide antibody (ACPA) status. When evaluating each of the 76 SNPs, we found that the number of SNPs presenting significant associations was not higher than expected by chance (5/76 SNPs had p < 0.05 in ACPA-positive RA, 4/76 in ACPA-negative RA).
  
  
  
  Overall, known RA risk SNPs do not predict response to TNFi, either individually or when combined into a risk score. This does not support the hypothesis that genes influencing RA onset would also influence its prognosis and treatment response.
authors.affiliation: Unit of Clinical Epidemiology (KEP), Department of Medicine, Karolinska University Hospital, SE-171 76, Stockholm, Sweden. xia.jiang@ki.se.|Department of Genetic Epidemiology, Harvard T.H. Chan School of Public Health, 02115, Boston, MA, USA. xia.jiang@ki.se.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Unit of Clinical Epidemiology (KEP), Department of Medicine, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.|Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Askling
authors.affiliation: Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Saedis
authors.initials: S
authors.lastname: Saevarsdottir
authors.affiliation: Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Cardiovascular Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Viatte
authors.affiliation: Unit of Clinical Epidemiology (KEP), Department of Medicine, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Frisell
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D015331:Cohort Studies; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013548:Sweden; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D018501:Antirheumatic Agents; D059811:HLA-DRB1 Chains; D014409:Tumor Necrosis Factor-alpha
keywords: Genetic; HLA-DRB1 haplotypes; Rheumatoid arthritis risk SNPs; Tumor necrosis factor inhibitor prediction