Abstract
ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic SNPs identified in GWAS; A391T has associations with an increased risk of schizophrenia, obesity, Crohn’s disease, and reduced blood Mn. Here, we used CRISPR/Cas9-mediated knockin (KI) to generate a mouse model of ZIP8 A391T (Zip8 393T-KI mice). Recapitulating the SNP association with blood Mn, blood Mn was reduced in Zip8 393T-KI mice. There was restricted abnormal tissue Mn homeostasis, with decreases in liver and kidney Mn and a reciprocal increase in biliary Mn, providing in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemically induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of patients with Crohn’s disease. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in complex human disease.
Highlights
A nonsynonymous SNP in SLC39A8 is one of the most pleiotropic variants in the human genome, ranking ninth of 341 genomic regions associating with more than one human disease or trait in GWAS [1]
The minor allele frequency (MAF) is approximately 0.05 in American population and, 0.08 in Northern European populations and increases to 0.14–0.25 in the Ashkenazi Jewish population; the major allele is monomorphic in African and East and South Asian populations [10,11,12]
Mn homeostasis is regulated by ZNT10 at the apical membrane of hepatocytes, which excrete Mn [23]; ZIP8 (SLC39A8) at the apical membrane of hepatocytes and bile canalicular cells, which reclaim Mn from bile [19]; and ZIP14 (SLC39A14) at the basolateral membrane of hepatocytes, which mediate liver uptake of Mn from blood [24]
Summary
A nonsynonymous SNP in SLC39A8 (rs13107325) is one of the most pleiotropic variants in the human genome, ranking ninth of 341 genomic regions associating with more than one human disease or trait in GWAS [1]. Our hypothesis is that the pleiotropic effects of ZIP8 391-Thr could, at least in part, be driven by perturbations in Mn homeostasis and Mn-dependent processes, including N-glycosylation, with underrecognized clinical relevance in human disease. Zip8 393T-KI mice showed no anatomical abnormalities, despite abnormal Mn homeostasis, with reduced whole blood Mn (male and female mice), reduced liver and kidney Mn (male mice), and increased biliary Mn excretion (male and female mice) Both heterozygous and homozygous male KI mice showed enhanced susceptibility to epithelial injury in a chemical model of colitis, consistent with the SNP-disease association with Crohn’s disease [6]; female KI mice did not exhibit a phenotype in the chemical model of colitis, suggesting possible sex-specific effects of Mn homeostasis and/or limitations of the dextran sodium sulfate (DSS) colitis model in female mice. The accumulating human data, supported by the Zip8 393T-KI mouse model, support the relevance of abnormal Mn homeostasis and dysregulation of Mn-using processes, including N-glycosylation, in complex human disease
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