β-纤维蛋白原基因-455G/A多态性对冠心病患者红细胞聚集的影响

Contribution of the -455G/A polymorphism at the beta-fibrinogen gene to erythrocyte aggregation in patients with coronary artery disease.

作者信息

Weng X, Cloutier G, Genest J

机构信息

Laboratory of Biomedical Engineering, Clinical Research Institute of Montréal, Québec, Canada.

出版信息

Thromb Haemost. 1999 Nov;82(5):1406-11.

PMID:10595628

Abstract

BACKGROUND

A high level of red blood cell (RBC) aggregation has been consistently found in patients with coronary artery disease (CAD) in case-control studies. Plasma fibrinogen has been shown to promote RBC aggregability. The purpose of this study was to investigate the influence of the genetic variability of the beta-fibrinogen gene on RBC aggregation in patients with CAD.

METHODS AND RESULTS

The genotype of the beta-fibrinogen gene locus was determined by polymerase chain reaction using the restriction enzyme HaeIII for a G to A substitution at position -455 upstream from the transcriptional start site in 135 French Canadians with premature CAD (age: 51+/-7 years). Indices measuring the RBC aggregation kinetics (S10) and shear resistance of the aggregates (gammaS) were obtained by laser reflectometry. Patients were separated into groups by using the medians of S10 and gammaS. Using chi2 analyses, the distribution of the -455GG, -455GA, and -455AA genotypes in the groups with high levels of S10 (0.43, 0.49, and 0.08) and gammaS (0.45, 0.49, and 0.06) were found to be significantly distinct from those in the groups with low levels of S10 (0.67, 0.27, and 0.06; p<0.05) and gammaS (0.70, 0.23, and 0.07; p<0.01). High levels of RBC aggregation were closely associated with the rare -455A allele. Multivariate linear regression analyses showed that S10 was positively correlated with the linear combination of the fibrinogen concentration, age, and the -455G/A genotype (adjusted r = 0.63, p<0.0001). Fibrinogen and age were positive determinants, and HDL-cholesterol was a negative predictor of gammaS (adjusted r = 0.51, p<0.0001).

CONCLUSION

These findings support the hypothesis that RBC hyperaggregation in premature CAD may be associated with the beta-fibrinogen -455G/A polymorphism. This association may be explained by a change in the concentration and/or the functional properties of the fibrinogen protein.

摘要

背景

在病例对照研究中，冠状动脉疾病（CAD）患者一直被发现存在高水平的红细胞（RBC）聚集。血浆纤维蛋白原已被证明可促进RBC聚集性。本研究的目的是调查β-纤维蛋白原基因的遗传变异性对CAD患者RBC聚集的影响。

方法与结果

采用聚合酶链反应，使用限制性内切酶HaeIII确定135例患有早发性CAD的法裔加拿大人（年龄：51±7岁）转录起始位点上游-455位由G到A替换的β-纤维蛋白原基因位点的基因型。通过激光反射法获得测量RBC聚集动力学（S10）和聚集体抗剪切性（γS）的指标。根据S10和γS的中位数将患者分组。使用卡方分析，发现S10高水平组（0.43、0.49和0.08）和γS高水平组（0.45、0.49和0.06）中-455GG、-455GA和-455AA基因型的分布与S10低水平组（0.67、0.27和0.06；p<0.05）和γS低水平组（0.70、0.23和0.07；p<0.01）中的分布有显著差异。高水平的RBC聚集与罕见的-455A等位基因密切相关。多变量线性回归分析表明，S10与纤维蛋白原浓度、年龄和-455G/A基因型的线性组合呈正相关（调整后r = 0.63，p<0.0001）。纤维蛋白原和年龄是γS的正向决定因素，而高密度脂蛋白胆固醇是γS的负向预测因子（调整后r = 0.51，p<0.0001）。