title: Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis.
abstract: BACKGROUND
  In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations.
  
  
  METHODS
  The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients.
  
  
  RESULTS
  None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis.
  
  
  CONCLUSIONS
  Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.
authors.forename: Ana
authors.initials: A
authors.lastname: Márquez
authors.forename: Aida
authors.initials: A
authors.lastname: Ferreiro-Iglesias
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Dávila-Fajardo
authors.forename: Ariana
authors.initials: A
authors.lastname: Montes
authors.forename: Dora
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.forename: Eva
authors.initials: E
authors.lastname: Perez-Pampin
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Moreno-Ramos
authors.forename: Rosa
authors.initials: R
authors.lastname: García-Portales
authors.forename: Federico
authors.initials: F
authors.lastname: Navarro
authors.forename: Virginia
authors.initials: V
authors.lastname: Moreira
authors.forename: César
authors.initials: C
authors.lastname: Magro
authors.forename: Rafael
authors.initials: R
authors.lastname: Caliz
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Ferrer
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Alegre-Sancho
authors.forename: Beatriz
authors.initials: B
authors.lastname: Joven
authors.forename: Patricia
authors.initials: P
authors.lastname: Carreira
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Vasilopoulos
authors.forename: Theologia
authors.initials: T
authors.lastname: Sarafidou
authors.forename: José
authors.initials: J
authors.lastname: Cabeza-Barrera
authors.forename: Javier
authors.initials: J
authors.lastname: Narvaez
authors.forename: Enrique
authors.initials: E
authors.lastname: Raya
authors.forename: Juan D
authors.initials: JD
authors.lastname: Cañete
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández-Nebro
authors.forename: María del Carmen
authors.initials: Mdel C
authors.lastname: Ordóñez
authors.forename: Arturo R
authors.initials: AR
authors.lastname: de la Serna
authors.forename: Berta
authors.initials: B
authors.lastname: Magallares
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gomez-Reino
authors.forename: Antonio
authors.initials: A
authors.lastname: González
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
mesh_terms: D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha