Plasma Levels of Glycoprotein Acetyls Linked to Incident Gout

According to a UK Biobank (UKB) study, plasma levels of glycoprotein acetyls (GlycA) are associated with reported onset of gout.

“Serum urate (SU) level is the strongest known causal predictor of clinical gout, but only [approximately] 20% with prolonged hyperuricemia develop gout, motivating the need for additional biomarkers for risk prediction and stratification,” investigators stated. “The metabolome represents a compelling intermediate trait between genome and phenome to elucidate disease mechanisms.”

In the discovery-based, large-scale, prospective metabolomics study, investigators identified novel biomarkers of incident gout and replicated novel metabolomic biomarkers of gout, including plasma levels of GlycA, in independent samples. In total, 105,703 patients with no prior gout diagnosis or history of urate lowering therapy and targeted nuclear magnetic resonance (NMR) metabolomic profiling (N=168 metabolites, including routine lipids and amino acids) available from samples taken between 2006 and 2010 in the UKB were included in the study. Ultimately, 46% of patients were males and the mean age was 57.2 years. Incident gout cases were recognized from linked medical records until gout diagnosis, patient death, or the end of the study (December 31, 2019).

A Cox proportional hazard model was used to obtain hazard ratios (HR) and 95% confidence intervals (CIs) per standard deviation (SD) increase for each of the 168 metabolites to evaluate their associations with incident gout. To replicate their findings, investigators analyzed the association of metabolome-wide significant metabolites via a replication set, which was limited to 4804 patients who were able to provide blood in a repeat assessment visit between 2012 and 2013.

The median follow-up period was 10.4 years, during which 1367 cases of incident gout were documented in the discovery set. After correcting multiple comparisons, including adjusting for age, sex, lifestyle, and clinical covariates, GlycA were positively associated with the risk of incident gout (multivariable HR per 1SD increase = 1.34 (1.27 to 1.41), P= 9.04x 10-28). Further, the association continued after SU adjustment (HR 1.07, P= 0.0091). The 4804 patients included in the replication set reported 22 cases during the follow-up period (median 6.89 years). Within this dataset, investigators replicated GlycA association with incident gout (multivariable HR per 1SD increase =1.56 (1.08 to 2.25), P= 0.017).

“GlycA is novel for gout, though this pro-inflammatory biomarker has predicted risk of other cardiometabolic-inflammatory phenotypes, independent of C-reactive protein (CRP),” investigators concluded. “These findings may provide insight into the metabolic-inflammatory pathogenesis of gout, with implications for risk prediction, even beyond SU, but call for further investigation with more extensive metabolome profiling and external replication.”

The study, “A Population-Based, Prospective metabolomics Study in the UK Biobank Identifies Glycoprotein Acetyls as a Novel Biomarker of Incident Gout,” was presented at the Annual European Congress of Rheumatology (EULAR 2022).