Muckian Clare, Fitzgerald Anthony, O'Neill Anne, O'Byrne Anna, Fitzgerald Desmond J, Shields Denis C
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin.
Blood. 2002 Aug 15;100(4):1220-3. doi: 10.1182/blood-2002-01-0283.
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.
尽管血小板胶原受体中的常见基因变异会影响血小板活化和血栓形成，但胶原基因多态性对心血管疾病的影响尚不清楚。为评估这一点，我们对编码III型胶原α1链的COL3A1基因的一个高度多态性内含子串联重复序列进行了基因分型。这揭示了4个常见等位基因（COL3A1-1、-2、-3和-4）。所研究的2个群体如下：（1）对703例患有心肌梗死（MI）和不稳定型心绞痛的急性冠状动脉综合征（ACS）患者的横断面研究，以及（2）对来自口服糖蛋白IIb/IIIa拮抗剂orbofiban的OPUS（不稳定冠状动脉综合征患者的orbofiban）-TIMI-16试验的924例白种人患者的前瞻性研究。此外，我们研究了306名对照受试者和224例稳定型心绞痛患者。在病例对照人群中，COL3A1-4携带者对ACS具有保护作用（比值比[OR]=0.57，95%可信区间[CI]=0.35-0.91，P=0.02）和稳定型心绞痛（OR=0.35，95%CI=0.16-0.74，P=0.006）。在OPUS人群中，等位基因4再次显示出对复合终点（死亡、MI、中风、复发性缺血和紧急再次住院）具有保护作用（相对风险[RR]=0.41，95%CI=0.17-1.00）。COL3A1-1和-3变异与治疗之间存在显著相互作用。等位基因COL3A1-3与随机接受orbofiban治疗的患者发生复合终点的风险增加相关（RR=1.65，95%CI=1.07-2.55），但在接受安慰剂治疗的患者中似乎具有保护作用（RR=0.53，95%CI=0.28-0.98）。我们得出结论，COL3A1基因的变异，其产物是一种血管壁蛋白和血小板配体，可调节冠状动脉疾病风险，也可能调节对抗血栓治疗的反应。这是首次报道的细胞外基质成分多态性与心血管风险之间的关联。
