Fibrinogen

Abstract

Fibrinogen (coagulation factor I) is a major player in thrombus formation; it is cleaved by thrombin to form fibrin, which is the most abundant component of a blood clot.1 Beyond the role played in the coagulation and cardiovascular diseases (CVDs), fibrinogen is a proinflammatory factor in autoimmune and inflammatory diseases (such as rheumatoid arthritis, vasculitides, inflammatory bowel disease, multiple sclerosis, chronic obstructive pulmonary diseases, kidney disorders, and posttransplantation fibrosis)2 and in several types of cancer.3 Fibrinogen has been demonstrated to interfere with the immunoinflammatory responses through binding to inflammatory cells via ligand - receptor interactions that are different from those involved in the coagulation cascade.2 Fibrinogen also stimulates angioneogenesis in vitro and in vivo4 and acts as a mitogen for fibroblasts.5 Therefore, fibrinogen is a multifaceted molecule that plays various roles in several human diseases. Article see p 1310 Family studies have demonstrated a major genetic component of the variance of fibrinogen (44%),6 and increased levels of fibrinogen have proved to be a marker of risk for CVD. Therefore, the elucidation of the genetic architecture of plasma fibrinogen levels is becoming a major undertaking in translational research and an emerging clinical need. Fibrinogen is a large, soluble plasma hexameric glycoprotein (360 kDa) composed of pairs of 3 polypeptides (Aα, Bβ, and γγ) that are encoded by the FGA (MIM+134820), FGB (MIM+134850), and FGG (MIM+134830) genes, all mapping in a cluster on chromosome 4 (4q28). The FGA , FGB , and FGG genes are expressed almost exclusively in hepatocytes; the expression is regulated by both proximal promoters and enhancers and posttranscriptionally by miRNAs and is influenced by functional regulatory variants and acute-phase stimulation.7 The highly variable range of plasma fibrinogen levels in the general population (1.5–4 g/L) is the dynamic result of genetic …