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An update on the genetics of hyperuricaemia and gout.
Nat Rev Rheumatol. 2018 06; 14(6):341-353.NR

Abstract

A central aspect of the pathogenesis of gout is elevated urate concentrations, which lead to the formation of monosodium urate crystals. The clinical features of gout result from an individual's immune response to these deposited crystals. Genome-wide association studies (GWAS) have confirmed the importance of urate excretion in the control of serum urate levels and the risk of gout and have identified the kidneys, the gut and the liver as sites of urate regulation. The genetic contribution to the progression from hyperuricaemia to gout remains relatively poorly understood, although genes encoding proteins that are involved in the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome pathway play a part. Genome-wide and targeted sequencing is beginning to identify uncommon population-specific variants that are associated with urate levels and gout. Mendelian randomization studies using urate-associated genetic variants as unconfounded surrogates for lifelong urate exposure have not supported claims that urate is causal for metabolic conditions that are comorbidities of hyperuricaemia and gout. Genetic studies have also identified genetic variants that predict responsiveness to therapies (for example, urate-lowering drugs) for treatment of hyperuricaemia. Future research should focus on large GWAS (that include asymptomatic hyperuricaemic individuals) and on increasing the use of whole-genome sequencing data to identify uncommon genetic variants with increased penetrance that might provide opportunities for clinical translation.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Major TJ
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Dalbeth N
Department of Medicine, University of Auckland, Auckland, New Zealand.
Stahl EA
Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Merriman TR
Department of Biochemistry, University of Otago, Dunedin, New Zealand. tony.merriman@otago.ac.nz.

MeSH

AnimalsDisease ProgressionGenetic Predisposition to DiseaseGenetic VariationGenome-Wide Association StudyGoutHumansHyperuricemiaSequence Analysis, DNAUric Acid

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

29740155

Citation

Major, Tanya J., et al. "An Update On the Genetics of Hyperuricaemia and Gout." Nature Reviews. Rheumatology, vol. 14, no. 6, 2018, pp. 341-353.
Major TJ, Dalbeth N, Stahl EA, et al. An update on the genetics of hyperuricaemia and gout. Nat Rev Rheumatol. 2018;14(6):341-353.
Major, T. J., Dalbeth, N., Stahl, E. A., & Merriman, T. R. (2018). An update on the genetics of hyperuricaemia and gout. Nature Reviews. Rheumatology, 14(6), 341-353. https://doi.org/10.1038/s41584-018-0004-x
Major TJ, et al. An Update On the Genetics of Hyperuricaemia and Gout. Nat Rev Rheumatol. 2018;14(6):341-353. PubMed PMID: 29740155.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An update on the genetics of hyperuricaemia and gout. AU - Major,Tanya J, AU - Dalbeth,Nicola, AU - Stahl,Eli A, AU - Merriman,Tony R, PY - 2018/5/10/pubmed PY - 2019/8/21/medline PY - 2018/5/10/entrez SP - 341 EP - 353 JF - Nature reviews. Rheumatology JO - Nat Rev Rheumatol VL - 14 IS - 6 N2 - A central aspect of the pathogenesis of gout is elevated urate concentrations, which lead to the formation of monosodium urate crystals. The clinical features of gout result from an individual's immune response to these deposited crystals. Genome-wide association studies (GWAS) have confirmed the importance of urate excretion in the control of serum urate levels and the risk of gout and have identified the kidneys, the gut and the liver as sites of urate regulation. The genetic contribution to the progression from hyperuricaemia to gout remains relatively poorly understood, although genes encoding proteins that are involved in the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome pathway play a part. Genome-wide and targeted sequencing is beginning to identify uncommon population-specific variants that are associated with urate levels and gout. Mendelian randomization studies using urate-associated genetic variants as unconfounded surrogates for lifelong urate exposure have not supported claims that urate is causal for metabolic conditions that are comorbidities of hyperuricaemia and gout. Genetic studies have also identified genetic variants that predict responsiveness to therapies (for example, urate-lowering drugs) for treatment of hyperuricaemia. Future research should focus on large GWAS (that include asymptomatic hyperuricaemic individuals) and on increasing the use of whole-genome sequencing data to identify uncommon genetic variants with increased penetrance that might provide opportunities for clinical translation. SN - 1759-4804 UR - https://www.unboundmedicine.com/medline/citation/29740155/An_update_on_the_genetics_of_hyperuricaemia_and_gout_ DB - PRIME DP - Unbound Medicine ER -