Proteomic footprint of serum urate concentration and urate transporter ABCG2 dysfunctional polymorphism: a cross-sectional study

Background Existing proteomic studies have primarily focused on gout flares or symptomatic hyperuricaemia, and few have comprehensively investigated circulating proteomic profiles in serum urate (SU) concentration as a continuous quantitative trait. This cross-sectional study investigated the association between SU concentration and serum proteomic profiles. Methods We enrolled 176 Japanese individuals aged ≥50 years and measured serum proteins using the Olink Explore 3072. To analyse the association between SU concentration and serum proteins, we applied linear regression adjusting for age, sex, renal function and insulin resistance with a false discovery rate threshold of 5%. Tissue-specific and gene set enrichment analyses were conducted based on the regression results. Results A total of 2886 proteins were analysed, among whom 63 showed significant associations with SU concentration; uromodulin demonstrated the strongest association (adjusted p=2.21×10 −5 ). These 63 SU-associated proteins were significantly enriched in the liver, kidneys and duodenum by tissue-specific enrichment analysis. We further examined p.Q141K—a dysfunctional variant of adenosine triphosphate-binding cassette subfamily G member 2 ( ABCG2 ). Among p.Q141K minor allele carriers (n=91), 11 SU-associated proteins were identified, whereas no significant SU-associated proteins were detected in wild-type homozygotes (n=85). Gene set enrichment analysis highlighted xenobiotic metabolism in wild-types and additional inflammation- and disease-related gene sets in minor allele carriers. Conclusions To the best of our knowledge, this is the first study to report a proteomic signature of SU concentration. These findings suggest that SU-associated proteomic signatures vary according to ABCG2 genotypes, highlighting the genetic contribution to pathophysiological processes associated with SU concentration variation. Trial registration number NCT00262691 .