Association of FCGR3A and FCGR3Bhaplotypes with rheumatoid arthritis and primary Sjögren's syndrome

Rheumatoid arthritis (RA) is an autoimmune disease that is thought to arise from a complex interaction between multiple genetic factors and environmental triggers. We have previously demonstrated an association between a Fc gamma receptor (FcγR) haplotype and RA in a cross-sectional cohort of RA patients. We have sought to confirm this association in an inception cohort of RA patients and matched controls. We also extended our study to investigate a second autoanti-body associated rheumatic disease, primary Sjögren's syndrome (PSS).

The FCGR3A-158F/V and FCGR3B-NA1/NA2 functional polymorphisms were examined for association in an inception cohort of RA patients (n = 448), and a well-characterised PSS cohort (n = 83) from the United Kingdom. Pairwise disequilibrium coefficients (D') were calculated in 267 Blood Service healthy controls. The EHPlus program was used to estimate haplotype frequencies for patients and controls and to determine whether significant linkage disequilibrium was present. A likelihood ratio test is performed to test for differences between the haplotype frequencies in cases and controls. A permutation procedure implemented in this program enabled 1000 permutations to be performed on all haplotype associations to assess significance.

There was significant linkage disequilibrium between FCGR3A and FCGR3B (D' = -0.445, P = 0.001). There was no significant difference in the FCGR3A or FCGR3B allele or genotype frequencies in the RA or PSS patients compared with controls. However, there was a significant difference in the FCGR3A-FCGR3B haplotype distributions with increased homozygosity for the FCGR3A-FCGR3B 158V-NA2 haplotype in both our inception RA cohort (odds ratio = 2.15, 95% confidence interval = 1.1–4.2 P = 0.027) and PSS (odds ratio = 2.83, 95% confidence interval = 1.0–8.2, P = 0.047) compared with controls. The reference group for these analyses comprised individuals who did not possess a copy of the FCGR3A-FCGR3B 158V-NA2 haplotype.

We have confirmed our original findings of association between the FCGR3A-FCGR3B 158V-NA2 haplotype and RA in a new inception cohort of RA patients. This suggests that there may be an RA-susceptibility gene at this locus. The significant increased frequency of an identical haplotype in PSS suggests the FcγR genetic locus may contribute to the pathogenesis of diverse autoantibody-mediated rheumatic diseases.

SM and JIR are joint first authors. This work was funded by the Arthritis Research Campaign.

Affiliations

1. Academic Unit of Musculoskeletal Disease, University of Leeds, UK

   • S Mackie
   • , JI Robinson
   • , CA Lawson
   • , S Martin
   • , L Haroon-Rashid
   • , D Cooper
   • , CT Pease
   • , PG Conaghan
   • , M Green
   • , M Quinn
   • , JD Isaacs
   • , P Emery
   •  & AW Morgan

2. Molecular Medicine Unit, University of Leeds, UK

   • JI Robinson
   • , CA Lawson
   • , S Martin
   • , L Haroon-Rashid
   • , D Cooper
   •  & AW Morgan

3. Cancer Research UK, Genetic Epidemiology Division, University of Leeds, UK

   • JH Barrett

4. Rheumatology Department, University Hospital Birmingham (Selly Oak), Birmingham, UK

   • SJ Bowman

5. School of Clinical Medical Sciences (Rheumatology), University of Newcastle-Upon-Tyne, UK

   • JD Isaacs

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