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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-01-0283.
Submitted January 31, 2002
Accepted April 9, 2002
Genetic Variability In The Extracellular Matrix As A Determinant Of Cardiovascular Risk: Association Of Type III Collagen COL3A1 Polymorphisms With Coronary Artery Disease
Denis C Shields*, Clare Muckian, Anthony Fitzgerald, Anne O'Neill, Anna O'Byrne, and Desmond J Fitzgerald
Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland; Epidemiology, Royal College of Surgeons in Ireland, Dublin, Ireland
Surgen Ltd., Dublin, Ireland
Epidemiology, Royal College of Surgeons in Ireland, Dublin, Ireland
Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland
* Corresponding author; email: dshields{at}rcsi.ie.
While 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 four common alleles (COL3A1-1,-2, -3 and -4). The 2 populations studied were: (1) a cross-sectional study of 703 Acute Coronary Syndrome (ACS) patients with myocardial infarction and unstable angina and (2) a prospective study of 924 Caucasian patients from the OPUS 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 (OR=0.57, CI=0.35-0.91, p=0.02), and stable angina (OR=0.35, 0.16-0.74, p=0.006). In the OPUS population, allele 4 again appeared protective of composite endpoints (death, MI, stroke, recurrent ischaemia, and urgent rehospitalisation) (RR=0.41, 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 composite endpoint (RR=1.65, CI=1.07-2.55) in patients randomised to orbofiban, but appeared protective in placebo (RR = 0.53, 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 anti-thrombotic therapy. This is the first reported association between polymorphisms of extracellular matrix components and cardiovascular risk.
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