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

Jeffery A. Goldstein, Lisa A. Bastarache, Joshua C. Denny, Dan M. Roden, Jill M. Pulley, David M. Aronoff*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)44-51
Number of pages8
JournalPharmacological Research
Volume130
DOIs
StatePublished - Apr 1 2018

Fingerprint

Drug Repositioning
Gestational Diabetes
Electronic Health Records
Calcium Channel Blockers
Glucose Tolerance Test
Glucose
Pharmaceutical Preparations
Pregnancy
Drug Tolerance
Pregnancy Proteins
Genes
Exome
Receptors, Serotonin, 5-HT3
L-Type Calcium Channels
Medical Genetics
Type 2 Diabetes Mellitus
Antihypertensive Agents
Single Nucleotide Polymorphism
Phenotype
Safety

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{d8c9fd7ca752452fa74bf12018f773cc,
title = "Calcium channel blockers as drug repurposing candidates for gestational diabetes: Mining large scale genomic and electronic health records data to repurpose medications",
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",
author = "Goldstein, {Jeffery A.} and Bastarache, {Lisa A.} and Denny, {Joshua C.} and Roden, {Dan M.} and Pulley, {Jill M.} and Aronoff, {David M.}",
year = "2018",
month = "4",
day = "1",
doi = "10.1016/j.phrs.2018.02.013",
language = "English (US)",
volume = "130",
pages = "44--51",
journal = "Pharmacological Research",
issn = "1043-6618",
publisher = "Academic Press Inc.",

}

Calcium channel blockers as drug repurposing candidates for gestational diabetes : Mining large scale genomic and electronic health records data to repurpose medications. / Goldstein, Jeffery A.; Bastarache, Lisa A.; Denny, Joshua C.; Roden, Dan M.; Pulley, Jill M.; Aronoff, David M.

In: Pharmacological Research, Vol. 130, 01.04.2018, p. 44-51.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Calcium channel blockers as drug repurposing candidates for gestational diabetes

T2 - Mining large scale genomic and electronic health records data to repurpose medications

AU - Goldstein, Jeffery A.

AU - Bastarache, Lisa A.

AU - Denny, Joshua C.

AU - Roden, Dan M.

AU - Pulley, Jill M.

AU - Aronoff, David M.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

AB - 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.

KW - Anxiety

KW - Calcium channel blockers

KW - Drug repurposing

KW - Drug safety

KW - Electronic health records

KW - Gene set enrichment analysis

KW - Gestational diabetes

KW - Glucose tolerance

KW - Hyperemesis

KW - Hypertension

KW - International classification of disease

KW - Major depressive disorder

KW - Placenta

KW - Pregnancy complications

KW - Serotonin

UR - http://www.scopus.com/inward/record.url?scp=85042170113&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042170113&partnerID=8YFLogxK

U2 - 10.1016/j.phrs.2018.02.013

DO - 10.1016/j.phrs.2018.02.013

M3 - Article

C2 - 29448118

AN - SCOPUS:85042170113

VL - 130

SP - 44

EP - 51

JO - Pharmacological Research

JF - Pharmacological Research

SN - 1043-6618

ER -