African-enriched SLC39A10 (ZIP10) missense variants differentially affect cellular zinc homeostasis and associate with health-related traits.

Abstract

BACKGROUND: Zinc deficiency remains a major global health concern and disproportionately affects populations in regions such as sub-Saharan Africa. Although inadequate dietary intake is a primary determinant of zinc status, genetic variation in zinc transport pathways may contribute to interindividual and interpopulation differences in zinc utilization. The SLC39A10 gene encodes the zinc importer ZIP10, which is upregulated under zinc-restricted conditions to sustain cellular zinc acquisition. This study sought to identify functional SLC39A10 variants and evaluate their potential physiological relevance, with particular attention to alleles enriched in populations of African ancestry. METHODS AND RESULTS: Missense variants in SLC39A10 were identified through analysis of sequencing data from the Genome Aggregation Database. The three most frequent minor alleles were markedly enriched in populations of African ancestry. Among these, two histidine-replacing variants, H194Q and H609Y, located near conserved histidine-rich regions of ZIP10, exhibited reduced capacity to increase cytosolic labile zinc levels and metallothionein expression in HEK293T cells, consistent with hypomorphic effects on transporter activity. These functional differences were not attributable to altered transcript abundance, protein expression, or subcellular localization. In silico variant effect prediction and evolutionary conservation analyses further supported the functional relevance of these substitutions. Phenome-wide association analyses in a large African ancestry cohort revealed nominal associations of these variants with hematologic and renal traits, suggesting potential physiological consequences of altered zinc transport capacity. CONCLUSIONS: These findings identify SLC39A10 as a locus of nutrigenetic diversity and demonstrate ancestry-linked variation in cellular zinc handling. The characterization of African-enriched hypomorphic ZIP10 variants provides mechanistic insight into genetic influences on micronutrient homeostasis. Incorporating genetic variation in zinc transport pathways may improve precision nutrition strategies and inform public health approaches aimed at reducing population-specific vulnerability to zinc deficiency.