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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-01-0283.
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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1220-1223
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Genetic variability in the extracellular matrix as a determinant
of cardiovascular risk: association of type III collagen COL3A1
polymorphisms with coronary artery disease
Clare Muckian,
Anthony Fitzgerald,
Anne O'Neill,
Anna O'Byrne,
Desmond J. Fitzgerald, and
Denis C. Shields
From the Department of Clinical Pharmacology, Surgen
Ltd, Department of Epidemiology, and Institute of Biopharmaceutical
Sciences, Royal College of Surgeons in Ireland, Dublin.
Although common genetic variants in platelet collagen receptors
influence platelet activation and thrombosis, the impact of polymorphisms in collagen genes on cardiovascular disease is unknown. To evaluate this, we genotyped a highly polymorphic intronic tandem repeat of the COL3A1 gene, encoding collagen type III, alpha 1. This
revealed 4 common alleles (COL3A1-1, -2, -3, and -4). The 2 populations
studied were as follows: (1) a cross-sectional study of 703 acute
coronary syndrome (ACS) patients with myocardial infarction (MI) and
unstable angina, and (2) a prospective study of 924 Caucasian patients
from the OPUS (Orbofiban in Patients with Unstable coronary
Syndromes)-TIMI-16 trial of the oral GPIIb/IIIa antagonist
orbofiban. In addition, we studied 306 control subjects and 224 patients with stable angina. In the case-control population, COL3A1-4
carriers were protected against ACS (odds ratio [OR] = 0.57, 95% CI = 0.35-0.91, P = .02) and stable
angina (OR = 0.35, 95% CI = 0.16-0.74, P = .006). In the OPUS population, allele 4 again appeared protective
against composite end points (death, MI, stroke, recurrent ischemia,
and urgent rehospitalization) (relative risk [RR] = 0.41, 95%
CI = 0.17-1.00). There were significant interactions between
COL3A1-1 and -3 variants and treatment. Allele COL3A1-3 was
associated with an increased risk of the composite end point (RR = 1.65, 95% CI = 1.07-2.55) in patients randomized to orbofiban,
but appeared protective in placebo patients (RR = 0.53, 95%
CI = 0.28-0.98). We conclude that variants in the COL3A1 gene, the
product of which is a vessel-wall protein and platelet ligand, modulate
the risk of coronary artery disease and could also modulate the
response to antithrombotic therapy. This is the first reported
association between polymorphisms of extracellular matrix components
and cardiovascular risk.
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