OP0171 MENDELIAN RANDOMIZATION SHOWS NO CAUSAL ASSOCIATION BETWEEN SERUM URATE OR GOUT AND TYPE-2 DIABETES
Authors: N. Mccormick, J. Choi, S. Marozoff, H. Choi
Journal: Annals of the Rheumatic Diseases (2020)

Background: Positive associations between gout 1,2 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 (&gt; 140,000 individuals); outcome SNPs sourced from DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM; &gt; 34,000 T2D cases and &gt; 114,000 controls) and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC; &gt; 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: R 2 =2.7%, beta=0.37 per mg/dL, p &lt; 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 R 2 values ≥ 1.9%, we had ≥ 90% power to detect the increased odds of T2D (OR ≥1.15 1,3 ) from observational studies. All Risk SNPs (meta-analysis) OUTCOME n SNPs Gout (vs. non-gout) Serum urate (per 1 mg/dL increase) Effect size (95% CI) p Effect size (95% CI) p HbA1c (%) 45 0.0046 (-0.0087 to 0.0179) 0.50 -0.0046 (-0.0275 to 0.0183) 0.70 Insulin resistance (HOMA-IR: log units) 45 0.0108 (-0.0049 to 0.0265) 0.18 0.0016 (-0.0240 to 0.0272) 0.90 Fasting insulin levels (log pmol/L) 18 0.0046 (-0.0037 to 0.0129) 0.28 -0.0221 (-0.1035 to 0.0593) 0.59 Type 2 Diabetes: odds ratio 43 0.98 (0.90 to 1.07) 0.72 1.01 (0.88 to 1.16) 0.84 SNPs in SLC29A Gene (single-SNP analysis ) OUTCOME rs4475146 Gout (vs. non-gout ) rs12498742 Serum urate (per 1 mg/dL increase ) Effect size (95% CI ) p Effect size (95% CI ) p HbA1c (%) 0.0032 (-0.0139 to 0.0203) 0.71 0.0005 (-0.0205 to 0.0216) 0.96 Insulin resistance (HOMA-IR: log units) 0.0128 (-0.0073 to 0.0328) 0.21 0.0126 (-0.0121 to 0.0373) 0.32 Fasting insulin levels (log pmol/L) 0.0038 (-0.0070 to 0.0147) 0.49 0.0048 (-0.0088 to 0.0185) 0.49 Type 2 Diabetes: odds ratio 0.98 (0.87 to 1.10) 0.70 0.98 (0.85 to 1.13) 0.75 HOMA-IR=homeostasis model assessment of insulin resistance 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. References: [1]Rho YH, Lu N, Peloquin CE, et al. Independent impact of gout on the risk of diabetes mellitus among women and men: a population-based, BMI-matched cohort study. Ann Rheum Dis . 2016;75(1):91-95. [2]Choi HK, De Vera MA, Krishnan E. Gout and the risk of type 2 diabetes among men with a high cardiovascular risk profile. Rheumatology . 2008;47(10):1567-1570. [3]Bhole V, Choi JWJ, Woo Kim S, De Vera M, Choi H. Serum Uric Acid Levels and the Risk of Type 2 Diabetes: A Prospective Study. Am J Med . 2010;123(10):957-961. Disclosure of Interests: Natalie McCormick: None declared, Jeewoong Choi: None declared, Shelby Marozoff: None declared, Hyon Choi Grant/research support from: HC reports research support from Ironwood and Horizon, Consultant of: HC reports consulting fees from Ironwood, Selecta, Horizon, Takeda, Kowa, and Vaxart.