title: Rheumatoid arthritis association with the FCRL3 -169C polymorphism is restricted to PTPN22 1858T-homozygous individuals in a Canadian population.
abstract: OBJECTIVE
  Variants in genes encoding the Fc receptor-like 3 (FcRL-3) and the class II major histocompatibility complex (MHC) transactivator proteins have been associated with an increased risk of rheumatoid arthritis (RA) in Japanese and Nordic populations, respectively. The aim of this study was to investigate these associations in a Canadian Caucasian cohort of RA cases and healthy controls.
  
  
  METHODS
  A total of 1,187 RA patients and 462 healthy controls were genotyped for FCRL3 and MHC2TA gene variants associated with RA. Epistasis between the FCRL3 -169C and the PTPN22 1858T variants was also examined.
  
  
  RESULTS
  An association was detected between RA and both the FCRL3 -169C allele (OR 1.19, P = 0.023) and the homozygous genotype (OR 1.41, P = 0.027), but association of the MHC2TA promoter region variant (-168G) with RA was not replicated. Stratification of the RA cohort by PTPN22 genotypes revealed the FCRL3 risk variant and RA association was stronger in the patient subgroup lacking PTPN22 1858T variants (P = 0.004) and was not detectable in the subgroup with PTPN22 1858T variants (P = 0.52). The PTPN22 association with RA was greater in the absence than in the presence of the FCRL3 -169C allele (P = 0.0008 versus P = 0.001). The PTPN22 1858T variant also increased the risk of autoimmune thyroid disease (AITD) in the RA patients, whereas the FCRL3 risk variant was protective against AITD.
  
  
  CONCLUSIONS
  Our findings support an association of RA with an FCRL3 functional polymorphism and reveal that this association is stronger in the absence of PTPN22 risk genotypes. These findings support a genetic heterogeneity across RA populations, suggesting that both the FCRL3 and PTPN22 genes play roles in RA susceptibility, but in different individuals.
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Liu
authors.forename: Erin
authors.initials: E
authors.lastname: Walker
authors.forename: Heather
authors.initials: H
authors.lastname: Ternan
authors.forename: Julie
authors.initials: J
authors.lastname: Owen
authors.forename: Ben
authors.initials: B
authors.lastname: Johnson
authors.forename: Wenda
authors.initials: W
authors.lastname: Greer
authors.forename: Dianne P
authors.initials: DP
authors.lastname: Mosher
authors.forename: Walter P
authors.initials: WP
authors.lastname: Maksymowych
authors.forename: Vivian P
authors.initials: VP
authors.lastname: Bykerk
authors.forename: Edward C
authors.initials: EC
authors.lastname: Keystone
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002170:Canada; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors; D013967:Thyroiditis, Autoimmune / Q000175:diagnosis / Q000235:genetics / Q000276:immunology
chemical_list: C457775:FCRL3 protein, human; D011971:Receptors, Immunologic; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases