title: Analysis of Fcgamma receptor haplotypes in rheumatoid arthritis: FCGR3A remains a major susceptibility gene at this locus, with an additional contribution from FCGR3B.
abstract: The Fcgamma receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A-FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13-8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44-17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis.
authors.affiliation: Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK. a.w.morgan@leeds.ac.uk
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: Bridget
authors.initials: B
authors.lastname: Griffiths
authors.forename: Deepak
authors.initials: D
authors.lastname: Subramanian
authors.forename: Jim I
authors.initials: JI
authors.lastname: Robinson
authors.forename: Viki H
authors.initials: VH
authors.lastname: Keyte
authors.forename: Manir
authors.initials: M
authors.lastname: Ali
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jones
authors.forename: Robert W
authors.initials: RW
authors.lastname: Old
authors.forename: Frederique
authors.initials: F
authors.lastname: Ponchel
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Boylston
authors.forename: R Deva
authors.initials: RD
authors.lastname: Situnayake
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D015331:Cohort Studies; D058851:GPI-Linked Proteins; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics*; D012016:Reference Values; D006113:United Kingdom; D044465:White People / Q000235:genetics
chemical_list: D015703:Antigens, CD; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG