Chronic Venous Hypertension

Background

Chronic venous hypertension refers to persistently elevated pressure within the venous system, most commonly affecting the lower extremities. This sustained increase in venous pressure can compromise venous valve function and lead to a range of clinical manifestations, including chronic venous insufficiency, varicose veins, and skin changes. It is also a significant predisposing factor for venous thromboembolism (VTE), which encompasses deep venous thrombosis (DVT) and pulmonary embolism (PE). ^[1] DVT involves the formation of blood clots in the deep veins, typically in the legs, while PE occurs when a portion of these clots dislodges and travels to the lungs, potentially causing life-threatening complications. ^[1] VTE is recognized as a common and clinically important cardiovascular condition associated with substantial mortality. ^[1]

Biological Basis

Chronic venous hypertension and its associated conditions, such as VTE, are complex multifactorial diseases resulting from an intricate interplay between genetic predispositions and various environmental factors. ^[2] Family and twin studies have demonstrated a strong heritable component for VTE, with genetic factors estimated to contribute between 50% to 60% of an individual's risk. ^[1] While some research estimates the total genetic variance for venous thrombosis to be around 35%, this still underscores the significant role of inherited traits. ^[2]

Extensive research, including genome-wide association studies (GWAS), has identified numerous genetic variants that influence the risk of venous thrombosis. Many of these identified variants are located within genes involved in the coagulation and fibrinolysis pathways, which are critical for regulating blood clot formation and breakdown. ^[1] Specific genetic loci, such as those involving FV, ABO, FGG, and F11, have been consistently linked to VT risk, collectively accounting for a portion of the total genetic variance. ^[2] Additionally, genes like PROCR, which influences protein C levels, and certain STAB2 haplotypes have been associated with an increased risk of VT. ^[2] GWAS typically involve systematically analyzing millions of single nucleotide polymorphisms (SNPs) across the entire genome, employing statistical methodologies like additive genetic models and logistic regression to pinpoint SNPs associated with disease risk, often with adjustments for demographic and ancestral factors. ^[2]

Clinical Relevance

The clinical significance of chronic venous hypertension is highlighted by its severe health outcomes. VTE, a major consequence, affects approximately 2 million adults with DVT annually in the United States, and leads to an estimated 600,000 hospitalizations for PE and 60,000 deaths each year. ^[1] It stands as the third most prevalent life-threatening cardiovascular condition, surpassed only by coronary heart disease and stroke. ^[1] Beyond acute events, individuals who experience venous thrombosis face a considerable risk of recurrence, estimated at roughly 6% per year. ^[2] Furthermore, about 25% of patients develop post-thrombotic syndrome within five years following a VT event, characterized by chronic pain, swelling, and skin changes. ^[2] A deeper understanding of the genetic underpinnings of chronic venous hypertension and its related conditions is therefore essential for early identification of at-risk individuals, the development of targeted preventive strategies, and the improvement of long-term patient care.

The societal impact of chronic venous hypertension and its complications is substantial. The high mortality rates associated with VTE, with tens of thousands of deaths reported annually in some regions ^[2] underscore its significant burden on public health systems. The condition also imposes considerable economic costs, stemming from hospitalizations, ongoing medical treatments, and the loss of productivity. ^[2] The chronic nature of venous hypertension and its potential progression to debilitating conditions like post-thrombotic syndrome profoundly affect the quality of life for affected individuals, emphasizing the critical need for continued research into its causes, prevention, and effective management.

Limitations

Studies investigating complex traits such as chronic venous hypertension often encounter several methodological, phenotypic, and population-specific challenges that can influence the interpretation and generalizability of findings. These limitations are critical to acknowledge for a balanced understanding of the current research landscape.

Methodological and Statistical Constraints

Genetic studies on chronic venous hypertension, similar to other complex diseases, are frequently constrained by modest sample sizes, which inherently limit their statistical power to detect genetic variants exerting small to moderate effects. ^[3] For instance, achieving genome-wide significance for variants with modest odds ratios often necessitates sample sizes exceeding 20,000 individuals, a scale rarely met in many individual studies. ^[2] This limitation means that numerous true genetic signals contributing to chronic venous hypertension may remain undetected, leading to an incomplete understanding of its underlying genetic architecture.

Furthermore, the process of replicating initial genetic associations can be complex, with some detected associations potentially overestimating effect sizes or arising by chance, even when replication signals are observed. ^[4] Heterogeneity in study designs between discovery and replication cohorts can impede the consistent validation of genetic loci, making it difficult to confirm initial findings. ^[4] Additionally, the rigorous quality control procedures essential for large datasets, such as filtering SNPs based on Hardy-Weinberg Equilibrium or minor allele frequency, require a careful balance; an overly stringent approach might inadvertently discard genuine signals, while a lenient one risks introducing spurious associations. ^[2]

Phenotypic Definition and Measurement Challenges

Accurately defining and measuring complex phenotypes like chronic venous hypertension poses a significant challenge, as variations in diagnostic criteria or disease progression can introduce considerable heterogeneity into study populations. ^[3] For example, in blood pressure research, the practice of applying fixed adjustments for individuals on medication or relying on single time-point measurements may obscure the dynamic genotype-phenotype effects that manifest over extended periods. ^[3] Such phenotypic imprecision can lead to misclassification bias, where individuals with the trait are inadvertently included in control groups, thereby diluting true genetic signals and diminishing statistical power. ^[5]

The genetic landscape of chronic venous hypertension may involve a substantial number of low-risk variants, each contributing a small effect and exhibiting low penetrance, a pattern observed in other complex conditions. ^[3] Conventional genome-wide association studies, which are primarily designed to identify common variants with moderate to large effects, may therefore lack the power to detect these subtle genetic contributions, resulting in a portion of the trait's heritability remaining unexplained. ^[3] Moreover, the failure to detect genuine susceptibility variants can also occur if they are poorly tagged by the genotyped single nucleotide polymorphisms, highlighting the need for denser genotyping arrays or advanced imputation methods. ^[5]

Population Diversity and Environmental Confounders

A critical limitation in genetic studies of chronic venous hypertension is the challenge of generalizability across diverse ancestral populations. ^[3] Many studies, particularly in their initial quality control phases, exclude individuals of non-European ancestry, which restricts the transferability of findings and may overlook population-specific genetic variants relevant to the trait. ^[2] Effective replication of genetic associations is highly dependent on population characteristics; ideally, replication cohorts should be genetically similar and share comparable lifestyles with the discovery population to ensure validity. ^[3]

Furthermore, the intricate interplay of environmental factors and gene-environment interactions significantly influences the manifestation of chronic venous hypertension, representing a substantial knowledge gap. ^[4] These complex interactions can either increase or decrease an individual's susceptibility, making it challenging to isolate the independent effects of genetic variants. ^[4] Unaccounted population structure can also undermine the accuracy of genetic inferences by generating spurious associations. ^[5] Addressing these confounders necessitates comprehensive data collection on lifestyle, environmental exposures, and detailed phenotypic characterization across a broad spectrum of diverse populations.

Variants

Variants in genes such as _F5_, _SLC19A2_, and _TCERG1_ can influence biological pathways related to coagulation, metabolism, and gene expression, respectively, which may contribute to the risk and progression of chronic venous hypertension. Chronic venous hypertension is a condition characterized by persistently elevated pressure in the veins, often leading to venous insufficiency, valve dysfunction, and symptoms like swelling, pain, and skin changes. Genetic predispositions, particularly those affecting blood vessel integrity and coagulation, play a significant role in an individual's susceptibility to this condition.

The _F5_ (Factor V) gene encodes a critical protein in the coagulation cascade, responsible for amplifying thrombin generation and facilitating blood clot formation. Variations within _F5_, such as rs1894692, could hypothetically alter the efficiency or regulation of Factor V activity, potentially leading to an increased propensity for venous thromboembolism (VTE) or altered clot stability. Such changes in coagulation can contribute to impaired venous blood flow and increased pressure, exacerbating the pathology of chronic venous hypertension. ^[2] Sustained venous hypertension can damage venous valves and vessel walls, perpetuating a cycle of inflammation and tissue remodeling that underlies the chronic nature of the disease. ^[1]

Similarly, the _SLC19A2_ (Solute Carrier Family 19 Member 2) gene is responsible for encoding the thiamine transporter 1 (_THTR1_), which plays a vital role in the cellular uptake of thiamine (vitamin B1). Thiamine is essential for numerous metabolic processes, including energy production and the synthesis of neurotransmitters. A variant like rs1894692 within _SLC19A2_ could potentially affect the transporter's efficiency, leading to altered intracellular thiamine levels and subsequent metabolic dysfunction. Such metabolic disruptions can impact endothelial cell health, vascular tone, and inflammatory responses, all of which are relevant to the development and severity of chronic venous hypertension. ^[6] Impaired endothelial function can compromise the integrity of venous walls, contributing to their dilation and increased permeability, which are hallmarks of chronic venous disease. ^[7]

The _TCERG1_ (Transcription Elongation Regulator 1) gene is involved in the complex process of gene expression, specifically by regulating transcription elongation and mRNA processing. Variants like rs543467832 in _TCERG1_ could theoretically influence the precise regulation of other genes, potentially altering the expression of proteins crucial for maintaining vascular structure, regulating inflammation, or controlling cellular growth and repair within venous tissues. Disrupted gene regulation orchestrated by _TCERG1_ could lead to abnormal extracellular matrix remodeling, impaired smooth muscle cell function, or chronic inflammation within the venous system, contributing to the pathogenesis of chronic venous hypertension. ^[8] These molecular changes can collectively weaken venous walls and valves, leading to the progressive symptoms associated with this condition. ^[9]

Key Variants

RS ID	Gene	Related Traits
rs1894692	SLC19A2 - F5	pneumonia blood protein amount atrial fibrillation tissue factor pathway inhibitor amount endometriosis
rs543467832	TCERG1	chronic venous hypertension

Causes of Chronic Venous Hypertension

Chronic venous hypertension is a condition characterized by persistently elevated pressure within the veins, often leading to symptoms such as swelling, skin changes, and ulceration. Its development is multifactorial, stemming from a complex interplay of genetic predispositions, environmental exposures, and the presence of other health conditions. A primary mechanism leading to chronic venous hypertension is damage to venous valves, which impairs blood flow back to the heart and causes blood to pool in the lower extremities, increasing pressure in the venous system.

Genetic Predisposition to Venous Dysfunction

Genetic factors play a significant role in determining an individual's susceptibility to conditions that can lead to chronic venous hypertension, particularly venous thromboembolism (VTE) which includes deep venous thrombosis (DVT). VTE is highly heritable, with estimates suggesting that genetic factors account for 50% to 60% of the risk. ^[10] Numerous genetic variants, predominantly within coagulation and fibrinolysis pathways, have been consistently linked to VTE risk. ^[11] For instance, common susceptibility alleles in genes such as ABO, F2, F5, and FGG are established risk factors for VTE, while recent genome-wide association studies (GWAS) have identified novel loci including GP6, HIVEP1, KNG1, STAB2, STXBP5, and VWF. ^[12]

Beyond single genetic variants, the cumulative effect of many common genetic variants, known as polygenic risk, contributes to the overall susceptibility. For example, the PROCR Ser219Gly variant and the alpha-fibrinogen Thr312Ala polymorphism have been associated with an increased risk of thrombotic disorders and VTE, respectively. ^[13] Furthermore, gene-gene interactions, or epistasis, where the effect of one gene is modified by another, are also important in modulating VTE risk, contributing to the unexplained heritability of the disease. ^[12] These genetic predispositions can lead to an increased likelihood of developing DVT, which in turn is a major cause of post-thrombotic syndrome and subsequent chronic venous hypertension. ^[2]

Environmental and Lifestyle Contributions

Environmental and lifestyle factors are critical modulators of venous health and can significantly influence the development of chronic venous hypertension, often interacting with genetic predispositions. Venous thrombosis, a primary precursor to chronic venous hypertension, is considered a multifactorial disease resulting from the interplay between environmental and genetic factors. ^[12] Lifestyle choices such as diet, physical activity levels, and exposure to certain conditions can impact blood viscosity, vessel wall integrity, and overall circulatory health. For instance, specific dietary habits, including sodium and potassium intake, can influence blood pressure regulation, which may indirectly affect venous pressure over time. ^[14]

Socioeconomic factors and geographic influences may also play a role by affecting access to healthcare, dietary patterns, and occupational exposures that predispose individuals to venous insufficiency or thrombosis. While specific details on the direct impact of these factors on chronic venous hypertension are complex, it is understood that such external elements can trigger or exacerbate underlying genetic vulnerabilities, thereby contributing to the disease's manifestation and progression. ^[15] The overall environment, encompassing both individual lifestyle and broader societal contexts, therefore acts as a critical determinant in the development of venous hypertension.

The presence of certain comorbidities and the natural process of aging are substantial contributors to the development and progression of chronic venous hypertension. Conditions such as general hypertension, diabetes mellitus, and chronic kidney disease (CKD) can exert systemic effects that compromise vascular health. ^[16] For example, hypertension itself is a highly prevalent condition with significant genetic and environmental underpinnings ^[3] and while distinct from venous hypertension, elevated systemic blood pressure can contribute to overall vascular stress and potentially worsen venous insufficiency.

Aging is a prominent risk factor, as the prevalence of conditions like CKD, which often co-occurs with hypertension and diabetes, dramatically increases with advancing age. ^[16] Over time, venous valves can weaken and become incompetent, leading to reflux and increased venous pressure. Furthermore, the most direct pathway to chronic venous hypertension often involves a prior episode of deep venous thrombosis (DVT), which can lead to post-thrombotic syndrome where damaged valves and persistent venous obstruction result in sustained high venous pressure. ^[2] The effects of certain medications, particularly those used to manage comorbidities, can also influence vascular tone and fluid balance, indirectly impacting venous dynamics and potentially contributing to the condition.

Biological Background for Chronic Venous Hypertension

Chronic venous hypertension is a condition characterized by persistently elevated pressure within the veins, often in the lower extremities. This sustained pressure can lead to a range of symptoms and complications due to impaired venous blood return. The underlying biological mechanisms involve a complex interplay of genetic predispositions, cellular signaling, vascular structural integrity, and systemic fluid dynamics.

Vascular Structure and Remodeling

The integrity and adaptability of blood vessel walls are crucial for maintaining proper vascular function, including in the venous system. Key biomolecules such as the calcium-dependent cell-cell adhesion glycoprotein T-cadherin, encoded by the CDH13 gene, play a role in vascular biology. This protein is predominantly expressed in the nervous and cardiovascular systems, particularly in the aorta, arteries, and heart, and is implicated in regulating vascular wall remodeling and angiogenesis. Under pathological conditions, such as within atherosclerotic lesions, CDH13 expression can be upregulated, highlighting its involvement in vascular responses to disease and its interactions with critical cardiovascular ligands like low-density lipoproteins and adiponectins, which are vital for cardiovascular physiology. ^[4]

Genetic Predisposition to Venous Pathology

Genetic mechanisms contribute significantly to the risk of venous disorders, including those that can lead to chronic venous hypertension. Studies indicate that venous thromboembolism (VTE), which encompasses deep venous thromboembolism (DVT) and pulmonary embolism (PE), is a common and highly heritable cardiovascular condition, with heritability estimates ranging from 0.5 to 0.6. A growing number of genetic variants, particularly within the coagulation and fibrinolysis pathways, have been consistently linked to VTE. These genetic factors influence the body's ability to regulate blood clotting and clot breakdown, thereby affecting the likelihood of thrombus formation in veins. ^[1]

Molecular and Cellular Regulation of Vascular Dynamics

While primarily studied in the context of arterial blood pressure, the molecular and cellular pathways that regulate overall vascular tone and fluid balance have systemic implications that influence venous pressure. Systemic blood pressure is fundamentally determined by cardiac output and total peripheral resistance, which are controlled by intricate regulatory networks. These networks involve key biomolecules and signaling pathways, such as the c-Src and Shc/Grb2/ERK2 pathway, activated by angiotensin II, which contributes to vascular smooth muscle cell proliferation. Other genes like CACNA1H, IGF-1, and AKT are recognized for their roles in blood pressure regulation and associated complications; CACNA1H specifically encodes a voltage-dependent calcium channel, underscoring the importance of calcium signaling in vascular function. ^[3] Renal handling of salt, influenced by genes like UMOD, NPPA, and NPPB, also plays a crucial role in maintaining fluid and electrolyte homeostasis, thereby affecting circulating blood volume and overall vascular pressure. ^[16]

Pathophysiology of Venous Thromboembolism and Post-Thrombotic Syndrome

A significant pathophysiological process leading to chronic venous hypertension is the development of post-thrombotic disease following an event of venous thrombosis (VT). Venous thrombosis is a common multifactorial disease with substantial mortality and a high recurrence risk, affecting many individuals annually. Within five years of a VT event, approximately 25% of patients develop post-thrombotic disease, which is characterized by damage to venous valves and obstruction of venous blood flow. This damage impairs the veins' ability to efficiently return blood to the heart, leading to venous stasis and chronically elevated venous pressure, thus contributing to the development of chronic venous hypertension. ^[2]

Vascular and Endothelial Signaling Dysregulation

Chronic venous hypertension involves complex interactions within vascular and endothelial signaling pathways that contribute to elevated blood pressure and vascular remodeling. Angiotensin II, a potent vasoconstrictor, plays a critical role by activating intracellular signaling cascades, notably through c-Src and the Shc/Grb2/ERK2 pathway, which drives the proliferation of vascular smooth muscle cells (VSMC). ^[17] The renal endothelin system also contributes to blood pressure regulation and can be dysregulated in hypertensive states. ^[18] Furthermore, the cell-cell adhesion glycoprotein CDH13 (T-cadherin), highly expressed in the aorta, arteries, and heart, interacts with ligands like low-density lipoproteins and adiponectins, regulating vascular wall remodeling and angiogenesis, and is notably upregulated in pathological conditions such as atherosclerotic lesions. ^[4] Reactive oxygen species (ROS) significantly modulate protein kinase activity and gene expression, impacting both normal vascular physiology and contributing to pathophysiology in hypertension. ^[19] Additionally, natriuretic peptides, encoded by genes such as NPPA and NPPB, are involved in the homeostatic regulation of blood pressure. ^[20]

Ion Channel and Neurohormonal Control

The precise regulation of ion channels and neurohormonal systems is fundamental to maintaining systemic blood pressure, and their dysregulation contributes to chronic venous hypertension. Calcium channels are central to vascular tone, with mechanisms like the CaVbeta2 subunit modulating the CaV1.2 calcium channel activity. ^[6] Specific calcium channel subtypes, including CACNA1H, are known to play roles in blood pressure regulation and hypertension, particularly within the kidney, influencing renal function and overall fluid balance. ^[3] Beyond ion channels, neurohormonal pathways, such as dopamine signaling, are implicated in blood pressure control. ^[3] The protein Phosducin, a protein kinase A-regulated G-protein regulator, is also critical, influencing sympathetic nervous system activity and demonstrating a capacity to prevent stress-induced hypertension in both humans and mice. ^[21]

Metabolic and Growth Factor Interplay

Metabolic pathways and growth factors are intricately linked to the pathogenesis of hypertension, influencing cellular growth, energy balance, and systemic vascular health. Insulin-like growth factor I (IGF-1) is a significant player, implicated in blood pressure regulation, the development of hypertension, and associated complications such as left ventricular hypertrophy. ^[3] Disturbances in cellular energy metabolism, for instance, through mutations in the gamma^[21] subunit of AMP-activated protein kinase (AMPK), can lead to severe cardiovascular conditions like familial hypertrophic cardiomyopathy, highlighting the critical role of energy compromise in disease progression. ^[22] Although specific details are not fully elucidated, pathway analyses have also indicated the involvement of ChREBP regulation, suggesting broader metabolic regulatory networks contribute to the complex etiology of hypertension. ^[3]

Genetic Regulation and Systems-Level Integration

The genetic underpinnings of chronic venous hypertension involve a complex interplay of various genes whose effects are integrated at a systems level. Genome-wide association studies have identified genetic variants in novel pathways and genes such as STK39 and UMOD that contribute to blood pressure determination and hypertension susceptibility. ^[23] These genetic variants often cluster within interconnected pathways and networks, demonstrating that hypertension is an emergent property of hierarchical regulation and extensive pathway crosstalk rather than isolated gene effects. ^[3] For example, mutations in TBX5 are associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation, illustrating how single genetic defects can propagate through molecular networks to exert broad systemic impacts on cardiovascular function. ^[24] This systems-level integration of genetic and molecular mechanisms ultimately defines the complex physiological trait of blood pressure regulation.

Frequently Asked Questions About Chronic Venous Hypertension

These questions address the most important and specific aspects of chronic venous hypertension based on current genetic research.

1. My parents have bad leg veins; will I definitely get them too?

Not necessarily, but your risk is definitely higher. Conditions like chronic venous hypertension and its severe complications like deep vein thrombosis (DVT) have a strong genetic component, with inherited factors contributing 50-60% to an individual's risk. While you might inherit a predisposition, your lifestyle and environmental factors also play a big role, so it's not a certainty.

2. Can my healthy lifestyle prevent inherited leg vein problems?

A healthy lifestyle can significantly help manage your risk, even if you have a genetic predisposition. Chronic venous hypertension is considered a multifactorial disease, meaning it results from a complex interplay between your genes and various environmental factors. By adopting healthy habits, you can potentially mitigate some of the genetic risks you might carry, helping to protect your veins.

3. Why do my legs swell, but my friend's don't, doing the same things?

This difference often comes down to your individual genetic makeup. Your genes, which can contribute 50-60% to the risk of venous issues and blood clots, influence how your venous system functions, including valve efficiency and blood clot formation. Even with similar lifestyles, genetic variations can make some individuals more prone to symptoms like swelling.

4. I had a DVT; am I guaranteed to get another one later?

You have an increased risk of recurrence, but it's not guaranteed. Individuals who have experienced venous thrombosis face roughly a 6% risk of recurrence per year. Your genetic profile, including variants in genes like FV, ABO, FGG, and F11 that affect blood clotting, can influence this ongoing risk.

5. Is it true that my blood type affects my chances of getting leg clots?

Yes, surprisingly, your blood type can play a role in your risk. Genetic variations associated with the ABO blood group system have been consistently linked to an increased risk of venous thrombosis. This means that certain blood types might have a slightly higher predisposition to developing blood clots in the legs.

6. Does standing all day at work make my genetic leg risk worse?

Yes, daily habits like prolonged standing can interact with your genetic predisposition. Chronic venous hypertension is a complex condition influenced by both your inherited traits and environmental factors. If you have genetic variants that increase your risk for venous issues, activities that put extra strain on your leg veins, like standing for long periods, could potentially exacerbate that risk.

7. How can I know if I'm at high risk for serious leg vein issues early?

Understanding your family history is a crucial first step, as genetic factors contribute significantly to risk. Research into specific genetic markers, such as variants in genes like PROCR or certain STAB2 haplotypes, is helping to identify individuals at higher risk. This knowledge is essential for doctors to develop targeted preventive strategies.

8. Why do some people only get mild varicose veins, but I get clots?

The severity of venous issues can vary greatly due to individual genetic differences. While both can stem from chronic venous hypertension, your unique genetic makeup, including specific variants in genes involved in blood clotting pathways, can predispose you to more severe manifestations like deep vein thrombosis rather than just surface varicose veins.

9. Would knowing my genes help doctors treat my leg vein issues better?

Yes, a deeper understanding of your genetic profile is becoming increasingly valuable for personalized care. Identifying specific genetic variants linked to chronic venous hypertension allows doctors to tailor preventive strategies and potentially choose more effective long-term treatments. This precision medicine approach aims to improve your outcomes.

10. Should I get a DNA test to check my leg vein problem risk?

A DNA test could provide insights into your genetic predisposition for conditions like venous thrombosis, which is a major consequence of chronic venous hypertension. While genetic factors contribute significantly (50-60% of risk), it's important to discuss the comprehensive picture, including your lifestyle and family history, with your doctor to determine if such testing is appropriate for you.

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] Tang, W. et al. "A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium." Genet Epidemiol, vol. 37, no. 5, 2013, pp. 496-506.

[2] Germain M. et al. "Genetics of venous thrombosis: insights from a new genome wide association study." PLoS One, 2011, PMID: 21980494.

[3] Adeyemo A. et al. "A genome-wide association study of hypertension and blood pressure in African Americans." PLoS Genet, 2009, PMID: 19609347.

[4] Org E. et al. "Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations." Hum Mol Genet, 2009, PMID: 19304780.

[5] Wellcome Trust Case Control Consortium. "Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls." Nature, 2007, PMID: 17554300.

[6] Levy D. et al. "Genome-wide association study of blood pressure and hypertension." Nat Genet, 2009, PMID: 19430479.

[7] Slavin, Thomas P., et al. "Two-marker association tests yield new disease associations for coronary artery disease and hypertension." Hum Genet, 2011.

[8] Ehret, G. B., et al. "Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk." Nature, vol. 478, no. 7367, 2011, pp. 103-109.

[9] Guo, Y., et al. "A genome-wide linkage and association scan reveals novel loci for hypertension and blood pressure traits." PLoS One, vol. 7, no. 2, 2012, e31489.

[10] Souto, J. C., et al. "Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia." Am J Hum Genet, vol. 67, no. 6, 2000, pp. 1452-1459.

[11] Bezemer, I. D., et al. "Gene variants associated with deep vein thrombosis." JAMA, vol. 299, no. 11, 2008, pp. 1306-1314.

[12] Greliche, N., et al. "A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis." BMC Med Genet, vol. 14, no. 1, 2013, p. 36.

[13] Carter, A. M., et al. "alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism." Blood, vol. 96, no. 3, 2000, pp. 1177-1179.

[14] Gu, D., et al. "Heritability of blood pressure responses to dietary sodium and potassium intake in a Chinese population." Hypertension, vol. 50, no. 1, 2007, pp. 116-122.

[15] Hamet, P., et al. "Hypertension: genes and environment." J Hypertens, vol. 16, no. 4, 1998, pp. 397-418.

[16] Gudbjartsson, D. F. et al. "Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases." PLoS Genet, vol. 6, no. 7, 2010, e1001032.

[17] Sayeski, P. P., and M. Showkat-Ali. "The critical role of c-Src and the Shc/Grb2/ERK2 signaling pathway in angiotensin II-dependent VSMC proliferation." Experimental Cell Research, vol. 287, 2003, pp. 339–349.

[18] Vogel, V., et al. "The renal endothelin system in the Prague hypertensive rat, a new model of spontaneous hypertension." Clin Sci (Lond), vol. 97, 1999, pp. 91–8.

[19] Griendling, K. K., et al. "Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology." Arterioscler Thromb Vasc Biol, vol. 20, 2000, pp. 2175–2183.

[20] Newton-Cheh, C. et al. "Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure." Nature Genetics, 2009.

[21] Bauer, P. H., et al. "Phosducin is a protein kinase A-regulated G-protein regulator." Nature, vol. 358, 1992, pp. 73–76.

[22] Blair, E., et al. "Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis." Hum Mol Genet, vol. 10, 2001, pp. 1215–1220.

[23] Padmanabhan S. et al. "Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension." PLoS Genet, 2010, PMID: 21082022.

[24] Postma, A. V., et al. "A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation." Circ Res, vol. 102, no. 11, 2008, pp. 1433–42.