02056nas a2200289   4500000000100000008004100001260001300042653002600055653002700081653002000108653001900128653002000147653002000167653001100187653002900198653001200227100001400239700001600253700001400269700001900283700001100302245005100313300001000364490000600374520137200380022001401752       1986                            d  c1986 Jun10aArthritis, Rheumatoid10aDisease Susceptibility10aGenetic Markers10aHLA-D Antigens10aHLA-DR Antigens10aHLA-DR4 Antigen10aHumans10aImmunoglobulin Allotypes10aleprosy1 aJongh B M1 aWestedt M L1 aVries R R1 aValkenburg H A1 aCats A00aGenetic heterogeneity of rheumatoid arthritis.  a29-330 v43 a<p>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.</p>  a0278-0240