Genetic determinants of zinc homeostasis and its role in cardiometabolic diseases

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#humans #zinc #genome-wide-association-study #homeostasis #cation-transport-proteins

Genetic determinants of zinc homeostasis and its role in cardiometabolic diseases

Sadler et al., 2025 | PLoS Genet | Meta Analysis

Citation

Sadler Marie C, Ghobril Jean-Pierre, ... Kutalik Zoltán. Genetic determinants of zinc homeostasis and its role in cardiometabolic diseases. PLoS Genet. 2025-Dec;21(12):e1011928. doi:10.1371/journal.pgen.1011928

Abstract

Zinc is essential for many physiological processes and its deficiency is highly prevalent worldwide. Its complex homeostasis involves membrane transporters from the SLC39/ZIP and SLC30/ZnT protein families. We conducted a genome-wide association study (GWAS) meta-analysis of urinary zinc levels in three European-ancestry cohorts (N = 10,113), followed by in silico and in vivo studies to elucidate their underlying public health and physiological relevance. We identified eleven genome-wide significant signals with six mapping to SLC39/ZIP and SLC30/ZnT gene regions. The lead signal (rs3008217C>G, p = 2.42E-110) in the SLC30A2 gene region which explained 6.1% of urinary zinc variation strongly colocalized with its expression in kidney tubules. Low phenotypic and genetic correlations between plasma and urinary zinc levels indicated distinct genetic regulation. High urinary zinc correlated with an unfavorable cardiometabolic profile, and Mendelian randomization analyses suggested causal roles for diabetes increasing urinary zinc levels, and elevated urinary zinc increasing stroke risk. Analyzing country-level allele frequencies and zinc deficiency prevalences revealed a 3-fold higher genetic zinc excretion risk in sub-Saharan Africa compared to Europe, significantly correlating with nutritional zinc deficiency prevalence. Although mutations in SLC30A2 are linked to insufficient zinc in human milk, we found no association with common variants using data generated from 387 mothers. Mice experiments showed that dietary zinc deficiency decreased urinary but not plasma zinc levels, and upregulated kidney Slc30a2 expression. This first GWAS on urinary zinc highlights the involvement of zinc transporters in its genetic regulation, as well as its role as a non-invasive biomarker for cardiometabolic diseases.

Key Findings

This first GWAS on urinary zinc highlights the involvement of zinc transporters in its genetic regulation, as well as its role as a non-invasive biomarker for cardiometabolic diseases.

Outcomes Measured

  • Requires manual extraction

Population

Field Value
Population See abstract
Sample Size 10113
Age Range See abstract
Condition diabetes

MeSH Terms

  • Humans
  • Zinc
  • Genome-Wide Association Study
  • Homeostasis
  • Cation Transport Proteins
  • Animals
  • Cardiovascular Diseases
  • Mice
  • Polymorphism, Single Nucleotide
  • Female
  • Male
  • Mendelian Randomization Analysis
  • Genetic Predisposition to Disease
  • Metabolic Diseases

Evidence Classification

  • Level: Meta Analysis
  • Publication Types: Journal Article, Meta-Analysis
  • Vertical: zinc

Provenance

Source extracted via PubMed E-utilities API on 2026-04-09