Progress Report - December 2009
State of Play
The study now has 91 cases and 158 controls fully documented. Nine of the cases were fatal.
Samples for DNA extraction have been received from 34 individuals – 12 cases and 22 controls
Because our fourth project application to the NHMRC was refused, we have decided to reduce our objective and to aim for around 100 cases and 400 controls. This will mean obtaining more than 100 cases in order to have 100 cases for which controls are available. We hope to complete data collection at the end of 2010.
Papers for publication
Our first article arising from the clozapine and myocarditis study should shortly be published in the Journal of Clinical Psychiatry. This article describes the case definition and compares characteristics of cases and controls.
Two other articles have been submitted, but not yet accepted. These articles:
· propose evidence-based monitoring guidelines
· describe 9 fatal cases of myocarditis
Preliminary analysis
A preliminary analysis of data up to the end of 2008 (66 cases, 78 controls) suggests that concurrent sodium valproate and high rates of clozapine dose titration may predispose to myocarditis. Zuclopenthixol may be protective. These effects account for only about 10% of the risk of myocarditis. The vast majority of cases were initiated on clozapine according to protocol and were not taking sodium valproate.
While there may be other environmental and host factors influencing risk, this result suggests that genetic predisposition may account for as much as 50% of the risk of clozapine-induced myocarditis.
A genetic marker of another hypersensitivity reaction
A recent publication by Daly et al1 found an association between flucloxacillin-induced liver injury and HLA-B*5701. This is the genotype that predisposes to hypersensitivity with abacavir.
84% of cases and 6% of controls were positive for the genotype. Disease severity in cases was not associated with the presence of the predisposing allele, nor did HLA-B*5701 indicate those likely to have extrahepatic manifestations of disease.
Despite the strong association, the authors estimated that only 1 in every 500 or 1000 with the predisposing allele will develop drug-induced liver injury when exposed to flucloxacillin.
This observation does not seem encouraging for the clozapine and myocarditis study. However, while Daly et al documented disease characteristics, they did not document potential environmental or host risk factors as we are doing for the present study. Genetic risks may be modified by non-genetic factors, as has been observed with serious skin reactions with allopurinol – renal dysfunction doubled the risk of the adverse reaction, in a setting in which all cases had the predisposing allele.2
1. Daly AK, Donaldson PT, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature Genetics 2009; 41: 816-9.
2. Hung SI, Chung WH, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA 2005; 102: 4134-9.
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