EXPLORING HYPERURICEMIA-INDEPENDENT PROTEIN CONTRIBUTORS TO GOUT USING PUBLICLY AVAILABLE GENOMIC DATA

Although elevated serum urate is the strongest risk factor for gout, not all individuals with hyperuricemia develop the disease. The factors that determine which hyperuricemic individuals eventually develop gout remain unclear. In recent years, large-scale genome-wide association study (GWAS) summary statistics have been publicly released, enabling researchers worldwide to perform extensive secondary analyses. Using GWAS summary statistics for serum urate and gout, we conducted downstream analyses such as proteome-wide association study (PWAS) and Mendelian randomization (MR) to explore risk factors for gout that are independent of serum urate.

We obtained European GWAS summary statistics for serum urate level (Cho C et al, Nat Commun, 2024; n = 677,373; European) and gout (Verma A et al, Science, 2024; n = 440,023; European) and conducted PWAS. Plasma proteins that were significantly associated with gout but not with serum urate in PWAS were extracted. We obtained protein quantitative trait loci (pQTL)-GWAS summary statistics for these proteins from the SomaScan platform (GH Eldjarn et al, Nature, 2023), and then evaluated the causal relationships between the identified proteins and gout using two-sample MR. When cis-pQTL data were used as exposures, we applied the Summary-data-based MR (SMR) method (Zhu Z et al, Nat Genet, 2016). When gout was used as exposure, MR analyses were conducted using the inverse-variance weighted (IVW), MR-Egger, and weighted median methods. For significant causal relationships, heterogeneity and pleiotropy were assessed as sensitivity analyses.

PWAS identified ten proteins associated with gout but not with serum urate, including adaptor related protein complex 2 subunit alpha 2 (AP2A2), β-arrestin-1, C-C motif chemokine ligand 19 (CCL19), fucosyltransferase 3 (FUT3), isopentenyl-diphosphate delta-isomerase 2 (IDI2), interleukin-1 receptor antagonist (IL1RN), interleukin-6 receptor (IL6R), interleukin-11 receptor alpha (IL11Rα), microfibrillar-associated protein 4 (MFAP4), and nudix hydrolase 2 (NUDT2). In SMR testing causality of these proteins on gout (protein as exposure, gout as outcome), six proteins showed significant associations (p < 0.005), without significant heterogeneity (Heterogeneity In Dependent Instruments test (HEIDI), pHEIDI > 0.05): AP2A2 (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.47-0.84, p = 1.8×10⁻³), β-arrestin-1 (OR = 0.67, 95% CI = 0.54-0.83, p = 2.2×10⁻⁴), FUT3 (OR = 0.96, 95% CI = 0.93-0.98, p = 1.5×10⁻³), IL6R (OR = 1.03, 95% CI = 1.02-1.04, p = 2.6×10⁻⁶), IL11Rα (OR = 0.92, 95% CI = 0.88-0.96, p = 9.4×10⁻⁴), and NUDT2 (OR = 0.91, 95% CI = 0.86-0.97, p = 3.8×10⁻³). In contrast, in MR testing reverse causation (gout as exposure, protein as outcome), no proteins showed consistent significance across all MR methods (IVW, MR-Egger, and Weighted median).

Through integrative analyses of publicly available genomic data, we identified AP2A2, β-arrestin-1, FUT3, IL6R, IL11Rα and NUDT2 as potential pathogenic factors for gout independent of serum urate. Among them, IL6R and IL11Rα are key mediators of inflammation, suggesting that inflammatory pathways may contribute to the genetic background of gout development. Further experimental and clinical studies are warranted to validate these causal associations and elucidate their mechanistic roles in gout pathogenesis.