Genetic Predisposition to Type 2 Diabetes and Insulin Levels Is Positively Associated with Serum Urate Levels

Abstract

Purpose: Previous epidemiological evidence showed that type 2 diabetes (T2D) is related with gout. However, the causality and the direction of this association are still not definitely elucidated. We investigated bidirectional associations of T2D and glycemic traits with serum urate concentrations and gout using a Mendelian randomization approach. Methods: Summary statistics from the large-scale genomewide association studies conducted for T2D (Ncase=62 892, Ncontrol=596 424), fasting glucose (N=133 010), fasting insulin (N=133 010), hemoglobin A1c (N=123 665), homeostasis model assessment of insulin resistance (N=46 186), urate (N=110 347), and gout (Ncase=2115, Ncontrol=67 259) among participants of European ancestry were analyzed. For each trait of interest, independent genomewide significant (P<5×10-8) single nucleotide polymorphisms were selected as instrumental variables. The inverse-variance weighted method was used for the primary analyses. Results: Genetic predisposition to higher risk of T2D [beta=0.042; 95% confidence interval (CI)=0.016-0.068; P=0.002] and higher levels of fasting insulin (beta=0.756; 95% CI=0.408-1.102; P=1.96e-05) were significantly associated with increased serum urate concentrations. Moreover, we found suggestively significant evidence supporting a causal role of fasting insulin on risk of developing gout (odds ratio=3.06; 95% CI=0.88-10.61; P=0.078). In the reverse direction analysis, genetic predisposition to both urate and gout were not associated with T2D or any of 4 glycemic traits being investigated. Conclusions: This study provides supportive evidence on causal associations of T2D and fasting insulin with serum urate concentrations and a suggestive association of fasting insulin with risk of gout. Future research is required to examine the underlying biological mechanisms on such relationships.