Factor Vii
Factor VII (FVII) is a vitamin K-dependent serine protease that plays a pivotal role in the initiation of the extrinsic pathway of blood coagulation, a fundamental process for maintaining hemostasis and preventing excessive bleeding. It is synthesized in the liver and circulates in the blood as an inactive zymogen. Upon injury to blood vessels, Factor VII binds to tissue factor (TF) exposed on the surface of cells, leading to its activation into Factor VIIa (FVIIa). This activated complex then initiates the cascade of reactions that ultimately results in the formation of a fibrin clot.
Genetic Basis of Factor VII Levels
Section titled “Genetic Basis of Factor VII Levels”Plasma levels of Factor VII exhibit considerable variation among individuals, influenced by a combination of genetic and environmental factors. Genome-wide association studies (GWAS) have been instrumental in identifying specific genetic loci that contribute to this variability. TheF7gene, located on chromosome 13q34, is a major genetic determinant of Factor VII levels. Single nucleotide polymorphisms (SNPs) within or nearF7, such as rs6046 (R353Q), are strongly associated with these levels.[1], [2] Beyond F7, other genomic regions and genes have also been linked to Factor VII levels, including 2p23, 4q25, 11q12, and 20q11.2, as well as genes likeMCF2L, F10, and PROCR.[1], [3] The association of variants in PROCRwith Factor VII levels represents a more recent discovery.[1]
Clinical Relevance
Section titled “Clinical Relevance”Due to its central role in the coagulation cascade, Factor VII levels are of significant clinical interest in various health contexts. Elevated circulating levels of Factor VII have been recognized as a risk marker for atherothrombotic cardiovascular disease, including conditions such as coronary heart disease (CHD), stroke, and other cardiovascular disease (CVD) events.[2]Understanding the genetic factors that influence Factor VII levels can provide valuable insights into an individual’s predisposition to these conditions and may contribute to improved risk assessment and the development of targeted therapeutic strategies. Factor VII levels can be measured in plasma through assays that quantify either its antigen concentration or its activity.[1]
Social Importance
Section titled “Social Importance”Research into Factor VII and its genetic underpinnings holds considerable social importance by advancing the understanding of complex diseases, particularly cardiovascular disease. Large-scale genetic studies involving diverse populations have been crucial in elucidating the intricate biological pathways involved in coagulation and thrombosis.[1] This growing body of knowledge contributes to the development of personalized medicine approaches, where genetic information could be utilized to predict an individual’s risk for thrombotic events or to guide more effective and tailored treatment decisions.
Methodological and Statistical Robustness
Section titled “Methodological and Statistical Robustness”The interpretation of findings for factor vii is subject to several methodological and statistical limitations. Genetic association studies, including Genome-Wide Association Studies (GWAS), are sensitive to sample size, with smaller cohorts, such as those with N=3025 individuals, potentially limiting the statistical power to detect associations or accurately estimate effect sizes.[4] Furthermore, the use of older genotyping arrays with less comprehensive genomic coverage, like a 100k chip, means that findings may not represent the full spectrum of genetic variation, potentially leading to an incomplete understanding of the trait’s genetic architecture.[5] Statistical challenges also arise in the estimation and replication of genetic effects. Effect sizes, often expressed as regression coefficients, can be influenced by specific cohort characteristics or statistical models, and their concordance across discovery and replication cohorts is crucial for validating associations.[6] Low minor allele frequencies have been observed to contribute to replication failure, indicating that some associations might not be robust across diverse studies.[7] Additionally, certain study designs, such as validating findings in a sample comprised solely of individuals from the center of a phenotypic distribution, may introduce spectrum bias, affecting the generalizability of results even within a seemingly homogeneous population.[5]
Generalizability Across Populations
Section titled “Generalizability Across Populations”A significant limitation lies in the generalizability of genetic findings for factor vii across different populations. While some studies implement measures like family-based designs or principal component analysis to minimize the impact of population stratification, the inherent genetic differences between diverse ancestry groups can affect the transferability of identified associations.[5] Cohorts predominantly composed of individuals from specific ancestral backgrounds may yield genetic variants that are less relevant or have different effect sizes in other populations, highlighting a potential bias in the current understanding.[4] Consequently, findings derived from one population might not be directly applicable to others, necessitating further research in globally diverse cohorts to ensure broad clinical and biological relevance.
Incomplete Genetic and Phenotypic Characterization
Section titled “Incomplete Genetic and Phenotypic Characterization”The current understanding of factor vii is also constrained by an incomplete characterization of its genetic architecture and the complex interplay with environmental factors. While studies often adjust for basic covariates like age and sex.[4] the intricate network of other environmental influences and gene-environment interactions is often not fully elucidated, potentially obscuring a more complete picture of the trait’s etiology. The fact that some genetic variants are only discovered through multi-trait meta-analyses, and the acknowledged “far from comprehensive” nature of genomic scans, indicates substantial remaining knowledge gaps regarding all contributing genetic loci and their functional mechanisms.[6]This suggests that a considerable portion of the genetic variance for factor vii may yet be undiscovered, pointing to the need for advanced methods and broader investigations to uncover the full genetic and environmental landscape influencing the trait.
Variants
Section titled “Variants”Genetic variations play a crucial role in determining an individual’s plasma levels of Factor VII, a key protein in the extrinsic pathway of blood coagulation. These variants can influence gene expression, protein function, or the overall regulation of the coagulation cascade, thereby impacting an individual’s propensity for bleeding or thrombotic events. Understanding these genetic associations is essential for assessing cardiovascular risk and hemostatic balance.
Several variants within or near the MCF2L and F7genes are strongly linked to Factor VII levels. The geneF7encodes Coagulation Factor VII, a vitamin K-dependent proenzyme that initiates the extrinsic pathway of blood coagulation upon binding to tissue factor. Variants likers6046 in F7 are in complete linkage disequilibrium with rs561241 and have been shown to account for approximately 9% of the total phenotypic variation in Factor VII levels, highlighting their significant impact.[2] Other variants in F7, such as rs6041 and rs488703 , along with those in the nearby MCF2L gene, including rs1046205 , rs10665 , and rs71446935 , can modulate the expression or activity of Factor VII. Specifically,rs10665 in the MCF2Llocus demonstrates a strong association with Factor VII clotting activity.[3] MCF2L (MCL1 F-box like 2) is a gene located in close proximity to F7, and variations in this region can affect the regulatory elements controlling F7 gene expression.
Beyond the immediate F7locus, other genes involved in the broader coagulation cascade and related pathways also contribute to Factor VII levels and overall hemostatic regulation. Variants inF5 (Coagulation Factor V), such as rs6025 , and in F11 (Coagulation Factor XI), like rs4253417 , can influence the efficiency of the coagulation pathway by affecting the activation and function of these critical factors. While Factor VII initiates the extrinsic pathway, its downstream effects are intricately linked to the overall cascade, making variations in these genes relevant to Factor VII’s clinical implications.[1] Similarly, KNG1 (Kininogen 1) plays a role in the kallikrein-kinin system, which interacts with coagulation. The variant rs710446 in KNG1 may alter kininogen levels, indirectly affecting the balance of pro- and anti-coagulant processes. The FGB gene, which codes for the Fibrinogen Beta Chain, is crucial for forming the fibrin clot. Variants like rs2227402 and rs4333166 in the PLRG1 - FGBregion can impact fibrinogen levels or function, reflecting the overall hemostatic potential that Factor VII contributes to.[1] The ABO blood group system, determined by variants like rs2769071 , is a well-established genetic determinant of plasma levels for several coagulation factors, including Factor VIII and von Willebrand factor, and also influences Factor VII levels. These variants affect the expression of ABO antigens, which in turn can impact the clearance and stability of various coagulation proteins in the bloodstream.[3] Furthermore, the CDKN2B-AS1gene, an antisense RNA involved in cell cycle regulation and cardiovascular risk, contains variants such asrs1537372 and rs7859727 . These variants may exert pleiotropic effects on inflammation or endothelial function, indirectly modulating Factor VII activity and its contribution to thrombotic risk. Lastly,LPA(Lipoprotein(a)) is a gene critical for lipoprotein(a) levels, a known cardiovascular risk factor. The variantrs55730499 in LPAinfluences lipoprotein(a) levels, and given the complex interplay between lipid metabolism, inflammation, and coagulation, alterations inLPAcan impact overall thrombotic potential, where Factor VII plays a pivotal role.[1]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs1046205 rs10665 rs71446935 | MCF2L | factor vii prothrombin time |
| rs710446 | HRG-AS1, KNG1 | Ischemic stroke, venous thromboembolism, stroke, Abnormal thrombosis, deep vein thrombosis, pulmonary embolism blood coagulation trait factor XI ESAM/SPINT2 protein level ratio in blood AGRP/NPY protein level ratio in blood |
| rs6041 rs6046 rs488703 | F7 | blood coagulation trait prothrombin time tissue factor factor vii |
| rs4253417 | F11 | venous thromboembolism blood protein amount factor XI pulmonary embolism factor vii |
| rs6025 | F5 | venous thromboembolism Ischemic stroke, venous thromboembolism, stroke, Abnormal thrombosis, deep vein thrombosis, pulmonary embolism inflammatory bowel disease peripheral arterial disease peripheral vascular disease |
| rs4333166 | PLRG1 - FGB | factor vii circulating fibrinogen levels, tissue plasminogen activator amount |
| rs2227402 | FGB | factor vii Ischemic stroke, circulating fibrinogen levels venous thromboembolism, circulating fibrinogen levels circulating fibrinogen levels, coronary artery disease |
| rs2769071 | ABO | blood protein amount protein fibroblast growth factor 23 amount factor vii factor XI , venous thromboembolism |
| rs1537372 rs7859727 | CDKN2B-AS1 | colorectal cancer, colorectal adenoma peripheral arterial disease colorectal cancer von Willebrand factor quality, coronary artery disease factor VIII , coronary artery disease |
| rs55730499 | LPA | coronary artery disease parental longevity stroke, type 2 diabetes mellitus, coronary artery disease lipoprotein A , apolipoprotein A 1 lipoprotein A , lipid or lipoprotein |
Causes of Factor VII Variation
Section titled “Causes of Factor VII Variation”The plasma levels of Factor VII (FVII), a critical component in the coagulation cascade, are influenced by a complex interplay of genetic predispositions and biological factors. Research indicates that individual differences in Factor VII levels are substantially heritable, with numerous genetic loci contributing to this variability, alongside demographic influences such as age and sex. Understanding these causal factors is essential for elucidating the mechanisms behind coagulation regulation and associated health outcomes.
Genetic Predisposition to Variable Factor VII Levels
Section titled “Genetic Predisposition to Variable Factor VII Levels”Genetic factors play a central role in determining an individual’s Factor VII levels, with variations in specific genes significantly impacting its synthesis, activity, and clearance. Genome-wide association studies have identified multiple genetic loci across the human genome that are significantly associated with Factor VII plasma concentrations. For instance, acis-acting single nucleotide polymorphism (SNP),rs561241 , located near the F7gene itself, has been strongly linked to Factor VII levels, indicating that variations within or close to the gene encoding Factor VII directly influence its expression or function.[2]Beyond this primary locus, extensive meta-analyses have revealed a polygenic architecture for Factor VII levels, identifying five distinct regions on chromosomes 2p23, 4q25, 11q12, 13q34 (which encompasses theF7 gene), and 20q11.2 that harbor genome-wide significant SNPs.[1]These findings suggest that multiple inherited genetic variants, potentially through gene-gene interactions, collectively contribute to the wide range of Factor VII levels observed in the population. Furthermore, polymorphisms within theF7gene are not only associated with varying Factor VII levels but also with prevalent cardiovascular disease, highlighting the clinical relevance of these genetic influences.[8]
Age and Demographic Influences on Factor VII Levels
Section titled “Age and Demographic Influences on Factor VII Levels”Beyond genetic makeup, an individual’s age and sex are recognized as significant biological factors that contribute to the variability in Factor VII plasma levels. Studies consistently observe a broad age range among participants, for example, from 44.9 to 72.3 years, suggesting that Factor VII levels may naturally fluctuate or change as individuals age.[1]These age-related changes could be attributed to alterations in hepatic synthesis, metabolic rates, or the overall physiological environment that impacts coagulation factor regulation over the lifespan. Similarly, demographic data often reveal a notable proportion of female participants, such as 54% in some cohorts, which points to sex-specific differences in Factor VII levels.[1]Hormonal variations between sexes, differences in body composition, or other sex-linked biological pathways are likely contributors to these observed distinctions, further complicating the precise and interpretation of Factor VII concentrations.
Key Biomolecules and Related Factors
Section titled “Key Biomolecules and Related Factors”Factor VII is identified as a specific biomarker trait for which measurements are performed in research studies.[9]The assessment of Factor VII is often conducted alongside other critical biomolecules that play roles in various physiological processes.[9]For instance, vitamin K status, quantified through phylloquinone concentrations, and the percentage of undercarboxylated osteocalcin are also measured biomarkers, indicating their relevance in a broader physiological context.[9]
Organ-Level Assessment
Section titled “Organ-Level Assessment”The analysis of serum samples includes the evaluation of liver-related markers.[9] The liver is a central organ involved in numerous metabolic and synthetic functions, and its status is often assessed in conjunction with other circulating biomarkers to provide a comprehensive physiological profile.[9]
Factor VII and Cardiovascular Disease Risk
Section titled “Factor VII and Cardiovascular Disease Risk”Factor VII (FVII) plays a critical role in hemostasis, and its circulating levels are significantly linked to cardiovascular health. Elevated levels ofFVIIare recognized as risk markers for the development of atherothrombosis, coronary heart disease (CHD), stroke, and other cardiovascular disease (CVD) events.[2]Large-scale prospective studies, such as the Atherosclerosis Risk in Communities (ARIC) Study, have investigated the relationship between hemostatic factors, includingFVII, and the incidence of coronary heart disease, demonstrating its relevance in disease prognosis.[10]Similarly, the Cardiovascular Health Study (CHS) has elucidated associations betweenFVIIlevels and various cardiovascular risk factors in elderly populations, further underscoring its diagnostic utility in assessing cardiovascular risk.[11]
Genetic and Environmental Influences on Factor VII Levels
Section titled “Genetic and Environmental Influences on Factor VII Levels”The variability in plasma FVIIlevels among individuals is influenced by both genetic and environmental factors, offering insights into personalized medicine approaches. Genome-wide association studies have identified multiple genetic loci and single nucleotide polymorphisms (SNPs) that are strongly associated withFVII levels, providing a foundation for understanding the inherited components of this hemostatic trait.[1] For instance, research from the Framingham Heart Study has highlighted associations between FVII gene polymorphisms, FVIIlevels, and the prevalence of cardiovascular disease, suggesting a genetic predisposition to alteredFVII activity.[8]Beyond genetics, environmental factors such as diet also play a role; the Rotterdam Study indicated an association between dietary fat and fiber intake andFVIIlevels in elderly individuals, illustrating how lifestyle can modulate this important coagulation factor.[12]
Prognostic and Stratification Utility in Cardiovascular Health
Section titled “Prognostic and Stratification Utility in Cardiovascular Health”The assessment of Factor VII, whether through antigen or activity measurements, holds significant prognostic value in predicting cardiovascular outcomes and facilitating risk stratification. ElevatedFVIIlevels serve as an indicator for increased risk of future atherothrombotic events, including myocardial infarction and stroke, making it a valuable marker in identifying high-risk individuals. This prognostic information can be integrated into broader risk assessment models to personalize prevention strategies. WhileFVII levels are established risk markers, the utility for guiding specific treatment selection or monitoring strategies based solely on FVII levels is an area of ongoing research, aiming to translate these associations into actionable clinical interventions.
Frequently Asked Questions About Factor Vii
Section titled “Frequently Asked Questions About Factor Vii”These questions address the most important and specific aspects of factor vii based on current genetic research.
1. My family has a history of heart issues. Does that mean I’m more likely to have them too?
Section titled “1. My family has a history of heart issues. Does that mean I’m more likely to have them too?”Yes, genetics play a significant role in your predisposition to heart issues. Variations in your genes, particularly within the F7gene, are major determinants of your Factor VII levels. Elevated Factor VII levels are recognized as a risk marker for conditions like coronary heart disease and stroke, meaning a family history could indicate a higher genetic susceptibility for you.
2. Why might my blood clot differently than my friend’s?
Section titled “2. Why might my blood clot differently than my friend’s?”Your plasma levels of Factor VII, a key protein for blood clotting, show considerable variation among individuals. This is influenced by a combination of genetic and environmental factors. Genes likeF7, and others such as MCF2L and PROCR, can impact how much Factor VII your body produces, leading to different clotting tendencies.
3. Could a special test tell me if I’m at higher risk for a stroke or heart attack?
Section titled “3. Could a special test tell me if I’m at higher risk for a stroke or heart attack?”Yes, measuring your Factor VII levels in plasma can provide valuable insights into your risk for atherothrombotic cardiovascular diseases, including stroke and coronary heart disease. Understanding your genetic factors, such as variants in theF7 gene, can further refine this risk assessment and contribute to more personalized prevention strategies.
4. Does my ethnic background affect my risk for heart problems?
Section titled “4. Does my ethnic background affect my risk for heart problems?”Yes, genetic differences between diverse ancestry groups can affect the relevance and impact of identified genetic associations. Findings from studies predominantly on one population might not be directly applicable to others, highlighting the need for research in globally diverse cohorts to fully understand how genetic factors influence Factor VII levels and cardiovascular risk across all backgrounds.
5. Can healthy habits really overcome my family’s history of heart issues?
Section titled “5. Can healthy habits really overcome my family’s history of heart issues?”While genetic factors, such as variants in the F7gene, significantly influence your predisposition to certain conditions, environmental factors also play a role. A healthy lifestyle can certainly help manage your overall risk. However, understanding your genetic profile can provide personalized insights into your individual susceptibility, guiding more effective preventative measures.
6. I heard about “clotting factors” in the blood. What does Factor VII do for me?
Section titled “6. I heard about “clotting factors” in the blood. What does Factor VII do for me?”Factor VII is a crucial protein in your blood that initiates the clotting process. When you get injured, Factor VII helps start a cascade of reactions that ultimately leads to the formation of a fibrin clot, which is essential for stopping bleeding and maintaining your body’s hemostasis.
7. Does eating certain foods affect my blood’s clotting ability?
Section titled “7. Does eating certain foods affect my blood’s clotting ability?”Factor VII is a vitamin K-dependent protein, meaning vitamin K is essential for its proper function in your body. While the article doesn’t detail specific dietary impacts, maintaining adequate vitamin K levels, often through a balanced diet, is necessary for Factor VII to play its pivotal role in blood coagulation.
8. Why do some people seem to have a higher risk of blood clots than others?
Section titled “8. Why do some people seem to have a higher risk of blood clots than others?”Individual differences in Factor VII levels, which are significantly influenced by your genetic makeup, contribute to varying risks for blood clot-related conditions. For example, specific variants in genes likeF7 or PROCRcan lead to higher circulating levels of Factor VII, increasing the risk for atherothrombotic cardiovascular diseases.
9. If I’m worried about my heart, what would a genetic test for Factor VII tell me?
Section titled “9. If I’m worried about my heart, what would a genetic test for Factor VII tell me?”A genetic test could identify specific variants, such as rs6046 in the F7gene, that are strongly associated with your plasma Factor VII levels. This information helps predict your individual predisposition to conditions like coronary heart disease or stroke, allowing for more targeted risk assessment and potentially guiding personalized health decisions.
10. My sibling is healthy, but I’m worried about my risk. Why the difference?
Section titled “10. My sibling is healthy, but I’m worried about my risk. Why the difference?”Even within families, genetic variations can lead to different health outcomes. While you share some genetic background, specific genetic differences, especially in genes like F7 and others like F10, can result in different Factor VII levels. These individual genetic differences contribute to varying risks for conditions like heart disease between siblings.
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
Section titled “References”[1] Smith NL et al. “Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.”Circulation, vol. 121, no. 12, 2010, p. 1388-97.
[2] Yang Q, et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet, 26 Sept. 2007, PMID: 17903294.
[3] Williams FM, et al. “Ischemic stroke is associated with the ABO locus: the EuroCLOT study.”Ann Neurol, Feb. 2013, PMID: 23381943.
[4] Weedon MN. “A common variant of HMGA2 is associated with adult and childhood height in the general population.” Nat Genet, 2007.
[5] Arnett DK. “Genome-wide association study identifies single-nucleotide polymorphism in KCNB1 associated with left ventricular mass in humans: the HyperGEN Study.”BMC Med Genet, 2009.
[6] Meyer HV. “Genetic and functional insights into the fractal structure of the heart.” Nature, 2020.
[7] Ishigaki K. “Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.” Nat Genet, 2020.
[8] Feng D, Tofler GH, Larson MG, O’Donnell CJ, Lipinska I, Schmitz C, Sutherland PA, Johnstone MT, Muller JE, D’Agostino RB, Levy D, Lindpaintner K. “Factor VII gene polymorphism, factor VII levels, and prevalent cardiovascular disease: the Framingham Heart Study.”Arterioscler Thromb Vasc Biol, vol. 20, 2000, pp. 593–600.
[9] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. S11.
[10] Folsom, Aaron R., et al. “Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.”Circulation, vol. 96, no. 4, 1997, pp. 1102–1108.
[11] Cushman, Mary, et al. “Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators.”American Journal of Epidemiology, vol. 143, no. 7, 1996, pp. 665–676.
[12] Mennen, L. I., et al. “The association of dietary fat and fiber with coagulation factor VII in the elderly: the Rotterdam Study.”American Journal of Clinical Nutrition, vol. 65, no. 3, 1997, pp. 732–736.