Correspondence on ‘Variants in urate transporters,ADH1B,GCKRandMEPEgenes associated with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank’

Takei, Riku; Sumpter, Nicholas A; Phipps‐Green, Amanda; Cadzow, Murray; Topless, Ruth; Reynolds, Richard J.; Merriman, Tony R.

doi:10.1136/annrheumdis-2021-220769

Cited by 3 publications

(2 citation statements)

References 6 publications

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“…And more importantly, they reported a single SNP in ABCG2 (ie, rs2231142) locus associated with gout after conditioning on rs2231142. 1 In our analysis, we reported 13 independent genetic variants mapped to ABCG2, SLC2A9, SLC22A11, GCKR, ADH1B, MEPE, PPM1K-DT and LOC105377323. Eight of which are located in chromosome 4, near the ABCG2 locus.…”

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confidence: 84%

Response to: ‘Correspondence on ‘Variants in urate transporters, ADH1B, GCKR and MEPE genes associated with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank’’ by Takeiet al

2021

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confidence: 84%

Response to: ‘Correspondence on ‘Variants in urate transporters, ADH1B, GCKR and MEPE genes associated with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank’’ by Takeiet al

2021

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“…There is some evidence for genetic variants controlling the progression from hyperuricemia to gout. GWAS in gout comparing to individuals with asymptomatic hyperuricemia have identified a small number of loci 10,23,24 (most of which also associate with serum urate levels 9,25 ), and a Polynesian-specific variant in IL-37 associates with gout compared to asymptomatic hyperuricemia 26 . However, these loci cannot necessarily be interpreted as controlling the progression from hyperuricemia to symptomatic gout because hyperuricemia is defined by a single urate measure in each study, which does not allow accounting for the lifetime burden of urate 27 .…”

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confidence: 99%

A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout

Major

Takei

Matsuo

et al. 2022

Preprint

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Gout is a chronic disease of monosodium urate crystal deposition in the setting of hyperuricemia that typically presents with recurrent flares of acute inflammatory arthritis that occur due to innate immune response to deposited crystals. The molecular mechanism of the progression from hyperuricemia to clinical gout is poorly understood. Here we provide insights into this progression from a genetic study of 2.6 million people, including 120,282 people with gout. We detected 376 loci and 410 genetically independent signals (148 new loci in urate and gout). We identified 1,768 candidate genes with subsequent pathway analysis revealing urate metabolism, type 2 diabetes, and chromatin modification and structure as top pathways in gout. Genes located within or statistically linked to significant GWAS loci were prioitized for their potential to control the progression from hyperuricemia to gout. This identified strong candidate immune genes involved in epigenetic remodelling, cell osmolarity, and regulation of NLRP3-inflammasome activity. The genetic association signal at XDH, encoding the urate-producing enzyme xanthine oxidoreductase (XOR), co-localizes with genetic control of XDH expression, but only in the prostate. We demonstrate XOR activity and urate production in the mouse prostate, and use single-cell RNA sequence data to propose a model of urate reuptake, synthesis, and secretion by the prostate. The gout-associated loci were over-represented for genes implicated in clonal hematopoeiesis of indeterminate potential (CHIP) and Mendelian randomization analysis provided evidence for a causal role of CHIP in gout. In concert with implication of epigenomic regulators, this provides support for epigenomic remodelling as causal in gout. We provide new insights into the molecular pathogenesis of gout and identify an array of candidate genes for a role in the inflammatory process of gout.

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Genetic association studies of the progression from hyperuricaemia to gout

et al. 2022

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Correspondence on ‘Variants in urate transporters,ADH1B,GCKRandMEPEgenes associated with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank’

Abstract: Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Cited by 3 publications

References 6 publications

Response to: ‘Correspondence on ‘Variants in urate transporters, ADH1B, GCKR and MEPE genes associated with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank’’ by Takeiet al

Response to: ‘Correspondence on ‘Variants in urate transporters, ADH1B, GCKR and MEPE genes associated with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank’’ by Takeiet al

A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout

Genetic association studies of the progression from hyperuricaemia to gout

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