Assessing the Causal Relationships Between Insulin Resistance and Hyperuricemia and Gout Using Bidirectional Mendelian Randomization

Abstract

Objective: Hyperuricemia is closely associated with insulin resistance syndrome (and its many cardiometabolic sequelae); however, whether they are causally related has long been debated. We undertook this study to investigate the potential causal nature and direction between insulin resistance and hyperuricemia, along with gout, by using bidirectional Mendelian randomization (MR) analyses.

Methods: We used genome-wide association data (n = 288,649 for serum urate [SU] concentration; n = 763,813 for gout risk; n = 153,525 for fasting insulin) to select genetic instruments for 2-sample MR analyses, using multiple MR methods to address potential pleiotropic associations. We then used individual-level, electronic medical record-linked data from the UK Biobank (n = 360,453 persons of European ancestry) to replicate our analyses via single-sample MR analysis.

Results: Genetically determined SU levels, whether inferred from a polygenic score or strong individual loci, were not associated with fasting insulin concentrations. In contrast, genetically determined fasting insulin concentrations were positively associated with SU levels (0.37 mg/dl per log-unit increase in fasting insulin [95% confidence interval (95% CI) 0.15, 0.58]; P = 0.001). This persisted in outlier-corrected (β = 0.56 mg/dl [95% CI 0.45, 0.67]) and multivariable MR analyses adjusted for BMI (β = 0.69 mg/dl [95% CI 0.53, 0.85]) (P < 0.001 for both). Polygenic scores for fasting insulin were also positively associated with SU level among individuals in the UK Biobank (P < 0.001). Findings for gout risk were bidirectionally consistent with those for SU level.

Conclusion: These findings provide evidence to clarify core questions about the close association between hyperuricemia and insulin resistance syndrome: hyperinsulinemia leads to hyperuricemia but not the other way around. Reducing insulin resistance could lower the SU level and gout risk, whereas lowering the SU level (e.g., allopurinol treatment) is unlikely to mitigate insulin resistance and its cardiometabolic sequelae.

Figure 1. Causal effect estimates for genetically determined concentration of serum urate (per 1 mg/dL) (A) and odds of gout (B) on BMI-adjusted concentrations of fasting insulin (log pmol/L), ascertained in individuals without diabetes, two-sample analysis.

IVW=inverse probability weighted, SNP=single nucleotide polymorphism.

Figure 2. Causal effect estimates for genetically determined concentration of fasting insulin (per log pmol/L) on concentrations of serum urate (mg/dL) (A) and odds of gout (B), ascertained in individuals without diabetes, two-sample analysis.

SNP=single nucleotide polymorphism. One of the candidate risk SNPs for fasting insulin was removed during harmonisation due to ambiguity in the strand direction, leaving 80 in the final analysis.

Figure 3. Serum urate concentration (mean) by decile of the polygenic score for fasting insulin in the UK Biobank.

The 71-SNP polygenic score, which excluded outliers, was used to generate this figure.