Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are two inflammatory diseases that are thought to arise from a complex interaction between multiple genetic factors and environmental triggers. We have previously demonstrated an association between the Fc gamma receptor (FcγR) genetic locus on chromosome 1q22-23 and rheumatoid arthritis, and have now extended our study to include other inflammatory/autoimmune diseases.
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. In view of the close molecular proximity between FCGR2A, FCGR3A, FCGR3B and FCGR2B we have examined FcγR haplotypes for association with rheumatoid arthritis. Pairwise disequilibrium coefficients (D') were initially calculated in 115 matched 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 borderline linkage disequilibrium between FCGR2A and FCGR3A (D' = -0.313, P = 0.03) with more significant disequilibrium between FCGR3A and FCGR3B (D' = -0.646, P = 0.0001). There was a significant difference in the FCGR2A allele (P = 0.03) and genotype frequencies (P = 0.03) with GCA compared with controls. Specifically, there was an increase in the FCGR2A-131RR genotype in both the PMR (odds ratio [OR] = 2.15; 95% confidence interval [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.
Increased homozygosity for the FCGR2A-FCGR3A 131R-158F haplotype 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. In addition, homozygosity for the FCGR3A-FCGR3B 158F-NA2 haplotype was found in 25% controls compared with 44% GCA subjects (OR = 2.35, 95% CI = 1.0–5.7, P = 0.06). Logistic regression analyses suggested that FCGR3A was the most important site contributing 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]). Additionally, the FCGR3A-FCGR3B haplotype was found in 11/13 individuals who sustained visual manifestations. Homozygosity was seen in 25% controls, 27% GCA without eye involvement and 63% GCA with visual manifestations (OR = 5.83, 95% CI = 0.9–38.9, P = 0.08). For each haplotype logistic regression analyses suggested FCGR3A was the most important site.
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.