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

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.

Figure 1. Toxicities leading to drug withdrawal from the US market

Drug-induced toxicities associated with 28 drugs that were withdrawn from the US market between 1976 and 2005 (REFS –13). Percentage of total and number of cases shown in brackets. Cardiotoxicity refers to heart-related toxicities other than torsades de pointes. ‘Other’ refers to haemolytic anaemia (1), skin disease (1), immune toxicity (2), gastrointestinal toxicity (1), respiratory toxicity (1), fatal (1), neurotoxicity (1), blood-related toxicity (1) and birth defects (1).

Figure 2. Screening for patients with statin-induced mytotoxicity

In this example of automated case screening a search of an adverse drug reaction (ADR) database resulted in 5,000,000 patients with creatine kinase (CK) measurements and 200,000 of those patients were exposed to statins. These cases included 20,000 patients with elevated CK levels (over 500 units per L), which were linked to their patient charts and were subsequently screened for inclusion/exclusion criteria by trained research coordinators and lastly, by an expert physician. Age and gender matched controls are selected in a similar fashion. This figure was courtesy of R. K. Mareedu (Marshfield Clinic, Wisconsin, USA).

Figure 3. Marked QT interval prolongation and torsades de pointes

An example of QT interval during administration of the anti-arrhythmic drug dofetilide. a | QT interval before drug administration, the patient was in atrial fibrillation with a well-controlled ventricular response rate. A QT interval of 420 msec is indicated by the red bar. b | Following a single dose of dofetilide, the rhythm reverted to sinus (the desired therapeutic effect), but the QT interval prolonged markedly, to 560 msec. c | Shortly after the patient developed an episode of typical torsades de pointes. The sinus beat just before the arrhythmia displayed a very long QT interval (greater than 640 msec) and the beat was preceded by a pause. These ECG features are typical of torsades de pointes due to anti-arrhythmic drugs as well as non-cardiovascular medications.