Expressive

rs114580333 (MEPE): Gout Transition Risk Variant

Key takeaways

  • rs114580333 near MEPE was identified as a novel genome-wide significant predictor of gout in people who already have elevated uric acid levels.
  • The association was discovered and replicated in a UK Biobank study with over 88,000 Caucasian participants.
  • A 17-SNP polygenic risk score including this variant predicted gout status with 58.5% accuracy, improving to 69.2% with demographic data.
  • The study population was limited to Caucasians, so findings may not apply to other ancestries.

Key takeaways

  • rs114580333 near the MEPE gene was identified as a novel genome-wide significant predictor of gout in people who already have elevated uric acid levels.
  • The association was discovered and independently replicated in a UK Biobank study spanning more than 88,000 Caucasian participants.
  • A 17-variant polygenic risk score including this variant predicted gout status with 58.5% accuracy, improving to 69.2% when demographic factors were added.
  • The study was restricted to Caucasian individuals, so these findings may not apply to other ancestral backgrounds.

What the research says rs114580333 falls in the MEPE gene region (also designated in relation to HSP90AB3P) and was identified in a genome-wide association study (GWAS) comparing Caucasian gout cases to people with asymptomatic hyperuricemia (AH) - a condition in which serum urate is elevated at or above 6.0 mg/dL without any symptoms. The variant reached genome-wide significance in a discovery cohort of 4,934 gout cases and 56,948 AH controls from the UK Biobank, and this finding was independently replicated in a separate cohort of 2,115 cases and 24,406 controls; it was one of 12 novel associations for this AH-to-gout transition phenotype out of 13 total replicated signals. A separate large GWAS of 35 blood and urine biomarkers in the UK Biobank (n=363,228) used Mendelian Randomization (a statistical technique for inferring causal relationships from population data) to establish that elevated urate levels have a causal influence on gout, providing broader mechanistic context for variants in urate-related pathways.

Reported associations

  • Gout (transition from asymptomatic hyperuricemia): rs114580333 in the MEPE region was one of 13 independent SNPs (single nucleotide polymorphisms, meaning single-letter changes in the DNA sequence) reaching genome-wide significance and replication as predictors distinguishing gout cases from AH controls in a Caucasian UK Biobank cohort (discovery: 4,934 cases, 56,948 controls; replication: 2,115 cases, 24,406 controls).
  • Polygenic risk score performance: When combined with 16 other SNPs in a polygenic risk score (PRS) model, this variant contributed to a model achieving 58.5% predictive accuracy (area under the receiver-operating-characteristic curve) for gout versus asymptomatic hyperuricemia, rising to 69.2% after demographic factors were incorporated.

Evidence quality The association of rs114580333 with gout-transition risk is based on a two-stage GWAS design with independent discovery and replication cohorts totaling more than 88,000 Caucasian participants from the UK Biobank, and it is described as one of 12 novel findings for this specific phenotype. No individual effect size (such as an odds ratio or beta coefficient) for rs114580333 alone is reported in the available study text, which limits interpretation of the magnitude of its contribution. The study notes that larger GWAS efforts will be needed to determine whether variants in inflammatory pathways also contribute to the AH-to-gout transition, indicating the field is still in an early-characterization phase for this phenotype. The analysis was restricted to Caucasian ancestry, so generalizability to other populations is not established by this evidence.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What does the MEPE gene have to do with gout?

A genome-wide association study found that rs114580333, a variant in the MEPE gene region, is associated with the transition from asymptomatic hyperuricemia (high uric acid without symptoms) to gout. The biological mechanism linking MEPE to gout is not described in the available research.

Is rs114580333 linked to gout risk?

Yes. rs114580333 reached genome-wide significance in a large GWAS comparing gout cases to individuals with elevated uric acid who had not developed gout, and the association was independently replicated in a separate cohort, strengthening confidence in the finding.

What is asymptomatic hyperuricemia?

Asymptomatic hyperuricemia means having elevated uric acid in the blood (generally at or above 6.0 mg/dL) without any symptoms such as gout attacks. Many people with elevated uric acid never develop gout.

How accurate is the polygenic risk score for gout that includes rs114580333?

A 17-variant polygenic risk score that included rs114580333 achieved 58.5% predictive accuracy for distinguishing gout from asymptomatic hyperuricemia, rising to 69.2% when demographic factors were also incorporated.

Does this variant apply to people of all ancestries?

The study that identified rs114580333 was conducted in Caucasian individuals from the UK Biobank. Whether this association holds in other ancestral populations has not been tested in the available research.