title: Lack of replication of interactions between polymorphisms in rheumatoid arthritis susceptibility: case-control study.
abstract: BACKGROUND
  Approximately 100 loci have been definitively associated with rheumatoid arthritis (RA) susceptibility. However, they explain only a fraction of RA heritability. Interactions between polymorphisms could explain part of the remaining heritability. Multiple interactions have been reported, but only the shared epitope (SE) × protein tyrosine phosphatase nonreceptor type 22 (PTPN22) interaction has been replicated convincingly. Two recent studies deserve attention because of their quality, including their replication in a second sample collection. In one of them, researchers identified interactions between PTPN22 and seven single-nucleotide polymorphisms (SNPs). The other showed interactions between the SE and the null genotype of glutathione S-transferase Mu 1 (GSTM1) in the anti-cyclic citrullinated peptide-positive (anti-CCP+) patients. In the present study, we aimed to replicate association with RA susceptibility of interactions described in these two high-quality studies.
  
  
  METHODS
  A total of 1,744 patients with RA and 1,650 healthy controls of Spanish ancestry were studied. Polymorphisms were genotyped by single-base extension. SE genotypes of 736 patients were available from previous studies. Interaction analysis was done using multiple methods, including those originally reported and the most powerful methods described.
  
  
  RESULTS
  Genotypes of one of the SNPs (rs4695888) failed quality control tests. The call rate for the other eight polymorphisms was 99.9%. The frequencies of the polymorphisms were similar in RA patients and controls, except for PTPN22 SNP. None of the interactions between PTPN22 SNPs and the six SNPs that met quality control tests was replicated as a significant interaction term--the originally reported finding--or with any of the other methods. Nor was the interaction between GSTM1 and the SE replicated as a departure from additivity in anti-CCP+ patients or with any of the other methods.
  
  
  CONCLUSIONS
  None of the interactions tested were replicated in spite of sufficient power and assessment with different assays. These negative results indicate that whether interactions are significant contributors to RA susceptibility remains unknown and that strict standards need to be applied to claim that an interaction exists.
authors.forename: Aida
authors.initials: A
authors.lastname: Ferreiro-Iglesias
authors.forename: Manuel
authors.initials: M
authors.lastname: Calaza
authors.forename: Eva
authors.initials: E
authors.lastname: Perez-Pampin
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Lopez Longo
authors.forename: Jose L
authors.initials: JL
authors.lastname: Marenco
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Blanco
authors.forename: Javier
authors.initials: J
authors.lastname: Narvaez
authors.forename: Federico
authors.initials: F
authors.lastname: Navarro
authors.forename: Juan D
authors.initials: JD
authors.lastname: Cañete
authors.forename: Arturo R
authors.initials: AR
authors.lastname: de la Serna
authors.forename: Isidoro
authors.initials: I
authors.lastname: Gonzalez-Alvaro
authors.forename: Gabriel
authors.initials: G
authors.lastname: Herrero-Beaumont
authors.forename: Jose L
authors.initials: JL
authors.lastname: Pablos
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fernandez-Gutierrez
authors.forename: Rafael
authors.initials: R
authors.lastname: Caliz
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gomez-Reino
authors.forename: Antonio
authors.initials: A
authors.lastname: Gonzalez
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics
chemical_list: D005982:Glutathione Transferase; D059811:HLA-DRB1 Chains; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516765:PTPN22 protein, human