Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains

Abstract

Fibrinogen is a highly pleiotropic protein that is involved in the final step of the coagulation cascade, wound healing, inflammation, and angiogenesis. Heterozygous mutations in Aα, Bβ, or γ fibrinogen-chain genes (FGA, FGB, FGG) have been described as being responsible for fibrinogen deficiencies (hypofibrinogenemia, hypo-dysfibrinogenemia, dysfibrinogenemia) and for more rare conditions, such as fibrinogen storage disease and hereditary renal amyloidosis. Instead, biallelic mutations have been associated with afibrinogenemia/severe hypofibrinogenemia, i.e., the severest forms of fibrinogen deficiency, affecting approximately 1–2 cases per million people. However, the “true” prevalence for these conditions on a global scale is currently not available. Here, we defined the mutational burden of the FGA, FGB, and FGG genes, and estimated the prevalence of inherited fibrinogen disorders through a systematic analysis of exome/genome data from ~140,000 individuals belonging to the genome Aggregation Database. Our analysis showed that the world-wide prevalence for recessively-inherited fibrinogen deficiencies could be 10-fold higher than that reported so far (prevalence rates vary from 1 in 106 in East Asians to 24.5 in 106 in non-Finnish Europeans). The global prevalence for autosomal-dominant fibrinogen disorders was estimated to be ~11 in 1000 individuals, with heterozygous carriers present at a frequency varying from 3 every 1000 individuals in Finns, to 1–2 every 100 individuals among non-Finnish Europeans and Africans/African Americans. Our analysis also allowed for the identification of recurrent (i.e., FGG-p.Ala108Gly, FGG-Thr47Ile) or ethnic-specific mutations (e.g., FGB-p.Gly103Arg in Admixed Americans, FGG-p.Ser245Phe in Africans/African Americans).

Hereditary Hypofibrinogenemia with Hepatic Storage

“…Those individuals with plasma fibrinogen levels below 150 mg/dL are usually suffering from a form of acquired or inherited fibrinogen deficiency. Concerning congenital defects, these are traditionally subdivided in type I (quantitative) and type II (qualitative) deficiencies [ 16 , 17 , 18 , 19 , 20 ]. Type I deficiencies include afibrinogenemia and hypofibrinogenemia, which are respectively characterized by the lack or by reduced amounts of immunoreactive fibrinogen (<150 mg/dL), and lead to hemorrhagic manifestations that can be very mild (or even absent) or extremely severe [ 18 ].…”

“…As for type II deficiencies, the limit of 150 mg/dL is not so clear-cut: These defects comprise dysfibrinogenemia and hypo-dysfibrinogenemia, in which there are normal (or reduced) immunoreactive fibrinogen levels associated with disproportionately low functional activity values; patients who show these conditions are usually asymptomatic, more rarely they can suffer from bleeding events, thrombophilia, or both [ 17 , 18 ]. Type I and type II deficiencies are both determined by mutations affecting one of the fibrinogen genes: Mutations are present in the heterozygous condition in the case of hypofibrinogenemia and dys/hypodysfibrinogenemia, and in the homozygous/combined heterozygous condition for afibrinogenemia [ 19 , 20 , 21 ].…”

“…Concerning dysfibrinogenemia and hypofibrinogenemia, these coagulopathies have always been thought to be more frequent than afibrinogenemia [ 48 ], especially considering that many patients are asymptomatic/paucisymptomatic and can go easily undetected [ 47 ]. With this in mind, we recently exploited the unprecedented power of publicly available genomic databases to define the global mutational landscape of FGA , FGB , and FGG as well as to determine prevalence rates of inherited fibrinogen disorders [ 20 ]. To this aim, we analyzed exome/genome data from ~140,000 individuals from the Genome Aggregation Database (GnomAD) [ 49 ], and evidenced that the world-wide prevalence for afibrinogenemia is 10-fold higher than that previously reported, and that heterozygous individuals are present in the general population at a frequency of ~1 every 100 individuals.…”

Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype

“…According to the "Annual Global Survey 2017" of "World Federation Hemophilia" (WFH), which assessed information from 116 countries, fibrinogen deficiencies represent 9.3% of cases of rare bleeding disorders (RBD), which are slighty more prevalent in women when compared to men (1249 vs. 1026, i.e., 54.9% vs. 45.1% in 160 cases where gender was not specified, data from the 68 countries reporting details on CFD) [28]. The estimated prevalence of afibrinogenemia has long been considered to be approximately 1 in 1,000,000 [29,30], though a recent report indicates that the world-wide prevalence for recessively-inherited fibrinogen deficiencies could be up to 10-fold higher than that reported so far [31]. Generally speaking, in populations with frequent consanguineous marriages, the prevalence of afibrinogenemia, and also the occurence of other disorders of hemostasis with autosomal recessive inheritance, is increased.…”

Research of the association of polymorphic variants of the FGB gene (-455G/A, C148T) with average level of fibrinogen in women with reproductive disorders

“…Серед найбільш досліджених поліморфних варіантів гена фібріногену (FGB), розглядають -455g/A (rs1800790) орИГІнАЛьнІ ДоСЛІДження та С148T (rs1800787). Поряд з фізіологічними причинами та екзогенними чинниками патологічної зміни рівня фібриногену не менш важливою є генетична складова -особливості поліморфних варіантів гена FGB [6,7]. Дослідження останніх років показали асоціацію поліморфних варіантів гена з розладами репродуктивної функції у жінок, з порушеннями системи зсідання крові, що супроводжуються змінами рівня фібриногену в плазмі крові [5,9].…”