Rare variants, autoimmune disease, and arthritis

Chung, Sharon A.; Shum, Anthony K.

doi:10.1097/bor.0000000000000298

Cited by 15 publications

(16 citation statements)

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“…The ‘Common Disease, Rare Variant’ hypothesis argues that genetic susceptibility to common diseases does not reside in common genetic variants, but rather in a multiplicity of individually rare genetic variations, each with relatively high penetrance 22. MIP-based resequencing is a novel, sensitive and affordable method for targeted sequencing, which enables the identification of all coding variants in candidate genes,23 31 41 42 and as such allows for the identification of rare variants in an unbiased way. Using this technology, we identified four distinct heterozygous rare variants in IL37 in six gout patients, all clustering in exon 5 encoding for the functional domain of IL-37 9…”

Section: Discussionmentioning

confidence: 99%

“…Supplementary to common polymorphisms, research from the past few decades has shown that rare and low-frequency variants are important contributors to genetic susceptibility in common diseases 22. In some autoinflammatory diseases, the disease mechanism even appeared to be monogenic due to rare causal variants detected in a single gene 23. For serum urate-associated loci and gout, it has also been shown that rare variants contribute to disease pathogenesis 24 25.…”

Section: Introductionmentioning

confidence: 99%

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Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Klück

Deuren

Cavalli³

et al. 2020

Ann Rheum Dis

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ObjectiveGout 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.MethodsVariant 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.ResultsWe 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.ConclusionHere, 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Klück

Deuren

Cavalli³

et al. 2020

Ann Rheum Dis

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“…Autoimmune disease is characterized by the body's immune response to its own antigens, which causes severe tissue injury . Reactive species are increased in autoimmune diseases.…”

Section: The Dual Roles Of Reactive Species In Diseasementioning

confidence: 99%

Physiological regulation of reactive oxygen species in organisms based on their physicochemical properties

Huang

2019

Acta Physiologica

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Oxidative stress is recognized as free radical dyshomeostasis, which has damaging effects on proteins, lipids and DNA. However, during cell differentiation and proliferation and other normal physiological processes, free radicals play a pivotal role in message transmission and are considered important messengers. Organisms maintain free radical homeostasis through a sophisticated regulatory system in which these "2faced" molecules play appropriate roles under physiological and pathological conditions. Reactive oxygen species (ROS), including a large number of free radicals, act as redox signalling molecules in essential cellular signalling pathways, including cell differentiation and proliferation. However, excessive ROS levels can induce oxidative stress, which is an important risk factor for diabetes, cancer and cardiovascular disease. An overall comprehensive understanding of ROS is beneficial for understanding the pathogenesis of certain diseases and finding new therapeutic treatments.This review primarily focuses on ROS cellular localization, sources, chemistry and molecular targets to determine how to distinguish between the roles of ROS as messengers and in oxidative stress. K E Y W O R D Shomeostasis, oxidative stress, reactive oxygen, redox signalling, signalling pathways 2 of 16 | HUANG ANd LI for the development of new therapeutic strategies for cancer and cardiovascular disease. | SOURCES AND PHYSICOCHEMICAL PROPERTIES OF ROS | ROS sourcessecond messengers, what are the corresponding acceptors for these special ROS? To better recognize ROS, a new tool that can monitor changes in ROS levels and position in real time must be developed. Determining how to utilize the characteristics of ROS to treat diseases, such as cardiovascular disease, diabetes, autoimmune diseases, cancer and Alzheimer's diseases, is worth further exploration.

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“…However, numerous studies have shown that some patients exhibit not only the characteristics of auto-in ammatory diseases, but also those of various autoimmune diseases. In genome-wide association studies, TNFAIP3 polymorphisms were found to be associated with a variety of autoimmune (15) and autoin ammatory diseases (16), such as systemic lupus erythematosus (17), Sjögren's syndrome, Crohn's disease, rheumatoid arthritis, Still's disease in adults, juvenile idiopathic arthritis, psoriatic arthritis, Hashimoto's thyroiditis (18), autoimmune lymphoproliferative syndrome (19), type 1 diabetes, and psoriasis. To date, 24 pathogenic variants of A20 have been reported.…”

Section: Resultsmentioning

confidence: 99%

Analysis of the Clinical and Genetic Characteristics of 3 Cases of A20 Haploinsufficiency

Zhang

Zhou

Lai

et al. 2020

Preprint

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Background To evaluate the clinical and genetic characteristics of 3 children with HA20. Methods The clinical and genetic testing data of 3 children with HA20 treated at CIP between August 2016 and October 2019 were retrospectively analysed. Results Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. For laboratory examination, In patient 1, the WBC,CRP and AESR showed high. In patient 2, the WBC was normal, but CRP and AESR showed high. In patient 3, the WBC, CRP, and AESR showed high. Patient 2 was positive for antinuclear antibodies, anti-Sjögren’s syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that the 3 patients were heterozygous for mutations in the TNFAIP3 gene. For treatment, patient 1 used TNFα antagonist and thalidomide, patient 2 used TNFαantagonist and sulfasalazine, and patient 3 used hormones and thalidomide. Patients 1 and 2 were followed up for 4 and 3 months, respectively. There was improvement in joint and gastrointestinal symptoms, inflammatory indices and RF were normal, dsDNA and Coombs test became negative. Patient 3 was treated at an outside hospital and showed gradual improvement in oral ulcers and perianal abscesses. Conclusion HA20 is a single-gene auto-inflammatory disease caused by mutation in the TNFAIP3 gene. It presents clinically as a Behçet-like syndrome and can present as various other autoimmune diseases as well. Hormones and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with an early age of onset or Behçet-like presentation to achieve early diagnosis and accurate treatment.

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Rare variants, autoimmune disease, and arthritis

Cited by 15 publications

References 48 publications

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Physiological regulation of reactive oxygen species in organisms based on their physicochemical properties

Analysis of the Clinical and Genetic Characteristics of 3 Cases of A20 Haploinsufficiency

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