Causal relationships between blood calcium, iron, magnesium, zinc, selenium, phosphorus, copper, and lead levels and multisystem disease outcomes in over 400,000 Caucasian participants.

Background & Aims: Metal elements have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. We aimed to explore the broad clinical effects of varying blood metal element levels and possible underlying mechanisms.

Methods: We performed a two-sample Mendelian randomization (MR) analysis by using metal element-associated genetic loci as instrumental variable to evaluate the causal associations between blood metal element levels and 1050 disease outcomes in a UK Biobank cohort. A total of 408,910 White British participants were enrolled in the analysis. We further used the metal element-related genes and disease-related genes to construct a protein-protein interaction (PPI) network.

Results: Eight metal elements were associated with 63 diseases in total. Notably, we found nine pairs of suggestive evidence between two different metal elements for the same disease. Selenium and lead share some of the associated clinical outcomes, including diabetes mellitus, type 2 diabetes, lymphoid leukemia, and acute pharyngitis. Lead and zinc share the associated disease of acquired hypothyroidism. Iron and copper share the associated disease of arthropathies. Copper and zinc share the associated disease of occlusion of cerebral arteries. Calcium and zinc share the associated disease of arthropathies. In addition, the PPI network provided potential links between metal elements and disease outcomes at the genetic level.

Conclusions: Our MR study of eight metal elements comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in multiple diseases. Given the modifiable nature of blood metal elements and the potential for clinical interventions, these findings warrant further investigation.