Advances in our understanding of gout as an auto-inflammatory disease

Bodofsky, Shari; Merriman, Tony R.; Thomas, Thresia; Schlesinger, Naomi

doi:10.1016/j.semarthrit.2020.06.015

Cited by 43 publications

(42 citation statements)

References 166 publications

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“…Cross-phenotype associations involving the metabolite uric acid and gout, an inflammatory arthritis driven by excess levels of uric acid [ 35 ], are illustrative of iCPAGdb’s usefulness. GWAS studies have been conducted on risk of gout [ 36 – 43 ] as well as uric acid or urate levels [ 44 – 51 ].…”

Section: Resultsmentioning

confidence: 99%

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

et al. 2021

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Background While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Results Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. Conclusions Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb.

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Section: Resultsmentioning

confidence: 99%

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

et al. 2021

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“…Cross-phenotype associations involving the metabolite uric acid and gout, an inflammatory arthritis driven by excess levels of uric acid (Bodofsky et al, 2020), are illustrative of iCPAGdb’s usefulness. GWAS studies have been conducted on risk of gout (Chen et al, 2018; Lai et al, 2012; Lee et al, 2019; Li et al, 2015; Matsuo et al, 2016; Nakayama et al, 2017; Nakayama et al, 2020; Sulem et al, 2011) as well as uric acid or urate levels (Boocock et al, 2020; Dehghan et al, 2008; Doring et al, 2008; Kamatani et al, 2010; Kottgen et al, 2013; Li et al, 2007; Tin et al, 2019; Tin et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

Wang

Balmat

Antonia

et al. 2020

Preprint

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While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb); http://cpag.oit.duke.edu) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs with severe COVID-19 demonstrated colocalization of the GWAS signal of the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN), pointing to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches.

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“…A recent study has also supported that the dysregulated innate immune response of neutrophils against monosodium urate (MSU) crystals in the gout are is a part of the autoin ammatory response because of the involvement of neutrophil extracellular traps (NETs) [21]. The release of NETs, a unique defense mechanism continuing from cell death (NETosis), is regarded as a valuable target for disease pathogenesis in gout [21][22][23]. NETs are primarily composed of their own DNA released as reticular structures with an oxidative burst in order to capture and eliminate pathogens, including DAMPs [22,23], and citrullinated histone H3 (citH3) plays a central role in NETosis.…”

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 96%

Tissue Accumulation of Neutrophil Extracellular Traps Mediates Muscle Hyperalgesia in a Mouse Model

Suzuki

Tsuchiya

Yoshida

et al. 2021

Preprint

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Accumulation of uric acid (UA) during muscular trauma is a causative factor involved in the development of muscle hyperalgesia. Neutrophil extracellular traps (NETs), DNA-based reticular structures to capture UA, play a central role in the pain onset of gout attacks; however, the involvement of NETs via the elevation of local UA level in muscle hyperalgesia due to overuse injuries remains unknown. The triceps surae muscles (TSMs) in the unilateral hindlimb of mice were electrically stimulated to induce excessive muscle contraction. Mechanical withdrawal thresholds, tissue UA levels, neutrophil recruitment, protein amount of citrullinated histone 3 (citH3), a major marker of NETs, were investigated. Furthermore, whether neutrophil depletion, extracellular DNA cleavage, and administration of the urate-lowering agent febuxostat could improve muscle hyperalgesia due to NET formation was examined. CitH3 expression upon neutrophil recruitment significantly increased in the stimulated TSMs with an increase in tissue UA levels, whereas febuxostat administration improved muscle hyperalgesia with decreases in citH3 and tissue UA levels, as observed in neutrophil depletion and extracellular DNA digestion. The underlying mechanism of muscle hyperalgesia associated with locally recruited neutrophils forming NETs due to the increased tissue UA levels potentially plays a significant role in creating a vicious circle of muscle pain.

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Advances in our understanding of gout as an auto-inflammatory disease

Cited by 43 publications

References 166 publications

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

Tissue Accumulation of Neutrophil Extracellular Traps Mediates Muscle Hyperalgesia in a Mouse Model

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