title: Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis.
abstract: The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of 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. These findings may ultimately provide new insights into disease pathogenesis.
authors.affiliation: Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK. a.w.morgan@leeds.ac.uk
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Jim I
authors.initials: JI
authors.lastname: Robinson
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Amy
authors.initials: A
authors.lastname: Walker
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Babbage
authors.forename: William E R
authors.initials: WE
authors.lastname: Ollier
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gonzalez-Gay
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
mesh_terms: D000483:Alleles; D015703:Antigens, CD / Q000235:genetics; D002874:Chromosome Mapping; D058851:GPI-Linked Proteins; D020022:Genetic Predisposition to Disease; D005838:Genotype; D013700:Giant Cell Arteritis / Q000235:genetics*; D006684:HLA-DR Antigens / Q000097:blood; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; C496124:FCGR3A protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D017452:Receptors, IgG