Fibrinogen Gamma Chain Amount
Introduction
Background and Biological Basis
Fibrinogen is a crucial glycoprotein that plays a central role in the body's hemostatic system, primarily in blood coagulation and wound healing. Beyond its role in clotting, fibrinogen is also involved in thrombosis, platelet aggregation, and inflammatory responses. It contributes to various cellular processes, including cell adhesion, vasoconstriction, and chemotactic activity. [1] This essential protein circulates in the blood plasma and is primarily synthesized in the liver. Fibrinogen is a hexamer, meaning it is composed of three pairs of non-identical polypeptide chains: alpha (FGA), beta (FGB), and gamma (FGG). [1] The FGG gene provides the instructions for producing the fibrinogen gamma chain, an integral component required for the proper assembly and function of the complete fibrinogen molecule. When activated by the enzyme thrombin, fibrinogen is converted into fibrin, which then polymerizes to form a stable clot, a critical step in stopping bleeding.
Clinical Relevance
The amount of circulating fibrinogen, and by extension its constituent gamma chain, holds significant clinical importance. Elevated plasma fibrinogen levels are a recognized risk factor for several major cardiovascular diseases, including myocardial infarction, stroke, and vascular mortality. [1] Therefore, variations in the amount of the fibrinogen gamma chain can influence an individual's susceptibility to these thrombotic and inflammatory conditions. Studies have demonstrated that fibrinogen levels have a substantial heritable component, with estimates from twin and family studies suggesting heritability between 25% and 51%. [1] Genetic research, including genome-wide association studies, has identified various genetic loci, particularly within the fibrinogen gene cluster (which encompasses FGA, FGB, and FGG), that significantly influence circulating fibrinogen levels. [1] While these genetic variants contribute to the observed variability, they typically explain a relatively small fraction of the overall variance in plasma fibrinogen [2] indicating a complex interplay with other genetic and environmental factors.
Social Importance
Understanding the genetic determinants of fibrinogen gamma chain amount provides valuable insights into the complex etiology of cardiovascular diseases and chronic inflammatory conditions. Identifying specific genetic variants that influence fibrinogen levels can contribute to the development of more refined risk prediction models for thrombotic events and inflammatory disorders. This knowledge also supports advancements in personalized medicine, where an individual's genetic profile could potentially guide tailored preventive strategies or targeted therapeutic interventions. As a key component of a widely recognized biomarker, the study of the fibrinogen gamma chain amount highlights the intricate link between an individual's genetic makeup and their predisposition to common, high-impact diseases, ultimately holding potential for enhancing public health outcomes through improved diagnostics and more effective prevention strategies.
Methodological and Statistical Constraints
The studies on circulating fibrinogen levels, while robust in their meta-analysis approach, encountered several methodological and statistical limitations. Different genotyping platforms were employed across the six initial cohorts, necessitating imputation of approximately 2.5 million SNPs to a HapMap CEU reference panel, which, while accurate, inherently yields less power than direct genotyping. [2] Furthermore, replication efforts sometimes relied on proxy SNPs, such as using rs6056 for rs1800789 with an r² of 0.95, which introduces a slight reduction in direct comparability and could potentially mask subtle differences in true association. [2] The genetic variants identified collectively explained less than 2% of the overall variance in plasma fibrinogen in most studies, indicating that these findings represent only a small fraction of the total genetic influence and suggest that individual effect sizes may be relatively modest. [2]
Differences in study design and statistical modeling also present limitations. While most studies used linear regression adjusted for age, sex, and recruitment site, the Framingham Heart Study (FHS) employed a linear mixed-effects model to account for family structure and within-family correlations. [2] The FHS cohort, despite its detailed phenotyping, was noted to have a relatively small sample size for a GWAS, potentially limiting its power to detect smaller genetic effects. [3] Additionally, to mitigate the multiple testing problem inherent in GWAS, some analyses were performed as sex-pooled, which might obscure potential sex-specific genetic effects on fibrinogen levels. [3]
Generalizability and Phenotypic Measurement Heterogeneity
A significant limitation concerning the generalizability of these findings is the predominant ancestry of the study populations. Participants in the Framingham Heart Study were exclusively Caucasian, and the Women's Genome Health Study (WGHS) focused on 17,686 Caucasian women after excluding individuals who did not cluster with other Caucasians. [3] This homogeneity means that the identified genetic associations may not be directly transferable or have similar effect sizes in other racial or ethnic groups, highlighting a critical gap in understanding the genetic architecture of fibrinogen levels across diverse populations. The imputation reference panel, HapMap CEU samples, further underscores this focus on European ancestry. [2]
Furthermore, the measurement of circulating fibrinogen levels was not fully standardized across all participating cohorts. While most studies utilized the Clauss method or another clotting assay, one cohort derived levels from the clotting curve of a prothrombin time assay, and another used nephelometry. [2] Although the effect estimates for the top SNPs were reported to be comparable despite these methodological differences, the lack of a universal standard introduces a degree of phenotypic heterogeneity that could subtly influence meta-analysis results and cross-study comparisons. Consistency in measurement techniques would enhance the robustness and direct interpretability of combined findings.
Unexplained Heritability and Complex Genetic Architecture
Despite the identification of novel genetic loci associated with circulating fibrinogen levels, a substantial portion of the heritable variation remains unexplained. The identified genetic variants collectively account for less than 2% of the overall variance in plasma fibrinogen, indicating a significant "missing heritability" gap. [2] This suggests that the genetic architecture underlying fibrinogen levels is far more complex than currently understood, involving factors not fully captured by the common variants assessed in these GWAS.
The remaining variation in fibrinogen levels is likely attributable to other genetic factors, such as rare variants, common variants with smaller individual effects that did not reach genome-wide significance, or complex interactions between multiple genetic variants. [2] Moreover, the interplay between genetic predispositions and environmental factors, including lifestyle choices like smoking, body mass index, hormone therapy, and menopausal status, is crucial. [1] While some studies adjusted for these major environmental determinants, the specific mechanisms of gene-environment interaction and their cumulative impact on fibrinogen levels represent considerable knowledge gaps that warrant further investigation beyond the scope of current additive genetic models. [2]
Variants
Fibrinogen, a crucial protein in blood coagulation, is a complex molecule composed of three distinct polypeptide chains: alpha, beta, and gamma. These chains are encoded by the _FGA_, _FGB_, and _FGG_ genes, respectively, which are clustered together on chromosome 4. Variants within any of these genes, particularly in _FGB_, can significantly influence the overall production, structure, and circulating levels of fibrinogen, thereby affecting the availability and proper assembly of all constituent chains, including the fibrinogen gamma chain. Such genetic variations contribute to individual differences in blood clot formation and susceptibility to related health conditions.
One notable genetic variant is *rs2227426*, located within the _FGB_ gene, which encodes the beta chain of fibrinogen. This variant is commonly associated with variations in plasma fibrinogen levels, with specific alleles often leading to higher concentrations of the protein in the bloodstream. While *rs2227426* directly impacts the _FGB_ gene, its influence on beta chain production or stability can indirectly alter the overall synthesis and assembly of the complete fibrinogen hexamer, consequently affecting the available amount of the fibrinogen gamma chain. Elevated fibrinogen levels, potentially influenced by this variant, are a recognized risk factor for thrombotic events, including heart attack and stroke, highlighting its importance in cardiovascular health.
Another significant variant, *rs10514670*, has also been linked to fibrinogen levels in large population studies, such as the Framingham Heart Study. [3] This variant is located within the broader fibrinogen gene cluster on chromosome 4, and its presence can modulate the transcriptional activity or splicing efficiency of one or more fibrinogen genes, leading to altered circulating fibrinogen concentrations. Like *rs2227426*, the influence of *rs10514670* on total fibrinogen amount ultimately affects the available pool of all fibrinogen chains, including the gamma chain, playing a role in an individual's hemostatic balance and predisposition to various cardiovascular diseases. [3]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs2227426 | FGB | blood sedimentation trait d-dimer measurement circulating fibrinogen levels fibrinogen gamma chain amount docosahexaenoic acid measurement |
Defining Fibrinogen and its Genetic Components
Fibrinogen, also known as coagulation factor I, is a soluble plasma glycoprotein that plays a critical role in hemostasis and inflammation. It is a complex hexameric protein composed of three distinct polypeptide chains: alpha (FGA), beta (FGB), and gamma (FGG), which are encoded by genes located within a specific fibrinogen gene cluster on chromosome 4q32.1. [1] The "fibrinogen gamma chain amount" refers to the contribution of the FGG gene and its genetic variants to the overall circulating levels of fibrinogen in the bloodstream. While total plasma fibrinogen levels are a well-established biomarker, the specific amount or expression of the gamma chain, influenced by its genetic locus, is integral to understanding the protein's structure and function. High fibrinogen levels are recognized as an inflammatory marker and a predictor of cardiovascular diseases. [1]
Quantification and Research Criteria for Fibrinogen Levels
The operational definition of fibrinogen levels in research studies typically involves its quantitative measurement in plasma. Common measurement approaches include the Clauss method, which assesses fibrinogen concentration based on the clotting curve of a prothrombin time assay, and other clotting assays. [2] Some studies also employ nephelometry for quantification. [2] These methods yield results in units such as mg/dL or g/L, with median levels in study cohorts reported around 350.6 mg/dL. [1] For genetic association studies, these plasma fibrinogen levels are often adjusted for major environmental and demographic determinants, including age, smoking status, body mass index, hormone therapy, menopausal status, and sex, to isolate genetic effects. [1]
Genetic Nomenclature and Classification of Fibrinogen-Associated Loci
Standardized nomenclature is crucial for identifying the genetic determinants influencing fibrinogen levels. The genes encoding the fibrinogen chains are designated FGA (alpha chain), FGB (beta chain), and FGG (gamma chain). [1] Genetic variants, primarily single nucleotide polymorphisms (SNPs), within these genes and their surrounding regions are often investigated through genome-wide association studies (GWAS) to identify loci associated with circulating fibrinogen levels. [1] For instance, the fibrinogen gene cluster on chromosome 4q32.1 is a well-known region containing multiple SNPs significantly associated with fibrinogen levels, indicating its central role in the genetic regulation of fibrinogen synthesis. [1] These genetic classifications help categorize individuals based on their genotype and predict potential variations in their fibrinogen production or circulating amounts.
Genetic Predisposition
Genome-wide association studies (GWAS) have been instrumental in identifying specific genetic loci associated with variations in circulating fibrinogen levels, which inherently includes the fibrinogen gamma chain amount. These studies, conducted in large population-based cohorts, reveal that inherited genetic variants contribute significantly to an individual's baseline fibrinogen levels, indicating a substantial polygenic component to this trait. [2] Such genetic influences mean that a combination of many genes, each with a small effect, collectively determines an individual's susceptibility to higher or lower fibrinogen gamma chain amounts.
The identified genetic variants likely exert their influence by modulating the expression or function of genes involved in the synthesis, assembly, or regulation of fibrinogen proteins. These genetic differences can affect the efficiency of protein production or stability, thereby directly impacting the circulating amount of the fibrinogen gamma chain.
Systemic Health and Inflammation
The amount of fibrinogen gamma chain is closely linked to various physiological states and comorbidities, particularly those involving systemic inflammation. Research, including studies like the Framingham Heart Study, has consistently identified fibrinogen as a significant risk factor for cardiovascular diseases such as coronary heart disease, stroke, and myocardial infarction. [4] This strong association implies that underlying conditions or inflammatory processes associated with these diseases can directly influence circulating fibrinogen levels, and thus the amount of its gamma chain.
As an acute-phase reactant, fibrinogen levels typically rise in response to inflammatory stimuli, infections, or tissue injury. Conditions like atherosclerosis, which underlies many cardiovascular diseases, involve chronic low-grade inflammation, leading to sustained elevation of fibrinogen. The increased production of fibrinogen, including its gamma chain, is part of the body's generalized inflammatory response, contributing to its role in hemostasis and potentially exacerbating disease progression.
Age-Related Dynamics
The amount of fibrinogen gamma chain can also be influenced by age-related physiological dynamics. Population-based studies frequently account for age as a significant demographic variable when analyzing hemostatic factors and hematological phenotypes. [2] While the precise mechanisms are complex, the aging process can lead to subtle yet cumulative changes in various bodily systems, including those involved in protein synthesis and degradation, as well as chronic inflammatory states.
These age-related changes can contribute to a gradual alteration in circulating fibrinogen levels over an individual's lifespan. For instance, the accumulation of inflammatory markers or changes in metabolic pathways associated with aging may contribute to modifications in the production or clearance of fibrinogen and its constituent chains, thereby influencing the observed amount of fibrinogen gamma chain in older populations.
Fibrinogen Structure and Its Role in Coagulation
Fibrinogen is a large, soluble plasma glycoprotein crucial for the formation of blood clots, a process central to hemostasis. It exists as a hexamer, composed of three pairs of non-identical polypeptide chains: Aα, Bβ, and γ (gamma) chains, which are linked together by disulfide bonds. The gamma chain, encoded by the FGG gene, is an integral component of this complex structure, playing a key role in mediating the molecular interactions necessary for the assembly of a stable fibrin clot. Upon activation by the enzyme thrombin, fibrinogen undergoes proteolytic cleavage, converting it into insoluble fibrin monomers that then spontaneously polymerize to form a mesh-like clot, effectively sealing vascular injuries.
Genetic Regulation of Fibrinogen Gamma Chain Levels
The amount of fibrinogen gamma chain circulating in the bloodstream is significantly influenced by genetic factors, with its synthesis primarily occurring within the liver. Genetic mechanisms, including specific gene functions and regulatory elements, dictate the expression levels of the FGG gene, which codes for the gamma chain. Genome-wide association studies have identified genetic loci associated with variations in circulating fibrinogen levels, indicating a substantial genetic component to its regulation. [3] These genetic variants can impact gene expression patterns, thereby influencing the circulating concentration of the fibrinogen gamma chain and, consequently, overall fibrinogen levels.
Fibrinogen's Role in Hemostasis and Cardiovascular Health
Fibrinogen is a central component of the hemostatic system, functioning to prevent excessive bleeding through its essential role in blood clot formation. Disruptions in the normal levels of fibrinogen, including alterations in the amount of its gamma chain, can impact the efficiency and stability of this crucial physiological process. Elevated circulating fibrinogen levels are recognized as an independent risk factor for various cardiovascular diseases, including stroke and myocardial infarction. [4] This highlights the delicate balance required for fibrinogen function, where both insufficient and excessive amounts can lead to adverse health outcomes and contribute to disease pathophysiology.
Systemic Control and Clinical Implications of Fibrinogen Levels
The liver is the primary organ responsible for the synthesis of fibrinogen, where its production is tightly regulated by a complex interplay of molecular and cellular pathways. Systemic factors, such as inflammatory responses, hormonal signals, and metabolic processes, can significantly influence the regulatory networks that control FGG gene expression and subsequent protein synthesis. The circulating amount of fibrinogen, and specifically its gamma chain, serves as a crucial biomarker in clinical settings, providing insights into an individual's hemostatic potential and their susceptibility to thrombotic events. Understanding the factors that modulate fibrinogen gamma chain levels is thus essential for both predicting and managing cardiovascular risk.
Genetic Regulation of Fibrinogen Biosynthesis
The amount of fibrinogen gamma chain, a crucial component of the fibrinogen protein, is primarily influenced by genetic factors, with significant heritability estimated between 25-51%. [1] Variants within the fibrinogen gene cluster, specifically encompassing FGA, FGB, and FGG genes on chromosome 4q32.1, are major determinants of circulating fibrinogen levels. [1] For instance, SNPs like rs6056 and rs1800788 within this cluster contribute substantially to the genetic variance of fibrinogen. [1] Beyond the core fibrinogen genes, transcription factors also play a critical role; IRF1 (interferon regulatory factor 1), located on chromosome 5, acts as a transcription activator for interferon-induced genes and is implicated in the regulation of acute phase proteins, thereby influencing fibrinogen levels. [2]
Inflammatory Signaling and Acute Phase Response
Fibrinogen is recognized as an acute phase reactant, and its levels are closely modulated by inflammatory signaling pathways. The interleukin 6 receptor (IL6R) locus on chromosome 1q21.3, marked by SNPs such as rs8192284, significantly contributes to the genetic variance of fibrinogen. [1] Activation of IL6R initiates intracellular signaling cascades that lead to the transcriptional upregulation of acute phase proteins, including fibrinogen, as part of the body's inflammatory response. [1] Furthermore, other inflammation-related genes, such as NLRP3 (NLR family, pyrin domain containing 3 isoforms) and CD300LF (immunoglobulin superfamily, member 13), have been identified as novel loci associated with fibrinogen levels, highlighting the intricate network of inflammatory mediators that converge to regulate its production . [1], [2]
Metabolic and Transport Pathway Interactions
Metabolic pathways also contribute to the regulation of fibrinogen levels, often through indirect mechanisms influencing cellular homeostasis or substrate availability. The CPS1 (carbamoyl phosphate synthetase I) gene on chromosome 2q34, involved in the urea cycle, shows an association with fibrinogen levels, suggesting a potential link between nitrogen metabolism and fibrinogen synthesis or clearance. [1] Another metabolic gene, PCCB (propionyl coenzyme A carboxylase), has also been identified in association with fibrinogen levels, indicating a broader involvement of metabolic regulation. [2] Additionally, solute carrier family 22 members, SLC22A5 and SLC22A4, located on chromosome 5q31.1, are involved in the transport of organic cations, which could influence the cellular environment or the availability of precursors for fibrinogen production or its post-translational modifications. [1]
Systems-Level Integration and Disease Pathophysiology
The regulation of fibrinogen gamma chain amount is a complex process involving extensive pathway crosstalk and network interactions, which ultimately contribute to its multi-functional role in various biological processes. Fibrinogen is integral to wound-healing, thrombosis, platelet aggregation, and inflammation, with additional roles in cell adhesion, vasoconstriction, and chemotactic activity. [1] Dysregulation in any of the contributing genetic, inflammatory, or metabolic pathways can lead to altered fibrinogen levels, which are consistently associated with an increased risk of cardiovascular diseases like myocardial infarction and stroke . [1], [2] The identification of novel loci related to common chronic inflammatory diseases, such as Crohn's disease and psoriasis, as genetic determinants of fibrinogen levels underscores the emergent properties of these integrated biological networks in health and disease, offering potential therapeutic targets for conditions linked to elevated fibrinogen . [1], [2]
Clinical Relevance
The fibrinogen gamma chain, encoded by the FGG gene, is a crucial component of the fibrinogen molecule, a circulating glycoprotein central to hemostasis and inflammation. While genetic determinants of fibrinogen levels have historically focused on the FGA, FGB, and FGG genes, recent genome-wide association studies (GWAS) have expanded our understanding by identifying novel genetic loci that influence overall circulating fibrinogen levels. [1] These studies provide insights into the complex genetic architecture underlying fibrinogen levels and their broad clinical implications, particularly concerning cardiovascular disease and inflammatory conditions.
Genetic Influences and Inflammatory Pathways
Variations in genes encoding fibrinogen chains, such as the FGB gene, have been consistently associated with stable and acute phase fibrinogen levels, as well as vascular events. [1] Beyond the classic fibrinogen gene cluster, GWAS have revealed additional loci influencing fibrinogen levels, including those near IRF1, PCCB, and NLRP3. [2] These genes are implicated in inflammatory pathways, suggesting that genetic predispositions to altered fibrinogen levels are intertwined with broader inflammatory responses. Understanding these genetic determinants helps elucidate the biological mechanisms linking fibrinogen to various comorbidities and offers potential targets for further research into inflammatory conditions and cardiovascular disease. [2]
Cardiovascular Risk and Prognostic Value
Elevated circulating fibrinogen levels are a well-established risk factor for major cardiovascular events, including myocardial infarction, stroke, and vascular mortality. [1] The prognostic value of fibrinogen extends to predicting outcomes and disease progression in coronary heart disease. [2] Fibrinogen's multifaceted roles in coagulation, platelet aggregation, and blood viscosity contribute to its strong association with cardiovascular risk. [2] Therefore, variations affecting fibrinogen levels, including those related to the gamma chain or other genetic determinants, can serve as indicators of an individual's long-term cardiovascular health and potential susceptibility to thrombotic events.
Personalized Risk Stratification and Treatment Approaches
Genetic insights into fibrinogen levels offer a foundation for personalized medicine by improving risk stratification for cardiovascular disease. For instance, a combined risk allele score, reflecting the accumulation of multiple genetic variants, has been shown to correlate with an increase in overall mean fibrinogen levels. [2] Identifying individuals with such genetic profiles could help pinpoint those at higher risk, allowing for earlier preventive strategies or more intensive monitoring. While genetic variants currently explain a relatively small fraction of the variance in plasma fibrinogen levels, these findings highlight biological pathways that could be targeted for treatment selection or the development of novel therapeutic strategies aimed at modulating fibrinogen levels and their associated risks. [2]
Frequently Asked Questions About Fibrinogen Gamma Chain Amount
These questions address the most important and specific aspects of fibrinogen gamma chain amount based on current genetic research.
1. If my parents had heart problems, am I destined for them?
Your risk is partly influenced by your genes, which are inherited. Fibrinogen levels, a factor in heart problems, have a 25-51% heritable component. However, genetics explain less than 2% of the overall variation, meaning many other factors, like your lifestyle, also play a huge role. So, while you might have a genetic predisposition, it's not a predetermined outcome.
2. Why do my siblings and I have different risks for heart issues?
Even with shared genes, your individual risk for heart issues can differ significantly from your siblings. While some genetic factors are inherited, many other genes and environmental influences like diet, exercise, and stress interact in unique ways for each person. This complex interplay means that even with similar genetic backgrounds, each person's overall risk profile is unique.
3. Can my daily habits really change my risk for a stroke?
Absolutely, your daily habits can significantly impact your risk. While your genes play a role in influencing things like fibrinogen levels—a factor in stroke risk—they only explain a small fraction of the overall picture. This means lifestyle choices such as diet, exercise, and managing stress have a substantial impact and can help mitigate any genetic predispositions you might have.
4. Would a DNA test tell me my true heart disease risk?
A DNA test can provide some insights into your genetic predispositions for conditions linked to heart health, like elevated fibrinogen levels. However, currently identified genetic variants explain less than 2% of the overall variation. This means while helpful, a DNA test offers only a partial picture, and your full risk is influenced by many other genetic and environmental factors not yet fully understood.
5. Does being [my ethnicity] change my risk for blood clots?
Your ethnic background might indeed affect your risk for blood clots and related conditions. Much of the current research identifying genetic links to factors like fibrinogen levels has been conducted primarily in people of Caucasian descent. This means that the specific genetic associations found might not be the same or have similar effects in other racial or ethnic groups, highlighting a gap in our understanding.
6. Why do some healthy people still get heart attacks?
Even seemingly healthy individuals can experience heart attacks due to a complex interplay of factors. While lifestyle is crucial, genetic predispositions can influence underlying risks like fibrinogen levels, which are a major risk factor for heart disease. The full genetic picture is still being uncovered, and many genetic and environmental influences contribute in ways we don't fully understand yet.
7. Is inflammation in my body connected to heart disease?
Yes, inflammation is strongly connected to heart disease risk. Fibrinogen, a key protein linked to heart health, is also deeply involved in your body's inflammatory responses. Variations in the amount of its gamma chain component can make you more susceptible to both thrombotic events and inflammatory conditions, showing a clear link between the two.
8. Can I overcome my 'bad' genes for heart health?
While you can't change your genes, you can certainly influence how they express themselves in relation to your heart health. Genetics contribute to about 25-51% of the variation in key factors like fibrinogen levels, but the known genetic variants explain only a small fraction of the overall risk. This leaves a large scope for lifestyle and environmental factors to significantly impact and potentially mitigate genetic predispositions.
9. What's the best way to prevent blood clots in my daily life?
Preventing blood clots involves managing factors that influence your body's clotting ability. While your genetic makeup plays a role in determining your baseline fibrinogen levels, which are crucial for clotting, lifestyle factors are also very important. Understanding your genetic predispositions can help tailor preventive strategies, but a healthy lifestyle remains key to reducing overall risk.
10. Are my childhood habits linked to adult heart health?
While the article doesn't specifically detail childhood habits, it emphasizes that many environmental factors interact with your genes to influence health outcomes like heart disease. Your genetic makeup, including factors affecting fibrinogen levels, is established early, but these genes interact with your diet, activity, and other influences throughout life. This complex interplay means that early life exposures likely contribute to your long-term heart health trajectory.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
[1] Danik, Jane S., et al. "Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study." Circ Cardiovasc Genet, 2010.
[2] Dehghan, A. et al. "Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts." Circ Cardiovasc Genet, vol. 3, 2010, pp. 159-167.
[3] Yang, Q. et al. "Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study." BMC Med Genet, vol. 8 Suppl 1, 2007, p. S7.
[4] Kannel, WB. et al. "Fibrinogen and risk of cardiovascular disease. The Framingham Study." JAMA, vol. 258, 1987, pp. 1183-1186.