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

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 aimed to investigate bidirectional associations of T2D and glycemic traits with serum urate concentrations and gout using a Mendelian randomization (MR) approach.Summary statistics from the large-scale genome-wide association studies conducted for T2D (Ncase=62,892, Ncontrol=596,424), fasting glucose (N=133,010), fasting insulin (N=133,010), hemoglobinA1c (N=123,665), homeostasis model assessment of insulin resistance (N=46,186), urate (N=110,347) and gout (Ncase=2,115, Ncontrol=67,259) among participants of European ancestry were analyzed. For each trait of interest, independent genome-wide significant (p<5×10 -8) single nucleotide polymorphisms were selected as instrumental variables. The inverse-variance weighted method was used for the primary analyses.Genetic predisposition to higher risk of T2D (beta=0.042; 95% 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 (OR=3.06; 95% CI=0.88-10.61; p=0.078). In the reverse direction analysis, both genetic predisposition to urate and gout were not associated with T2D and any of four glycemic traits being investigated.This study provides supportive evidence on causal associations of T2D and fasting insulin with serum urate concentrations, and suggestive association of fasting insulin with risk of gout. Future research is required to examine the underlying biological mechanisms on such relationships.

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Authors: Jiahao Zhu, Lingling Sun, Jing Yang, Jiayao Fan, Lap Ah Tse, Yingjun Li