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Pharmacol Res. 2018 Apr;130:44-51. doi: 10.1016/j.phrs.2018.02.013. Epub 2018 Feb 12.

Calcium channel blockers as drug repurposing candidates for gestational diabetes: Mining large scale genomic and electronic health records data to repurpose medications.

Author information

1
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, United States.
2
Department of Biomedical Informatics, Vanderbilt University Medical Center, United States.
3
Department of Biomedical Informatics, Vanderbilt University Medical Center, United States; Department of Medicine, Vanderbilt University Medical Center, United States.
4
Department of Biomedical Informatics, Vanderbilt University Medical Center, United States; Department of Medicine, Vanderbilt University Medical Center, United States; Department of Pharmacology, Vanderbilt University School of Medicine, United States.
5
Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, United States.
6
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, United States; Department of Medicine, Vanderbilt University Medical Center, United States. Electronic address: d.aronoff@vanderbilt.edu.

Abstract

New therapeutic approaches are needed for gestational diabetes mellitus (GDM), but must show safety and efficacy in a historically understudied population. We studied associations between electronic medical record (EMR) phenotypes and genetic variants to uncover drugs currently considered safe in pregnancy that could treat or prevent GDM. We identified 129 systemically active drugs considered safe in pregnancy targeting the proteins produced from 196 genes. We tested for associations between GDM and/or type 2 diabetes (DM2) and 306 SNPs in 130 genes represented on the Illumina Infinium Human Exome Bead Chip (DM2 was included due to shared pathophysiological features with GDM). In parallel, we tested the association between drugs and glucose tolerance during pregnancy as measured by the glucose recorded during a routine 50-g glucose tolerance test (GTT). We found an association between GDM/DM2 and the genes targeted by 11 drug classes. In the EMR analysis, 6 drug classes were associated with changes in GTT. Two classes were identified in both analyses. L-type calcium channel blocking antihypertensives (CCBs), were associated with a 3.18 mg/dL (95% CI -6.18 to -0.18) decrease in glucose during GTT, and serotonin receptor type 3 (5HT-3) antagonist antinausea medications were associated with a 3.54 mg/dL (95% CI 1.86-5.23) increase in glucose during GTT. CCBs were identified as a class of drugs considered safe in pregnancy could have efficacy in treating or preventing GDM. 5HT-3 antagonists may be associated with worse glucose tolerance.

KEYWORDS:

Anxiety; Calcium channel blockers; Drug repurposing; Drug safety; Electronic health records; Gene set enrichment analysis; Gestational diabetes; Glucose tolerance; Hyperemesis; Hypertension; International classification of disease; Major depressive disorder; Placenta; Pregnancy complications; Serotonin

PMID:
29448118
PMCID:
PMC5965292
DOI:
10.1016/j.phrs.2018.02.013
[Indexed for MEDLINE]
Free PMC Article

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