title: Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.
abstract: OBJECTIVE
  The detection of phenotype-determining genes as opposed to disease susceptibility genes requires precise phenotypic characterization of patients. Peripheral arthropathies in inflammatory bowel disease (IBD) are well recognized and are classified with the HLA-B*27-related spondyloarthropathies by the European Spondyloarthropathy Study Group. However, previous HLA studies in IBD have only shown this association with axial disease rather than peripheral arthropathy. We recently reported a clinical classification that describes 2 types of peripheral arthropathy, distinguished by their natural history and articular distribution. We now report the results of immunogenetic studies in these patients and compare them with other spondyloarthropathies.
  
  
  METHODS
  IBD patients with type 1 (n = 57) and type 2 (n = 45) peripheral arthropathy were identified by case note review and questionnaire. Patients and 603 controls from Oxfordshire were assigned HLA-A, -B, -C, -DR, and -DQ genotypes by sequence-specific primer polymerase chain reaction. Patient results were compared with controls (corrected for multiple comparisons), then with each other in light of existing hypotheses. The results were compared with those of a cohort of 30 patients with postenteric reactive arthritis (ReA) and 16 patients with IBD-associated ankylosing spondylitis (IBD-AS).
  
  
  RESULTS
  Type 1 arthropathy was associated with HLA-DRB1*0103 (DR103; a rare subtype of DR1) in 33% (P < 0.0001; relative risk [RR], 12.1), B*35 in 30% (P = 0.01; RR, 2.2), and B*27 in 26% (P = 0. 001; RR, 4.0). In contrast, type 2 was associated with HLA-B*44 in 62% (P = 0.01; RR, 2.1). Similar significant associations to type 1 arthropathy were found in ReA, except that the HLA-B*27 association was significantly stronger and an association was found with DRB1*0101 (DR1) in 43% (P = 0.001; RR, 2.2). IBD-AS was associated only with HLA-B*27 and DRB1*0101.
  
  
  CONCLUSIONS
  These data suggest that the clinical classification into type 1 and type 2 arthropathies describes immunogenetically distinct entities and establish that in polygenic disorders, genes may determine clinical phenotype without conferring overall disease susceptibility (in this case, HLA genes). Type 1 arthropathy is clinically and immunogenetically similar to the spondyloarthropathies, but different HLA associations may define phenotypically distinct groups. Type 2 arthropathy has different HLA associations and may have a different etiology. Further studies are now required to confirm these associations and to elucidate the different pathogenetic mechanisms.
authors.affiliation: Gastroenterology Unit, University of Oxford, Radcliffe Infirmary, Oxford, England.
authors.forename: T R
authors.initials: TR
authors.lastname: Orchard
authors.forename: S
authors.initials: S
authors.lastname: Thiyagaraja
authors.forename: K I
authors.initials: KI
authors.lastname: Welsh
authors.forename: B P
authors.initials: BP
authors.lastname: Wordsworth
authors.forename: J S
authors.initials: JS
authors.lastname: Hill Gaston
authors.forename: D P
authors.initials: DP
authors.lastname: Jewell
mesh_terms: D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics*; D015236:HLA-C Antigens / Q000235:genetics; D006681:HLA-D Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D007592:Joint Diseases / Q000150:complications* / Q000235:genetics / Q000276:immunology; D008285:Major Histocompatibility Complex; D010641:Phenotype; D000091402:Prohibitins; D012016:Reference Values
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D006681:HLA-D Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C000717331:PHB2 protein, human; D000091402:Prohibitins