title: Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.
abstract: BACKGROUND
  Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach.
  
  
  METHODS
  We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity.
  
  
  RESULTS
  772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology.
  
  
  CONCLUSIONS
  Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, , Nijmegen, The Netherlands.
authors.forename: Maša
authors.initials: M
authors.lastname: Umiċeviċ Mirkov
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.forename: Erik J M
authors.initials: EJ
authors.lastname: Toonen
authors.forename: Remco R
authors.initials: RR
authors.lastname: Makkinje
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Renee
authors.initials: R
authors.lastname: Allaart
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
authors.forename: Corinne Richard
authors.initials: CR
authors.lastname: Miceli
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.forename: Niek
authors.initials: N
authors.lastname: de Vries
authors.forename: Saedis
authors.initials: S
authors.lastname: Saevarsdottir
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: van Schaardenburg
authors.forename: Tim L
authors.initials: TL
authors.lastname: Jansen
authors.forename: Ellen A J
authors.initials: EA
authors.lastname: Dutmer
authors.forename: Mart A F J
authors.initials: MA
authors.lastname: van de Laar
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004351:Drug Resistance / Q000235:genetics*; D000068800:Etanercept; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D000069285:Infliximab; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012042:Registries; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D005819:Genetic Markers; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept