To investigate a possible association between a functional polymorphism in the intermediate‐affinity receptor for IgG called Fcγ receptor type IIIA (FcγRIIIA [CD16]) and rheumatoid arthritis (RA).

This was an allelic association study in which a single nucleotide polymorphism in FcγRIIIA was examined as a susceptibility and/or severity factor for RA. The FcγRIIIA‐158V/F polymorphism was genotyped by direct sequencing in 2 well‐characterized ethnic groups, UK Caucasians (141 RA patients and 124 controls) and North Indians and Pakistanis (108 RA patients and 113 controls).

The FcγRIIIA‐158V/F polymorphism was associated with RA in both ethnic groups (P = 0.028 for UK Caucasians, P = 0.050 for North Indians and Pakistanis, and P = 0.003 for both groups combined). FcγRIIIA‐158VF and ‐158VV individuals had an increased risk of developing RA in both populations (UK Caucasians odds ratio [OR] 1.6, P = 0.050; North Indians and Pakistanis OR 1.9, P = 0.023; and combined groups OR 1.7, P = 0.003). In the UK Caucasian group, the highest risk was for nodular RA, a more severe disease subset, associated with homozygosity for the FcγRIIIA‐158V allele (OR 4.4, P = 0.004). There was also evidence for an interaction between the RA‐associated HLA–DRB1 allele and the presence of at least 1 FcγRIIIA‐158V allele in predicting susceptibility to RA (OR 5.5, P = 0.000).

We have demonstrated that the FcγRIIIA‐158V/F polymorphism is a susceptibility and/or severity marker for RA in 2 distinct ethnic groups. This finding may ultimately provide additional insights into the pathogenesis of RA and other autoantibody/immune complex–driven autoimmune diseases.