The associations between metals status and the risk of health-related outcomes and all-cause mortality: a Mendelian randomization-phenome-wide association study

Guangxi Medical University

Lay summary

Despite the great advances that have been made in the prevention and treatment of diseases, the etiology and mechanisms of many diseases are not fully understood. Metals are vital nutrients integral to various physiological processes such as metabolism, immune function, and cognitive development. Given the crucial role of metals, deviations in their levels can have notable health implications. Some observational studies have shown that there are relationships between metals and health-related outcome. For example, moderate calcium supplementation helps reduce T2D risk; higher magnesium is negatively associated with Alzheimer's disease. However, the associations between metals and a range of diseases remains inconclusive, as most of the observational epidemiological studies are susceptible to confounding and reverse causation, and thus it remains unclear whether these associations are genuine.

We propose to access the UK Biobank and use Mendelian randomization design to indirectly infer causality among metals and a range of health-related outcomes. Calcium-associated genetic variants were derived from GWAS results including rs4306808, rs7336933, rs17711722, rs17267388, rs1067, rs13095172, rs11929034, rs4491840, rs16832956, rs17251221, rs10222633, rs10491003, and rs9864290. Copper-associated genetic variants include rs1175550, rs2769264, and rs2769270. Zinc-associated genetic variants include rs1138477, rs1532423, and rs2120019. Selenium-associated genetic variants include rs672413, rs567754, rs10944, rs6586282, rs1789953, rs234709, rs705415, rs3797535, rs11951068, and rs921943. The Mendelian randomization design enables us to use the genetic variants as a proxy for the long-term differences in metals status, thereby largely avoiding confounding and reverse causation.

By accessing the UK biobank and using the whole cohort we can explore the causal association between the genetically determined calcium/ copper/zinc/ selenium status and the risk of health-related outcomes such as asthma, COPD, stroke, Parkinson's disease, endocrine diseases, digestive system disorders, and cancer as well as all-cause mortality.

This study might be the largest population-based study to explore the causal association between calcium/ copper/zinc/ selenium and a range of health-related outcomes using Mendelian randomization study design. The results will provide adequate evidence whether metals status is associated with a range of health-related outcomes. Such information will be important for the general population about the health consequences of metals status. If metals status does cause diseases, these would be of clinical relevance, since metals supplement is common and metals status could be safely correctable.

We propose to complete this project in 36 months.