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Understanding the genetic basis for adverse drug effects: the calcineurin inhibitors

Jane P F Bai1, Lawrence J Lesko, Gilbert J Burckart

  • 1Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA.

Pharmacotherapy
|January 27, 2010
PubMed

Insights

Calcineurin inhibitors cause adverse drug effects like nephrotoxicity and diabetes. Gene variations linked to these diseases may predict transplant patients

Area of Science:

  • Pharmacogenomics and Transplantation Immunology

Background:

  • Calcineurin inhibitors (cyclosporine, tacrolimus) are vital immunosuppressants in solid organ transplantation.
  • These drugs are associated with severe adverse drug effects (ADEs), including nephrotoxicity, posttransplantation diabetes mellitus, and hypertension.
  • Growing evidence links specific DNA genotypes to the development of type 2 diabetes, hypertension, and renal failure.

Purpose of the Study:

  • To review and compare genes involved in common disease processes (diabetes, hypertension, renal failure) with those implicated in calcineurin inhibitor-induced ADEs.
  • To explore the potential of disease-associated genes as genomic biomarkers for predicting and preventing calcineurin inhibitor-related ADEs.

Main Methods:

  • Literature review comparing genetic associations of type 2 diabetes, hypertension, and renal failure with calcineurin inhibitor-induced ADEs.
  • Identification of candidate genes implicated in both disease development and drug-induced toxicity.

Main Results:

  • Renin-angiotensin system, cytokine, and plasminogen activator inhibitor type 1 genes are linked to calcineurin inhibitor-induced nephrotoxicity and renal failure.
  • Genes such as VDR, HNF, TCF7L2, ACE, PPARG, and ABCC8 are associated with calcineurin inhibitor-induced diabetes.
  • ACE, endothelial constitutive nitric oxide synthase, and CYP3A genes are implicated in calcineurin inhibitor-induced hypertension.

Conclusions:

  • Gene polymorphisms play a role in the development of both common diseases and similar drug-induced adverse effects.
  • Disease-associated genes serve as valuable candidates for investigating calcineurin inhibitor-induced ADEs.
  • Identifying these genetic biomarkers can aid in assessing patient risk and developing personalized preventive strategies for adverse drug reactions.

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