Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

Ann Rheum Dis. 2019 Oct;78(10):1430-1437. doi: 10.1136/annrheumdis-2019-215521. Epub 2019 Jul 8.

Abstract

Objective: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.

Methods: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia).

Results: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level.

Conclusions: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

Keywords: asymptomatic hyperuricemia; genome-wide association study; gout; individually-tailored preemptive medicine; uric acid.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
  • Adult
  • Aldehyde Dehydrogenase, Mitochondrial / genetics
  • Asymptomatic Diseases
  • Contactins / genetics*
  • Genetic Loci / genetics
  • Genome-Wide Association Study
  • Genotyping Techniques
  • Glucose Transport Proteins, Facilitative / genetics
  • Gout / blood
  • Gout / genetics*
  • Humans
  • Hyperuricemia / genetics*
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Risk Factors
  • Uric Acid / blood
  • Zinc Fingers / genetics*

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • CNTN5 protein, human
  • Contactins
  • Glucose Transport Proteins, Facilitative
  • MIRN302A microRNA, human
  • MicroRNAs
  • Neoplasm Proteins
  • SLC2A9 protein, human
  • Uric Acid
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase, Mitochondrial