Genetic determinants of zinc homeostasis and its role in cardiometabolic diseases.

Summary

This first GWAS-meta analysis of urinary zinc identifies 11 loci, with a lead SLC30A2 variant explaining 6.1% of variance and colocalizing with kidney tubular expression. Urinary zinc is genetically distinct from plasma zinc and associates with adverse cardiometabolic profiles; Mendelian randomization suggests diabetes increases urinary zinc and higher urinary zinc causally increases stroke risk. Cross-population analyses and mouse experiments support a kidney zinc transporter axis and highlight urinary zinc as a non-invasive biomarker.

Key Findings

• Identified 11 genome-wide significant loci for urinary zinc, with SLC30A2 rs3008217 explaining 6.1% of variance and colocalizing with kidney tubular expression.
• Urinary and plasma zinc show low phenotypic and genetic correlation, indicating distinct regulation.
• Mendelian randomization suggested diabetes causally increases urinary zinc, and elevated urinary zinc increases stroke risk.
• Cross-population analysis showed ~3-fold higher genetic risk of zinc excretion in sub-Saharan Africa correlating with nutritional deficiency prevalence.
• Dietary zinc deficiency in mice decreased urinary, but not plasma, zinc and upregulated renal Slc30a2.

Clinical Implications

Urinary zinc could serve as a noninvasive biomarker for cardiometabolic and stroke risk stratification, especially in diabetes. Population differences in genetic zinc excretion highlight the need for tailored nutrition and public health strategies.

Limitations

• Primary discovery cohorts were European-ancestry; external validity to diverse ancestries requires further study.
• MR assumptions may be violated by pleiotropy; causal estimates rely on instrument validity.
• Limited sample for human milk SLC30A2 variant analyses (n=387 mothers).

Future Directions

Validate urinary zinc as a prospective biomarker across ancestries; dissect transporter-specific mechanisms in kidney; test whether nutritional or pharmacologic modulation of zinc handling alters cardiometabolic and stroke risk.