Grant P J
Unit of Molecular Vascular Medicine, Research School of Medicine, Leeds General Infirmary, University of Leeds, UK.
Prostaglandins Leukot Essent Fatty Acids. 1997 Oct;57(4-5):473-7. doi: 10.1016/s0952-3278(97)90431-2.
Circulating concentrations of plasminogen activator inhibitor-1 (PAI-1), factor VII and fibrinogen have all been related to vascular risk in large prospective studies. Evidence indicates that all three proteins are increased in the presence of insulin resistance and factor VII and PAI-1 correlate strongly with circulating levels of insulin and lipids. Polymorphisms of the genes coding for PAI-1, factor VII and fibrinogen have been investigated in relation to gene environment interactions and vascular risk. Three polymorphisms have been described in the PAI-1 gene, a 3' Hind III RFLP, an intronic CA repeat and a 4G/5G insertion deletion 675 bp 5' of the start site of transcription. The 4G/5G site has been shown to be triglyceride responsive and higher levels of PAI-1 have been reported in subjects homozygous for the 4G allele. Three out of four case control studies have related possession of the 4G/4G genotype to an increased risk of coronary artery disease and our studies in patients undergoing coronary angiography indicate that this is due to increased myocardial infarction rather than atheroma. We have investigated 600 subjects with cerebrovascular disease and found no relationship to the 4G/5G polymorphism. Two major polymorphisms have been identified in the factor VII gene, a promoter decanucleotide repeat and a G-A substitution at codon 353. Evidence indicates that the latter mutation affects factor VII levels by interfering with intracellular processing of the molecule and subjects homozygous for the adenine genotype (M2/M2) have levels of factor VII 20-30% lower than M1/M2 or M1/M1 carriers. Two studies have, however, failed to show a relationship between genotype and cardiovascular disease and we have found no association with cerebrovascular disease. A number of mutations have been described in the genes coding for the alpha, beta and gamma chains of fibrinogen. These polymorphisms are reported to be responsible for from 3% to 50% of circulating levels in various studies and there is evidence that the effect of smoking is genotype specific. In the ECTIM study the beta Bcl I polymorphism has been related to cardiovascular disease and work from our unit has related the Bbeta448 polymorphism to the presence of cerebrovascular disease in women. Further prospective studies are warranted to evaluate the role of these genes in disease.
在大型前瞻性研究中，纤溶酶原激活物抑制剂-1（PAI-1）、凝血因子VII和纤维蛋白原的循环浓度均与血管风险相关。有证据表明，在存在胰岛素抵抗的情况下，这三种蛋白质的水平都会升高，并且凝血因子VII和PAI-1与胰岛素及血脂的循环水平密切相关。关于PAI-1、凝血因子VII和纤维蛋白原编码基因的多态性，已针对基因-环境相互作用及血管风险进行了研究。PAI-1基因已发现三种多态性，一种是3' Hind III限制性片段长度多态性（RFLP），一种是内含子CA重复序列，还有一种是转录起始位点5'端675 bp处的4G/5G插入缺失多态性。已证明4G/5G位点对甘油三酯有反应，并且在4G等位基因纯合子个体中，PAI-1水平更高。在四项病例对照研究中，有三项研究表明携带4G/4G基因型会增加患冠状动脉疾病的风险，而我们对接受冠状动脉造影的患者进行的研究表明，这是由于心肌梗死增加，而非动脉粥样硬化。我们对600名脑血管疾病患者进行了研究，发现其与4G/5G多态性无关。在凝血因子VII基因中已鉴定出两种主要多态性，一种是启动子十核苷酸重复序列，另一种是密码子353处的G-A替换。有证据表明，后一种突变通过干扰该分子的细胞内加工过程来影响凝血因子VII水平，腺嘌呤基因型（M2/M2）的纯合子个体的凝血因子VII水平比M1/M2或M1/M1携带者低20%-30%。然而，有两项研究未能表明基因型与心血管疾病之间存在关联，并且我们也未发现其与脑血管疾病有关联。在纤维蛋白原α、β和γ链编码基因中已发现多种突变。在各项研究中，这些多态性被认为可解释3%至50%的循环水平差异，并且有证据表明吸烟的影响具有基因型特异性。在欧洲颈动脉疾病前瞻性研究（ECTIM）中，β Bcl I多态性与心血管疾病有关，而我们单位的研究表明，Bbeta448多态性与女性脑血管疾病的发生有关。有必要进行进一步的前瞻性研究，以评估这些基因在疾病中的作用。
