Genetic determinants of zinc homeostasis and its role in cardiometabolic diseases

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.

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Journal
PLoS Genetics
Published
2025-12-01
DOI
https://doi.org/10.1371/journal.pgen.1011928
Citations
1
Primary Topic
Trace Elements in Health
Type
article
Field-Weighted Citation Impact
1.12
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article

Genetic determinants of zinc homeostasis and its role in cardiometabolic diseases

Marie C. Sadler, Sébastien Lenglet, Belén Ponte, Courtney L. Meehan et al.
1 citations
PLoS Genetics
Trace Elements in Health
1.12
article

Genetic determinants of zinc homeostasis and its role in cardiometabolic diseases

Marie C. Sadler, Sébastien Lenglet, Belén Ponte, Courtney L. Meehan, Aurélien Thomas, Olivier Devuyst, Silvia Stringhini, Zulema Rodriguez-Hernandez, Guglielmo Schiano, Jean-Pierre Ghobril, Menno T Pruijm, Shelley McGuire, Bruno Vogt, Katalin Suszták, Tanguy Corre, Halit Ongen, Georg Ehret, Dušan Petrović, Maïwenn Perrais, Brenda M. Murdoch, Murielle Bochud, Zoltán Kutalik, Daniel Ackermann, Janet E. Williams, Idris Guessous, Oleg Borisov, Yong Li, Eunji Ha, Emmanouil Dermitzakis, Pierre-Yves Martin, Julien Vaucher, Anna Köttgen
article en
1 citations

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.

PLoS GeneticsVol. 21(12)
University of Geneva (CH), University of Bern (CH), SIB Swiss Institute of Bioinformatics (CH), University of Fribourg (CH), University of Idaho (US), University of Freiburg (DE), University of Zurich (CH), University Hospital of Bern (CH), University Medical Center Freiburg (DE), Centre Hospitalier Universitaire Vaudois (CH), ETH Zurich (CH), University Hospital of Geneva (CH), Centre Hospitalier de Saint-Malo (FR), University Centre of Legal Medicine (CH), Centre universitaire de médecine générale et santé publique, Lausanne (CH), Geneva College (US), Washington State University (US), University of Pennsylvania (US), University of Lausanne (CH)
Openalex Percentile: Top 17%
Trace Elements in Health
1.12
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