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An update on the genetic architecture of hyperuricemia and gout.
Arthritis Res Ther. 2015 Apr 10; 17:98.AR

Abstract

Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense. Although etiological variants at SLC2A9 are yet to be identified, it is clear that considerable genetic complexity exists at the SLC2A9 locus, with multiple statistically independent genetic variants and local epistatic interactions. The positions of implicated genetic variants within or near chromatin regions involved in transcriptional control suggest that this mechanism (rather than structural changes in SLC2A9) is important in regulating the activity of SLC2A9. ABCG2 is involved primarily in extra-renal uric acid under-excretion with the etiological variant influencing expression. At the other 26 loci, probable causal genes can be identified at three (PDZK1, SLC22A11, and INHBB) with strong candidates at a further 10 loci. Confirmation of the causal gene will require a combination of re-sequencing, trans-ancestral mapping, and correlation of genetic association data with expression data. As expected, the urate loci associate with gout, although inconsistent effect sizes for gout require investigation. Finally, there has been no genome-wide association study using clinically ascertained cases to investigate the causes of gout in the presence of hyperuricemia. In such a study, use of asymptomatic hyperurcemic controls would be expected to increase the ability to detect genetic associations with gout.

Links

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Authors+Show Affiliations

Merriman TR
Department of Biochemistry, University of Otago, Box 56, Dunedin, 9054, New Zealand. tony.merriman@otago.ac.nz.

MeSH

ATP Binding Cassette Transporter, Subfamily G, Member 2ATP-Binding Cassette TransportersFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyGlucose Transport Proteins, FacilitativeGoutHumansHyperuricemiaMaleNeoplasm ProteinsPolymorphism, Single Nucleotide

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

25889045

Citation

Merriman, Tony R.. "An Update On the Genetic Architecture of Hyperuricemia and Gout." Arthritis Research & Therapy, vol. 17, 2015, p. 98.
Merriman TR. An update on the genetic architecture of hyperuricemia and gout. Arthritis Res Ther. 2015;17:98.
Merriman, T. R. (2015). An update on the genetic architecture of hyperuricemia and gout. Arthritis Research & Therapy, 17, 98. https://doi.org/10.1186/s13075-015-0609-2
Merriman TR. An Update On the Genetic Architecture of Hyperuricemia and Gout. Arthritis Res Ther. 2015 Apr 10;17:98. PubMed PMID: 25889045.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An update on the genetic architecture of hyperuricemia and gout. A1 - Merriman,Tony R, Y1 - 2015/04/10/ PY - 2015/4/19/entrez PY - 2015/4/19/pubmed PY - 2016/1/20/medline SP - 98 EP - 98 JF - Arthritis research & therapy JO - Arthritis Res Ther VL - 17 N2 - Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense. Although etiological variants at SLC2A9 are yet to be identified, it is clear that considerable genetic complexity exists at the SLC2A9 locus, with multiple statistically independent genetic variants and local epistatic interactions. The positions of implicated genetic variants within or near chromatin regions involved in transcriptional control suggest that this mechanism (rather than structural changes in SLC2A9) is important in regulating the activity of SLC2A9. ABCG2 is involved primarily in extra-renal uric acid under-excretion with the etiological variant influencing expression. At the other 26 loci, probable causal genes can be identified at three (PDZK1, SLC22A11, and INHBB) with strong candidates at a further 10 loci. Confirmation of the causal gene will require a combination of re-sequencing, trans-ancestral mapping, and correlation of genetic association data with expression data. As expected, the urate loci associate with gout, although inconsistent effect sizes for gout require investigation. Finally, there has been no genome-wide association study using clinically ascertained cases to investigate the causes of gout in the presence of hyperuricemia. In such a study, use of asymptomatic hyperurcemic controls would be expected to increase the ability to detect genetic associations with gout. SN - 1478-6362 UR - https://www.unboundmedicine.com/medline/citation/25889045/An_update_on_the_genetic_architecture_of_hyperuricemia_and_gout_ DB - PRIME DP - Unbound Medicine ER -