title: The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis.
abstract: The objective of this study was to examine HLA-DRB1 and HLA-DQB1 genotypes in patients with severe extra-articular rheumatoid arthritis (ExRA) and to compare them with the genotypes of rheumatoid arthritis (RA) patients without extra-articular manifestations. Patients with severe ExRA were recruited from a large research database of patients with RA, from two cohorts of prevalent RA cases, and from a regional multicenter early RA cohort. Cases with ExRA manifestations (n = 159) were classified according to predefined criteria. Controls (n = 178) with RA but no ExRA were selected from the same sources. Cases and controls were matched for duration of RA and for clinical center. PCR based HLA-DRB1 and HLA-DQB1 genotyping was performed using the Biotest SSP kit, with additional sequencing in order to distinguish DRB1*04 subtypes. Associations between alleles and disease phenotypes were tested using multiple simulations of random distributions of alleles. There was no difference in global distribution of HLA-DRB1 and HLA-DQB1 alleles between patients with ExRA and controls. DRB1*0401 (P = 0.003) and 0401/0401 homozygosity (P = 0.002) were more frequent in Felty's syndrome than in controls. The presence of two HLA-DRB1*04 alleles encoding the shared epitope (SE) was associated with ExRA (overall odds ratio 1.79, 95% confidence interval 1.04-3.08) and with rheumatoid vasculitis (odds ratio 2.44, 95% confidence interval 1.22-4.89). In this large sample of patients with ExRA, Felty's syndrome was the only manifestation that was clearly associated with HLA-DRB1*0401. Other ExRA manifestations were not associated with individual alleles but with DRB1*04 SE double dose genotypes. This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations.
authors.affiliation: Department of Rheumatology, Malmö University Hospital, Södra Förstadsgatan 101, 205 02 Malmö, Sweden. turesson.carl@mayo.edu
authors.forename: Carl
authors.initials: C
authors.lastname: Turesson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.forename: Lennart T H
authors.initials: LT
authors.lastname: Jacobsson
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Ingemar F
authors.initials: IF
authors.lastname: Petersson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Nyhäll-Wåhlin
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Sonja A
authors.initials: SA
authors.lastname: Dechant
authors.forename: Eric L
authors.initials: EL
authors.lastname: Matteson
mesh_terms: D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D004198:Disease Susceptibility; D000939:Epitopes / Q000235:genetics; D005258:Felty Syndrome / Q000150:complications / Q000235:genetics / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged
chemical_list: D000939:Epitopes; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen