Fibrinogen is a 340 KDa plasma glycoprotein synthesized and secreted mainly by liver cells. As the coagulation factor with the highest content, it is not only an crucial component of the coagulation system but also an important acute reactive protein, participate in a variety of physiological and pathological processes.[6,36] The structural and functional abnormalities of fibrinogen caused by single nucleotide polymorphisms (SNPs) in the coding region of fibrinogen gene are associated with a variety of clinical diseases.[9,37–39]
The 3 polypeptide chains of fibrinogen are encoded by 3 independent genes: fibrinogen alpha (FGA), fibrinogen beta (FGB), and fibrinogen gamma (FGG), all of which are located at chromosome 4 (4q23 ∼ q32). The FGB gene contains 8 exons with a total length of 1476 kb and is responsible for encoding the β chain which is composed of 461 amino acid residues.[6,7,40]
The synthesis of fibrinogen β chain is the dominating speed limiting step in fibrinogen production, so the FGB gene is considered to be associated with changes in plasma fibrinogen levels. At present, more than 10 kinds of SNPs of FGB gene have been found, among which 2 SNPs, -455G>A and -148C>T, have been studied most extensively and intensively. -455G>A is the earliest and most studied locus of FGB gene polymorphisms. A subsequent case-control study confirmed this inference and suggested that A-allele of -455G>A mutation was significantly associated with elevated fibrinogen levels. Most subsequent studies reached similar conclusions, suggesting that the A allele was positively related to the increase of plasma fibrinogen concentration. Comprehensive assessment of all common gene polymorphisms involving FGA, FGB, and FGG genes suggested that approximately 2% of plasma fibrinogen levels are affected by inherent fibrinogen gene polymorphisms. Another large-sample study also demonstrated that the FGB -455G>A polymorphism had the strongest influence on increasing fibrinogen levels, and this polymorphism impact on approximately 1% of fibrinogen level variation. In addition, the FGB -455G>A mutation has different effects on increasing fibrinogen in different ethnic groups. Study revealed that FGB -455G>A had the most intense correlation with elevated fibrinogen levels among the European-American, while no similar significant correlation was observed among Asian Americans. Cook et al tested and compared the -455G>A and -148C>T polymorphisms of white, black, and Indian people living in London, and found that there were differences in allele frequency and linkage imbalance among the 3 ethnic groups, which caused changes in plasma fibrinogen level, suggesting that genetic polymorphism and disease susceptibility were different due to diverse ethnicities. The relationship between these 2 SNPs of FGB gene with the susceptibility of arteriosclerotic diseases and arterial thrombotic diseases has been extensively explored. Maat et al revealed that the progression of coronary atherosclerosis was rapid in patients with genotype AA, which was speculated to lead to the progression of coronary artery disease by increasing the plasma fibrinogen level. Schmidt et al conducted -148C> T polymorphism analysis on 399 middle-aged and elderly individuals and demonstrated that TT genotype was more advanced than CT and CC genotype in carotid atherosclerosis, suggesting that TT genotype was a genetic risk factor for carotid atherosclerosis in middle-aged and elderly people. However, some studies suggested that the -148C> T polymorphism has no positive significance, a large-scale prospective study showed that -148C> T mutation does not increase the risk of cardiovascular events. Recently, a number of meta-analyses summarized the data of previous studies and concluded that FGB -455G>A and -148C>T polymorphisms were significantly correlated with arterial thrombotic disorders such as acute myocardial infarction, acute coronary syndrome, and ischemic stroke, pooled results indicated these 2 SNPs significantly increase the risk of these diseases.[17,45,46]
The authors sincerely thank all the colleagues working in the Department of Vascular Surgery of the First People's Hospital of Lianyungang.
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