Leo Joosten, Viola Klück and Rosanne van Deuren, theme Infectious diseases and global health, and in collaboration with the Department of Human Genetics, discovered that rare genetic variants in interleukin-37 link the anti-inflammatory cytokine to the pathogenesis and treatment of gout. They have published their findings in the journal Annals of the Rheumatic Diseases.
Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, they conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout.
Viola and her colleagues identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher’s exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10−5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and they substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry.
With this method they provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.