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Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges

A Corrigendum to this article was published on 01 February 2008

Key Points

  • Serious adverse drug reactions (SADRs) are a significant cause of death. Genetic factors may underlie some of the susceptibility to SADRs.

  • We review three SADRs: drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes with an emphasis on genetic risk factors.

  • Characteristics of SADRs that increase the likelihood of informative genetic/genomic analysis include: evidence for a familial or genetic component, accepted criteria for unambiguous diagnosis, low background incidence and availability of sufficient numbers of cases and appropriately matched controls. Furthermore, information about the molecular mechanisms of drug action and elimination can add to candidate gene and pathway selection and investigation.

  • Clearly defined phenotypes along with standardization of these phenotypes must be in place to ascertain cases and controls and to facilitate replication studies.

  • Networks of scientists and healthcare providers in academia, industry, healthcare systems and regulatory agencies are needed to drive this effort. Effective and standardized procedures for enlisting physician and patient participation in research protocols, collection and transfer of information, DNA, plasma and other specimens must be developed. Confidentiality and ethical issues must be considered in the design and implementation of studies.

  • Study design and the methods for data gathering, storing and analysis must be continually addressed.

  • Replication of findings in diverse population subgroups is important for validating conclusions of these types of studies. For rare SADRs, national and international consortia and networks involving regulatory authorities, health care systems, academic medical centres and industry are crucial for increasing the numbers of cases.

  • Genome-wide association studies may be used to discover new mechanisms responsible for SADRs.

Abstract

Serious adverse drug reactions (SADRs) are a major cause of morbidity and mortality worldwide. Some SADRs may be predictable, based upon a drug's pharmacodynamic and pharmacokinetic properties. Many, however, appear to be idiosyncratic. Genetic factors may underlie susceptibility to SADRs and the identification of predisposing genotypes may improve patient management through the prospective selection of appropriate candidates. Here we discuss three specific SADRs with an emphasis on genetic risk factors. These SADRs, selected based on wide-sweeping clinical interest, are drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes. Key challenges for the discovery of predictive risk alleles for these SADRs are also considered.

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Figure 1: Toxicities leading to drug withdrawal from the US market.
Figure 2: Screening for patients with statin-induced mytotoxicity.
Figure 3: Marked QT interval prolongation and torsades de pointes.

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Acknowledgements

We would like to acknowledge support from the National Institutes of Health (NIH) Pharmacogenetics Research Network: GM61390, U01 HL65962, U01 GM061373, HL 69757, U01 GM074492, U01 DK065201 and K24RR02815 and TR2GM008425 as well as the PhRMA Predoctoral Fellowship. Much of the variant data cited in this article have been deposited in www.pharmgkb.org.

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Correspondence to Ronald M. Krauss.

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David Flockhart is on the advisory board of Labcorp.

Ronal Krauss is a consultant for Merck & Co. Inc, Merck/Schering-Plough, Celeara Diagnostics and a recipient of grants from Merck & Co. Inc. and Merck/Schering-Plough.

Dan Roden is a consultant for Novartis Pharmaceuticals Corp., the International Life Sciences Health and Environmental Sciences Institute, Sapphire Therapeutics Inc., Atlas Venture Advisors Inc., Pfizer, Avanir, Baker Brothers Advisors LLC, Cardiokine Inc., Eli Lilly, Johnson & Johnson and Teva.

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Glossary

Adverse drug reaction

(ADR). Any noxious, unintended and undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis or therapy. This excludes therapeutic failures, intentional and accidental poisoning and drug abuse.

Pharmacokinetics

The study of processes impacting absorption, distribution, metabolism and excretion of a drug and its metabolites in the body.

Pharmacodynamics

The study of the mechanism of action of a drug, including but not limited to processes such as receptor binding and signal transduction.

Gilbert's syndrome

A common, mild liver disorder caused by reduced activity of glucuronyltransferase, an enzyme required for excreting bilirubin; typically it does not require treatment or pose serious complications.

Creatine kinase

(CK). An enzyme often measured clinically as a severity marker of muscle damage.

Phase I metabolism

Phase I reactions may occur by oxidation, reduction, hydrolysis, cyclization and decyclization reactions. The process of oxidation takes place in the presence of mixed function oxidases and mono-oxygenases in the liver.

Phase II metabolism

Phase II reactions (conjugation reactions) are usually detoxicating and involve the interactions of the polar functional groups of phase I metabolites.

Hypokalaemia

Hypokalaemia is a potentially fatal condition in which the body fails to retain sufficient potassium to maintain health. The condition is also known as potassium deficiency.

Penetrance

The frequency, under given environmental conditions, with which a specific phenotype results from a predetermined genotype; it is usually given as a percentage.

Subclinical mutation carrier

A carrier of a mutation who does not manifest the pathological effects of the mutation.

Pharmacogenetics

The study of how variations in a few genes affect the response to medications.

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Wilke, R., Lin, D., Roden, D. et al. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6, 904–916 (2007). https://doi.org/10.1038/nrd2423

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