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.

Using mendelian randomization (MR), we assessed how genetically predicted systemic iron status affected T2D risk.

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.

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).

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.