Several variants in urate transporters, including ADH1B, GCKR, and MEPE genes, were found to be associated with an increased risk for transition from asymptomatic hyperuricemia to gout, according to study results published in Annals of the Rheumatic Diseases.
Several genetic variants in inflammatory genes were previously reported to be associated with an increased risk for transition from asymptomatic hyperuricemia to gout.
The objective of the current genome-wide association study was to examine the genetic variants linked to the transition from hyperuricemia to gout by developing a polygenic risk score that will help in identifying patients with asymptomatic hyperuricemia at increased risk of developing gout.
The study sample included 80.77% men; 100% White. Using data from 7094 patients with gout and 81,354 control participants with asymptomatic hyperuricemia (serum urate of ≥6.0 mg/dL) from the UK Biobank, participants were divided into a discovery cohort (4934 gout cases and 56,948 control participants) and a replication cohort (2115 gout cases and 24,406 participants). The genetic risk score was generated using summary statistics in the discovery cohort, which was tested in the replication cohort.
A total of 13 single-nucleotide polymorphisms (SNPs) reached genome-wide significance and were selected for the replication study. The SNP with the greatest effect was rs2231142 in the ABCG2 gene (odds ratios [ORs] of 1.66 and 1.64 in the discovery and replication stage, respectively), followed by rs1229984 in the ADH1B gene (ORs of 1.51 and 1.44 in the discovery and replication stage, respectively). The remaining SNPs were located in or near GCKR, PPM1K-DT, SLC2A9, MEPE, LOC105377323, and SLC22A11.
The SNP rs2231142 in ABCG2 vs the SNP rs16890979 in SLC2A9 had a larger effect size and twice as much effect on serum urate in patients with gout compared with control participants with asymptomatic hyperuricemia.
The best polygenic risk score included 17 SNPs, with a predictive ability of 58.5% that increased to 69.2% when demographic factors (age, sex, and body mass index) were included.
Using serum urate cutoff values less than 6.0 mg/dL and less than 7.0 mg/dL, 2 genome wide-associated studies of gout vs normouricemia were conducted; 2 novel SNPs, rs760077 (MTX1) and rs3800307 (PRSS16), achieved significance for association with gout compared with normouricemia, using both serum urate thresholds.
The study had several limitations, including the determination of gout via self-reported physician diagnosis and prescriptions, the classification of patients with asymptomatic hyperuricemia based on a single serum urate measurement, and the use of nonimputed data.
“The association of urate transporters with gout supports the central role of hyperuricemia in its pathogenesis. Larger [genome-wide association studies] are required to identify if variants in inflammatory pathways contribute to progression from [asymptomatic hyperuricemia] to gout,” the researchers concluded.
Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for the author’s disclosure.
Sandoval-Plata G, Morgan K, Abhishek A. Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank. Ann Rheum Dis. Published online April 8, 2021. doi:10.1136/annrheumdis-2020-219796