A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes.
Sluijs I., Holmes MV., van der Schouw YT., Beulens JW., Asselbergs FW., Huerta JM., Palmer TM., Arriola L., Balkau B., Barricarte A., Boeing H., Clavel-Chapelon F., Fagherazzi G., Franks PW., Gavrila D., Kaaks R., Khaw KT., Kühn T., Molina-Montes E., Mortensen LM., Nilsson PM., Overvad K., Palli D., Panico S., Quirós JR., Rolandsson O., Sacerdote C., Sala N., Schmidt JA., Scott RA., Sieri S., Slimani N., Spijkerman AM., Tjonneland A., Travis RC., Tumino R., van der A DL., Sharp SJ., Forouhi NG., Langenberg C., Riboli E., Wareham NJ., InterAct Consortium None.
We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk.