title: Genetic heterogeneity of rheumatoid arthritis.
abstract: In a population survey in The Netherlands we investigated 6584 individuals for the presence of rheumatoid diseases and their determinants. We observed no overall association of rheumatoid arthritis (RA) with HLA-DR4 or GM. This result is in contrast to the marked association of HLA-DR4 with RA found in studies based mainly on hospital rheumatology clinics. The findings thus suggest a genetic basis for the disease heterogeneity. A study of 16 multicase RA families showed a co-segregation of RA with the DR4 carrying haplotype from the unaffected parent, whereas the non-DR4 haplotype was preferentially segregating to the healthy siblings (p = 0.001). These data suggest that HLA-DR4 is associated with disease susceptibility rather than with a disease modifying factor. In a further attempt to define a genetic basis for disease heterogeneity we compared five well-defined clinical groups of patients with RA. Although the frequency of HLA-DR4 was significantly elevated in all patient groups as compared to healthy controls, we observed a preferential association of HLA-DR4 with severe extra-articular manifestations as compared to patients without extra-articular manifestations (p = 0.002). These results provide an immunogenetical basis for the disease heterogeneity observed in RA and further extend the immunological analogy between RA and leprosy.
mesh_terms: D001172:Arthritis, Rheumatoid / Q000145:classification / Q000235:genetics* / Q000276:immunology; D004198:Disease Susceptibility; D005819:Genetic Markers; D006681:HLA-D Antigens / Q000032:analysis*; D006684:HLA-DR Antigens / Q000032:analysis* / Q000235:genetics; D015804:HLA-DR4 Antigen; D006801:Humans; D007126:Immunoglobulin Allotypes / Q000032:analysis / Q000235:genetics; D007918:Leprosy / Q000235:genetics / Q000276:immunology
chemical_list: D005819:Genetic Markers; D006681:HLA-D Antigens; D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D007126:Immunoglobulin Allotypes