Rheumatoid arthritis: inheritance and association with other autoimmune diseases

This paper reviews the significance of the associations between rheumatoid arthritis (RA) and both diabetes mellitus and autoimmune thyroid disorders (ATD). All three disorders are thought to result from an interaction between genetic susceptibility and environmental factors. There is a probable real but not dramatic aggregation of insulin-dependent diabetes mellitus (IDDM) in the families of RA probands and a significant aggregation of ATD in both first- and second-degree relatives of RA probands. HLA-linked genes predispose to all three disorders while genes linked to Gm have been implicated in predisposition to RA and ATD. Within the HLA region two or more genes may predispose independently to RA; one of these genes is in linkage disequilibrium with HLA-DR4 and a second is in linkage disequilibrium with DR1 and 3. The familial aggregation of RA and IDDM is at least partially attributable to a single gene linked to HLA-DR4 predisposing to both disorders. By contrast, although 'DR4 negative RA' seems more frequent in sibships containing members with ATD, the familial aggregation of RA and ATD cannot be accounted for by a single gene linked to HLA predisposing to both disorders. Neither can this familial aggregation be accounted for by a single gene linked to Gm predisposing to RA and ATD so that any genetic predisposition common to both disorders is likely to involve at least a third locus which is still to be defined. A simple model with an interaction between at least three independent genetic loci and genetic heterogeneity is proposed to account for the known facts concerning the genetic susceptibility to RA.