Genetic links between the acute‐phase response and arthritis development in rats

Olofsson, Peter; Nordquist, Niklas; Vingsbo‐Lundberg, Carina; Larsson, Anders; Falkenberg, Cecilia; Pettersson, Ulf; Åkerström, Bo; Holmdahl, Rikard

OBJECTIVE: The acute‐phase inflammatory response is closely correlated with the development of rheumatoid arthritis, but the pathophysiologic role of its specific components is largely unknown. We investigated the genetic control of the acute‐phase protein response in pristane‐induced arthritis (PIA), which is a chronic erosive arthritis model in rats. METHODS: Plasma levels of the acute‐phase proteins interleukin‐6 (IL‐6), α(1)‐acid glycoprotein (orosomucoid), fibrinogen, and α(1)‐inhibitor(3) were quantified in 3 strains of rats during the development and progression of disease: DA and LEW.1F, which are susceptible to arthritis, and E3, which is resistant. Genetic linkage analysis was performed on an F(2) intercross between E3 and DA to determine the genetic control of the acute‐phase response in arthritis. Elevated levels of α(1)‐acid glycoprotein were associated with acute inflammation, whereas levels of IL‐6 were increased during the entire course of the disease. RESULTS: Using these acute‐phase markers as quantitative traits in linkage analysis revealed a colocalization of loci controlling the acute‐phase response and regions previously shown to control the development of arthritis in chromosomes 10, 12, and 14. In addition, 2 loci that were not associated with arthritis were found to regulate serum levels of the acute‐phase protein Apr1 (acute‐phase response 1) at the telomeric end of chromosome 12 and Apr2 on chromosome 5. CONCLUSION: The PIA model in rats is a useful tool for understanding some of the pathways leading to chronic erosive arthritis. The analysis of acute‐phase proteins in PIA and its application as quantitative traits for studying the genetics of arthritis will promote the understanding of the genetic regulation of the acute‐phase response.