Journal Article

OP0285 Identification of rare coding variants in il-1-related pathways in patients with adult-onset still’s disease

Dinarello, C.A., Cavalli, G, Gilissen, C., Arts, P., van Deuren, R., Sfriso, P., Priori, R., Steehouwer, M., Dagna, L., van de Veerdonk, F., Rodolfi, S., De Luca, G., Hoischen, A., Baldissera, E., Galozzi, P., Lucherini, O.M., Colafrancesco, S., Cantarini, L.

2018

Overview

BackgroundAdult-onset Still’s disease (AOSD) is a rare autoinflammatory disease characterised by fever, arthritis, and multi-organ involvement. Inflammation in AOSD is mediated by interleukin (IL)−1β, as confirmed by the dramatic clinical efficacy of selective blockers of this cytokine. The genetic predisposition to this rampant IL-1-driven inflammation remains nevertheless elusive. Previous studies failed to identify associations between polymorphisms in the genes encoding IL-1 and AOSD, thus pointing at more complex genetic mechanisms. This ‘missing heritability’ cannot be adequately investigated with traditional techniques for genetic partitioning, such as GWAS, which only assess common variants and polymorphisms. Studies focusing on highly penetrant rare variants or different types of mutations (i.e. small copy-number variations; insertions/deletions) are warranted.ObjectivesWe hypothesised that genetically determined changes in IL-1-related pathways resulting in excessive IL-1β activity lead to the development of autoinflammation in AOSD. Scope of this study was to unravel the combined mutational variation of a network of IL-1-related receptors, pathways, counter-regulators, and cellular processes possibly involved in the pathogenesis of AOSD and IL-1-mediated inflammation in general.MethodsWe collected clinical, demographic, and genetic data from a large cohort of 76 AOSD patients and developed an innovative platform based on molecular inversion probes (MIP) technology for performing highly multiplexed targeted-resequencing. This allows efficient sequencing of the coding sequence of 48 genes related to the IL-1-pathway, and allows studying rare and common variants in one assay. We have also screened 500 healthy controls, and 1000s of samples with other disorders using the same assay.ResultsWe identified rare and unique (i.e. private variants) in the IL1 pathway in several individuals with AOSD. Whether any these are involved in a strong predisposition to AOSD is currently followed-up. Rare genetic variants have been identified in six IL-1-pathway ‘clusters’:Deregulated activation of the inflammasome and release of IL–1β and IL–18.IL–1 family receptors and intracellular signalling mediators.Other pro–inflammatory cytokines and receptors.Regulatory molecules, including IL–1Ra or IL–37.Cellular processes regulating production of IL–1 and IL–18 (i.e. autophagy).Production of ROS, which function as markers of cellular damage and trigger inflammation.ConclusionsUnravelling the genetic bases of inflammation in AOSD deepens our understanding of the human innate immunome. Of note, this study platform may serve for the genetic analysis of other IL-1-mediated conditions, including gout and other autoinflammatory diseases, whose genetic predisposition remains elusive. Equally important, the identification of pathways amenable to targeting with small molecules or biologics may translate into remarkable clinical implications.Disclosure of InterestNone declared

• Publisher: Elsevier Limited
• Subject: Arthritis / Autophagy / Disease / Fever / Genetic analysis / Genetic diversity / Gout / Heritability / Inflammasomes / Inflammation / Interleukin 1 / Interleukin 1 receptor antagonist / Interleukin 1 receptors / Interleukin 18 / Intracellular signalling / Juvenile rheumatoid arthritis / Phagocytosis / Signal transduction