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Rheumatoid Arthritis (RA) is typically associated with the presence of rheumatoid factors (RF), autoreactive immunoglobulins capable of complexing with IgG. Receptors for IgG may play a key role in clearance of immune complexes and the genes encoding FcgammaR are potential candidates in RA.
A single nucleotide polymorphism (559 T/G) in FcgammaRIIIa results in an amino-acid substitution (Phe/Val) at position 158 which has functional significance: 158Val has a higher affinity for binding some IgG allotypes than 158Phe. Published studies of associations of this polymorphism with autoimmune diseases have given variable results.
To investigate this in RA, we have analysed this polymorphism in two genetically diverse populations: UK Caucasians (398 RA cases and 289 healthy controls) and Northern Indians (63 RA cases and 93 controls). Reliable typing of the 559 T/G polymorphism is greatly hindered by the high homology between FcgammaRIIIa and the neighbouring FcgammaIIIb, which has an invariant G at position 559. A rigorous review of the published typing methods revealed an average error rate of over 10% of genotypes obtained by a single method. The typing in this study was therefore done by complementing two different approaches: PCR-RFLP and allele specific PCR.
A significant reduction in the frequency of the rare GG genotype was seen among the Indian RA cases (RR=0.2 [0.05-0.7], P < 0.02), although the allele frequencies were similar to those found in the control cohort (see table). Among the UK Caucasians, no significant differences were found for either the allele or genotype frequencies (the study had 95% statistical power to detect a genotype relative risk of 2 and an allelic association with OR of 1.6).
We conclude that the 158Phe/Val functional polymorphism in the FcgammaRIIIa gene does not predispose to RA in Caucasians, although there may be an effect among Indians. Further studies will be required to confirm this.