In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 12 ( 2019-12), p. 2322-2336
Abstract:
Lithium causes nephrogenic diabetes insipidus and hypercalcemia in 20% and 10% of patients, respectively, and may lead to metabolic acidosis. To determine the potential role of genetic predisposition in these adverse effects, the authors fed mice from 29 genetically different inbred strains a normal or a lithium-supplemented diet. Some strains developed adverse effects, whereas others did not. Genome-wide association studies revealed eight loci containing different candidate genes that were associated with development of lithium-induced nephrogenic diabetes insipidus. Of these, Acer2 is specifically expressed in the collecting duct; mice lacking Acer2 were more likely to develop lithium-induced nephrogenic diabetes insipidus. These findings demonstrate the importance of genetic variation in susceptibility for lithium-induced adverse effects in mice, and the genes identified may facilitate subsequent identification of human susceptibility genes. Background Lithium, mainstay treatment for bipolar disorder, causes nephrogenic diabetes insipidus and hypercalcemia in about 20% and 10% of patients, respectively, and may lead to acidosis. These adverse effects develop in only a subset of patients treated with lithium, suggesting genetic factors play a role. Methods To identify susceptibility genes for lithium-induced adverse effects, we performed a genome-wide association study in mice, which develop such effects faster than humans. On day 8 and 10 after assigning female mice from 29 different inbred strains to normal chow or lithium diet (40 mmol/kg), we housed the animals for 48 hours in metabolic cages for urine collection. We also collected blood samples. Results In 17 strains, lithium treatment significantly elevated urine production, whereas the other 12 strains were not affected. Increased urine production strongly correlated with lower urine osmolality and elevated water intake. Lithium caused acidosis only in one mouse strain, whereas hypercalcemia was found in four strains. Lithium effects on blood pH or ionized calcium did not correlate with effects on urine production. Using genome-wide association analyses, we identified eight gene-containing loci, including a locus containing Acer2 , which encodes a ceramidase and is specifically expressed in the collecting duct. Knockout of Acer2 led to increased susceptibility for lithium-induced diabetes insipidus development. Conclusions We demonstrate that genome-wide association studies in mice can be used successfully to identify susceptibility genes for development of lithium-induced adverse effects. We identified Acer2 as a first susceptibility gene for lithium-induced diabetes insipidus in mice.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2018050549
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2019
detail.hit.zdb_id:
2029124-3
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