dc.contributor.author |
Klück, Viola |
en |
dc.contributor.author |
van Deuren, Rosanne C |
en |
dc.contributor.author |
Cavalli, Giulio |
en |
dc.contributor.author |
Shaukat, Amara |
en |
dc.contributor.author |
Arts, Peer |
en |
dc.contributor.author |
Cleophas, Maartje C |
en |
dc.contributor.author |
Crișan, Tania O |
en |
dc.contributor.author |
Tausche, Anne-Kathrin |
en |
dc.contributor.author |
Riches, Philip |
en |
dc.contributor.author |
Dalbeth, Nicola |
en |
dc.contributor.author |
Stamp, Lisa K |
en |
dc.contributor.author |
Hindmarsh, Jennie Harré |
en |
dc.contributor.author |
Jansen, Tim L Th A |
en |
dc.contributor.author |
Janssen, Matthijs |
en |
dc.contributor.author |
Steehouwer, Marloes |
en |
dc.contributor.author |
Lelieveld, Stefan |
en |
dc.contributor.author |
van de Vorst, Maartje |
en |
dc.contributor.author |
Gilissen, Christian |
en |
dc.contributor.author |
Dagna, Lorenzo |
en |
dc.contributor.author |
Van de Veerdonk, Frank L |
en |
dc.contributor.author |
Eisenmesser, Elan Z |
en |
dc.contributor.author |
Kim, SooHyun |
en |
dc.contributor.author |
Merriman, Tony R |
en |
dc.contributor.author |
Hoischen, Alexander |
en |
dc.contributor.author |
Netea, Mihai G |
en |
dc.contributor.author |
Dinarello, Charles A |
en |
dc.contributor.author |
Joosten, Leo Ab |
en |
dc.date.accessioned |
2020-05-11T22:17:18Z |
en |
dc.date.issued |
2020-04 |
en |
dc.identifier.issn |
0003-4967 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/50616 |
en |
dc.description.abstract |
OBJECTIVE: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, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout. METHODS:Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout. RESULTS:We 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 we 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. CONCLUSION:Here, we 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. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Annals of the rheumatic diseases |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Neutrophils |
en |
dc.subject |
Leukocytes, Mononuclear |
en |
dc.subject |
Animals |
en |
dc.subject |
Humans |
en |
dc.subject |
Mice |
en |
dc.subject |
Gout |
en |
dc.subject |
Genetic Predisposition to Disease |
en |
dc.subject |
Uric Acid |
en |
dc.subject |
Recombinant Proteins |
en |
dc.subject |
Interleukin-8 |
en |
dc.subject |
Interleukin-1 |
en |
dc.subject |
Interleukin-6 |
en |
dc.subject |
Case-Control Studies |
en |
dc.subject |
Polymorphism, Genetic |
en |
dc.subject |
Adult |
en |
dc.subject |
Aged |
en |
dc.subject |
Aged, 80 and over |
en |
dc.subject |
Middle Aged |
en |
dc.subject |
European Continental Ancestry Group |
en |
dc.subject |
Oceanic Ancestry Group |
en |
dc.subject |
Female |
en |
dc.subject |
Male |
en |
dc.subject |
Interleukin-1beta |
en |
dc.subject |
In Vitro Techniques |
en |
dc.title |
Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1136/annrheumdis-2019-216233 |
en |
pubs.issue |
4 |
en |
pubs.begin-page |
536 |
en |
pubs.volume |
79 |
en |
dc.rights.holder |
Copyright: The author |
en |
pubs.end-page |
544 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
796846 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
School of Medicine |
en |
pubs.org-id |
Medicine Department |
en |
dc.identifier.eissn |
1468-2060 |
en |
pubs.record-created-at-source-date |
2020-03-02 |
en |
pubs.dimensions-id |
32114511 |
en |