The genetic basis of urate control and gout: Insights into molecular pathogenesis from follow-up study of genome-wide association study loci

Best Pract Res Clin Rheumatol. 2021 Dec;35(4):101721. doi: 10.1016/j.berh.2021.101721. Epub 2021 Nov 1.

Abstract

This review focuses on the post-genome-wide association study (GWAS) era in gout, i.e., the translation of GWAS genetic association signals into biologically informative knowledge. Analytical and experimental follow-up of individual loci, based on the identification of causal genetic variants, reveals molecular pathogenic pathways. We summarize in detail the largest GWAS in urate to date, then we review follow-up studies and molecular insights from ABCG2, HNF4A, PDZK1, MAF, GCKR, ALDH2, ALDH16A1, SLC22A12, SLC2A9, ABCC4, and SLC22A13, including the role of insulin signaling. One common factor in these pathways is the importance of transcriptional control, including the HNF4α transcription factor. The new molecular knowledge reveals new targets for intervention to manage urate levels and prevent gout.

Keywords: ABCG2; Gene; Genome-wide association study; Gout; HNF4A; Polymorphism; SLC2A9; Urate.

Publication types

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

MeSH terms

  • Aldehyde Dehydrogenase, Mitochondrial
  • Follow-Up Studies
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Glucose Transport Proteins, Facilitative / genetics
  • Gout* / genetics
  • Humans
  • Organic Anion Transporters* / genetics
  • Organic Cation Transport Proteins / genetics
  • Uric Acid

Substances

  • Glucose Transport Proteins, Facilitative
  • Organic Anion Transporters
  • Organic Cation Transport Proteins
  • SLC22A12 protein, human
  • SLC2A9 protein, human
  • Uric Acid
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase, Mitochondrial