OP0171 MENDELIAN RANDOMIZATION SHOWS NO CAUSAL ASSOCIATION BETWEEN SERUM URATE OR GOUT AND TYPE-2 DIABETES

Abstract

Background: Positive associations between gout1,2 or serum urate (SU)3 and risk of type-2 diabetes (T2D) have been reported in population-based observational studies, but may be due to residual confounding. As such, causal roles of SU and gout on development of T2D are unclear. Objectives: Use two-sample mendelian randomization to estimate the causal effects of SU and gout on T2D and glycemic traits. Methods: Aggregate data from three large genome-wide association studies were used to identify genetic variants (SNPs) associated with the exposures and outcomes. Exposure SNPs were sourced from Global Urate Genetics Consortium (> 140,000 individuals); outcome SNPs sourced from DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM; > 34,000 T2D cases and > 114,000 controls) and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC; > 46,000 non-diabetics). We analysed SNPs associated with SU levels (n=28) and gout (n=6) for associations with T2D and three glycemic traits (insulin resistance, fasting insulin levels, and HbA1c) using inverse variance weighted meta-analysis methods. We also specifically examined two SNPs mapping to the SLC2A9 gene, which encodes the GLUT9 transporter (for glucose and urate), estimating Wald ratios for these individual SNPs. Analyses were performed with TwoSampleMR package in R and mRnd power calculator. Results: Estimated effects of genetically-determined gout on each of the four outcomes (T2D, insulin resistance, fasting insulin levels, and HbA1c) were small and non-significant (p ≥ 0.18), as were the effects of changes in genetically-determined SU levels (Table). Although the two SNPs in the SLC2A9 gene were strongly associated with SU (rs12498742: R2=2.7%, beta=0.37 per mg/dL, p < 10-700) and gout (rs4475146: odds ratio=0.63, p=4.1x10-26), neither was associated with T2D nor any of the glycemic traits (Table). Applying R2 values ≥ 1.9%, we had ≥ 90% power to detect the increased odds of T2D (OR ≥1.151,3) from observational studies. Conclusion: Evidence from this instrumental variable analysis suggests gout and SU are signals for future T2D, but neither SU or gout itself are causally associated with the development of this condition. As such, interventions targeting SU levels alone are unlikely to lower the risk of T2D.