To investigate the genetic regulation of rheumatoid factor (RF) in a rat model of rheumatoid arthritis, in order to gain understanding of the enigmatic role of RF in the disease.

IgM‐RF and IgG‐RF, as well as total levels of immunoglobulins of different subclasses, were measured in sera from rats with pristane‐induced arthritis (PIA). The major gene regions were identified by linkage analysis of genetically segregating crosses.

The production of RF was found to correlate with development of arthritis and to be higher in females than in males. Surprisingly, the relatively arthritis‐resistant E3 strain had higher levels of RF than the arthritis‐susceptible DA strain. In an (E3 × DA)F₂ cohort a major locus controlling the levels of IgM‐RF in serum was identified on chromosome 11 (Rf1) and another on chromosome 16 (Rf3), and these were not related to arthritis susceptibility. However, the Rf2 locus on chromosome 4 controlled IgG‐RF levels, IgG2a levels, and chronic arthritis in males (Pia5). Some previously defined arthritis loci (Pia4, Pia6, Pia7, and Pia8) were found to also control immunoglobulin levels in serum.

RFs are produced in the rat PIA model and correlate with development of arthritis. Gene regions controlling RF and serum immunoglobulin levels were identified, of which some cosegregated with arthritis. This suggests a new focus of study to elucidate the role of RF in the pathogenesis of arthritis.