Genetic Support of A Causal Relationship Between Iron Status and Type 2 Diabetes: A Mendelian Randomization Study

Abstract Context Iron overload is a known risk factor for type 2 diabetes (T2D); however, iron overload and iron deficiency have both been associated with metabolic disorders in observational studies. Objective Using mendelian randomization (MR), we assessed how genetically predicted systemic iron status affected T2D risk. Methods A 2-sample MR analysis was used to obtain a causal estimate. We selected genetic variants strongly associated (P < 5 × 10−8) with 4 biomarkers of systemic iron status from a study involving 48 972 individuals performed by the Genetics of Iron Status consortium and applied these biomarkers to the T2D case-control study (74 124 cases and 824 006 controls) performed by the Diabetes Genetics Replication and Meta-analysis consortium. The simple median, weighted median, MR-Egger, MR analysis using mixture-model, weighted allele scores, and MR based on a Bayesian model averaging approaches were used for the sensitivity analysis. Results Genetically instrumented serum iron (odds ratio [OR]: 1.07; 95% CI, 1.02-1.12), ferritin (OR: 1.19; 95% CI, 1.08-1.32), and transferrin saturation (OR: 1.06; 95% CI, 1.02-1.09) were positively associated with T2D. In contrast, genetically instrumented transferrin, a marker of reduced iron status, was inversely associated with T2D (OR: 0.91; 95% CI, 0.87-0.96). Conclusion Genetic evidence supports a causal link between increased systemic iron status and increased T2D risk. Further studies involving various ethnic backgrounds based on individual-level data and studies regarding the underlying mechanism are warranted for reducing the risk of T2D.