Abstract
Background: The Fc gamma Receptor (FcγR) genetic locus on chromosome 1q22-23 was investigated as a genetic susceptibility factor for polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). Methods: The FCGR2A-131H/R, FCGR3A-158F/V and FCGR3B-NA1/NA2 functional polymorphisms and a novel FCGR2B 3′UTR polymorphism were examined for association with PMR (n = 69) and GCA (n = 83) in two well-characterised clinical cohorts from Northern Spain. The EHPlus program was used to estimate haplotype frequencies for patients and controls and to determine if significant linkage disequilibrium was present. Results: There was a significant difference in the FCGR2A allele (P = 0.03) and genotype frequencies (P = 0.03) with GCA compared to controls. Specifically, there was an increase in the FCGR2A-131RR genotype in both the PMR (OR 2.15, 95% CI 1.0-4.7, P = 0.05) and GCA (OR 2.53, 95%CI 1.3-5.1, P = 0.01) populations compared with controls. The FCGR2A-FCGR3A 131R-158F haplotype demonstrated the strongest associations and was found in 8% controls compared with 25% of PMR (OR 4.20, 95%CI 1.3-13.1, P = 0.01) and 24% GCA (OR 4.46, 95%CI 1.5-3.3, P = 0.004) individuals. Logistic regression analyses suggested that both FCGR2A and FCGR3A contributed to GCA susceptibility. A subgroup of GCA patients who had experienced visual symptoms was examined as a marker of disease severity. The most significant findings were increased homozygosity of a FCGR2A-FCGR3A 131R-158F haplotype (8% controls, 16% GCA without visual manifestations and 50% GCA with visual manifestations [OR 12.86, 95%CI 1.3–128.2, P = 0.03]). Logistic regression analyses suggested FCGR3A was the most important gene. Conclusions: We have demonstrated that FCGR2A may contribute to the “susceptibility” of PMR and GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. In addition, FcγR haplotypes may potentially define a subpopulation of individuals at greater risk of vascular occlusion. These findings may ultimately provide new insights into disease pathogenesis. This work was funded by The Health Foundation and Dr Ann Morgan is currently funded by the arc.