Pharmacogenetics of drug-induced arrhythmias: a feasibility study using spontaneous adverse drug reactions reporting data.
OBJECTIVE
The bottleneck in pharmacogenetic research on rare adverse drug reactions (ADR) is retrieval of patients. Spontaneous reports of ADRs may form a useful source of patients. We investigated the feasibility of a pharmacogenetic study, in which cases were selected from the database of a spontaneous reporting system for ADRs, using drug-induced arrhythmias as an example.


METHODS
Reports of drug-induced arrhythmias to proarrhythmic drugs were selected from the database of the Netherlands Pharmacovigilance Centre (1996-2003). Information on the patient's general practitioner (GP) was obtained from the original report, or from another health care provider who reported the event. GPs were contacted and asked to recruit the patient as well as two age, gender and drug matched controls. Patients were asked to fill a questionnaire and provide a buccal swab DNA sample through the mail. DNA samples were screened for 10 missense mutations in 5 genes associated with the congenital long-QT (LQT) syndrome (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2).


RESULTS
We identified 45 eligible cases, 29 GPs could be contacted of which seven were willing to participate. Four cases and five matched controls could be included in the study, giving an overall participation rate of 9% (4/45). The main reason for GPs not being willing to participate was lack of time. Variants were identified in KCNH2, SCN5A and KCNE1.


CONCLUSIONS
Spontaneous reporting systems for ADRs may be used for pharmacogenetic research. The methods described, however, need to be improved to increase participation and international collaboration may be required.
De Bruin
Marie L
ML
Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht, The Netherlands. m.l.debruin@pharm.uu.nl
van Puijenbroek
Eugene P
EP
Bracke
Madelon
M
Hoes
Arno W
AW
Leufkens
Hubert G M
HG
D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000235:genetics*; D016022:Case-Control Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005240:Feasibility Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009426:Netherlands; D010597:Pharmacogenetics / Q000379:methods; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels