The Pharmacogenomics Journal (2002) 2, 182–190  2002 Nature Publishing Group All rights reserved 1470-269X/02 $25.00 www.nature.com/tpj Received: 16 November 2001 Revised: 24 January 2002 Accepted: 2 February 2002 ORIGINAL ARTICLE The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists DC Shields 1,3 AP Fitzgerald 2 PA O’Neill 3 C Muckian 3 D Kenny 1 B Moran 3 CP Cannon 4 CE Byrne 1 DJ Fitzgerald 1 1 Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland; 2 Department of Epidemiology, Royal College of Surgeons in Ireland, Dublin, Ireland; 3 Surgen Ltd, Royal College of Surgeons in Ireland, Dublin, Ireland; 4 TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA Correspondence: D Shields, Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland. Tel: +353 1 4022381 Fax: +353 1 4022388 E-mail: dshieldsrcsi.ie ABSTRACT Genetic variants are risk factors for coronary disease, but their role in recur- rent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIb; platelet ligands -fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P- selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone ( 2 = 20.4, 10 df, P = 0.04). There was a significant interac- tion of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treat- ment-associated bleeding among coronary patients. The Pharmacogenomics Journal (2002) 2, 182–190. doi: 10.1038/ sj.tpj.6500100 Keywords: platelet; GPIIb/IIIa antagonist; ischemic heart disease; glycoprotein; polymorphism INTRODUCTION Genetic factors have a clear impact on the development of coronary artery dis- ease, as established by studies of twin disease concordance and by case-control or prospective studies of genetic polymorphism. 1,2 Given the complexity and overlap of atherosclerotic and thrombotic disease processes, it is not clear whether such factors continue to be associated with the recurrence risk of coron- ary events in patients with a history of unstable coronary syndromes. Currently, there is little or no clinical data regarding this important question. To address this issue, we analysed genetic variation in a population with Acute Coronary Syndromes, presenting with either unstable angina or myocardial infarction. These patients participated in the OPUS TIMI-16 clinical trial of oral glycoprotein GPIIb/IIIa antagonists, 3 and were followed prospectively to deter- mine the incidence of recurrent events and of bleeding complications. Our initial analyses of the PLA2 polymorphism 4 and the GPIb T-5C variant 5 in this popu- lation suggested that these individual factors appeared to modulate disease risk. However, no single common genetic variant confers a very large risk of coronary ischemia, so that a particular association is unlikely to be consistently found without very large sample sizes. 6 Secondly, underlying genetic risks conferred by a particular polymorphism are likely to vary from study to study according to differences in inclusion criteria, treatment, and diagnostic definition of events. Therefore, individual estimates of risk of recurrent disease conferred by particular