Portal Hypertension

Background

Portal hypertension is a clinical condition characterized by an abnormally elevated blood pressure within the portal venous system. This specialized system of veins collects blood from the stomach, intestines, pancreas, and spleen, transporting it to the liver. The increase in pressure typically arises from increased resistance to blood flow through the liver, most commonly due to chronic liver diseases such as cirrhosis. If left unmanaged, portal hypertension can lead to a cascade of severe complications.

Biological Basis

The underlying biological mechanism of portal hypertension involves two main factors: increased resistance to blood flow through the liver and an augmented splanchnic blood flow. Liver diseases, particularly cirrhosis, cause structural changes, including fibrosis and the formation of regenerative nodules, which obstruct the normal passage of blood through the hepatic sinusoids. This obstruction forces blood to find alternative routes, leading to the development of collateral vessels (varices) in areas like the esophagus, stomach, and rectum.

While the researchs predominantly examines systemic blood pressure and its genetic influences, the broader understanding of vascular regulation and genetic predispositions to hypertension is pertinent. Numerous genetic variants (single nucleotide polymorphisms or SNPs) have been identified that are associated with blood pressure regulation and various cardiovascular traits. For instance, common variants in genes such asNPPA and NPPB, which are involved in encoding natriuretic peptides, have been linked to circulating natriuretic peptide levels and systemic blood pressure.^[1]The renin-angiotensin-aldosterone pathway, a critical system for blood pressure control, is also a subject of genetic studies, with SNPs in or near its constituent genes implicated in hypertension and altered vascular properties.^[2] Furthermore, research has identified SNPs, such as those in KCNB1, associated with left ventricular mass, a common consequence of hypertension.^[3] Variants in genes like HFE (involved in metal ion transport) and SLC39A8 (encoding a zinc transporter) have also been correlated with blood pressure.^[4]These genetic insights into systemic hypertension suggest that genetic factors may influence the vascular tone and hepatic blood flow dynamics that contribute to the susceptibility or progression of portal hypertension.

Clinical Relevance

The clinical significance of portal hypertension primarily stems from its severe complications, which arise from the diversion of blood through collateral vessels and the impaired function of the liver. Life-threatening variceal bleeding, particularly from esophageal varices, is a major concern. Other common clinical manifestations include ascites (the accumulation of fluid in the abdominal cavity), hepatic encephalopathy (a decline in brain function due to the liver’s inability to remove toxins from the blood), and splenomegaly (enlargement of the spleen), which can lead to a reduction in platelet count (thrombocytopenia). Diagnosis typically relies on imaging techniques such as ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI), and sometimes involves direct of portal venous pressure. Treatment strategies focus on reducing portal pressure and preventing complications, often utilizing medications like non-selective beta-blockers, endoscopic therapies to manage varices, transjugular intrahepatic portosystemic shunts (TIPS) to reroute blood flow, and, in advanced cases, liver transplantation.

Social Importance

Portal hypertension carries significant social importance due to its strong association with prevalent chronic liver diseases, including viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease. These conditions are widespread globally, making portal hypertension a substantial public health concern. The severe complications, particularly acute variceal hemorrhage, contribute significantly to morbidity and mortality rates, placing a considerable burden on healthcare systems. Patients often require extensive long-term medical care, frequent monitoring, and emergency interventions, which profoundly impact their quality of life and economic productivity. A deeper understanding of the genetic and environmental factors that contribute to portal hypertension and its underlying liver diseases is essential for developing effective prevention strategies, facilitating early diagnosis, and pioneering targeted therapeutic interventions.

Statistical Power and Generalizability

The statistical power of the genome-wide association study is a significant consideration, given the sample sizes for different phenotypes, which ranged from 673 to 984 participants.^[5] While these numbers are considerable, they may restrict the ability to robustly detect genetic variants contributing to the trait with subtle effects, potentially leading to an overestimation of effect sizes for the identified associations. The study’s reliance on a single cohort, the Framingham Heart Study, also introduces potential cohort-specific biases and limits the immediate generalizability of findings to broader, more diverse populations, necessitating validation in independent and ethnically varied cohorts to confirm the universality of the genetic signals. The lack of specific details on the ancestry of participants in the researchs further underscores this limitation, making it challenging to assess the transferability of the observed associations across different ancestral backgrounds.

Phenotypic Complexity and Missing Heritability

The characterization of phenotypes, despite using advanced techniques such as those yielding ABI, carotid IMT, and MDCT data, inherently presents challenges in capturing the full spectrum of the underlying biological processes.^[5] The precise definition and of complex traits can influence the detectability of genetic associations, and variations in methodology or interpretation might introduce error. Furthermore, even for statistically significant findings, such as those with p < 10^-5, the identified genetic variants typically explain only a fraction of the observed phenotypic variance, pointing to a substantial ‘missing heritability’. This suggests that a considerable proportion of the genetic influence on the trait remains undiscovered, likely due to a combination of rare variants, epistatic interactions, gene-environment interactions, and epigenetic factors not fully captured by current GWAS methodologies.^[5]

Remaining Knowledge Gaps and Causal Inference

Despite identifying several statistically significant genetic associations, including specific SNPs like rs1376877 located in ABI2 and rs3849150 near LRRC18, considerable gaps persist in our understanding of the complete genetic architecture and biological mechanisms underlying the trait.^[5]The functional consequences of these associated variants are often not immediately clear, and their precise roles in disease pathogenesis require extensive post-GWAS functional validation. Moreover, the observational nature of GWAS makes it challenging to infer direct causality; associations may reflect linkage disequilibrium with true causal variants, or they could be influenced by unmeasured environmental or gene-environment confounders. Further research is essential to elucidate the complex interplay between genetic predispositions, environmental factors, and lifestyle choices that contribute to the development and progression of the trait, particularly for variants not located near known genes, such asrs2390582 .^[5]

Variants

Genetic variations play a crucial role in an individual’s susceptibility to liver diseases and their progression to complications like portal hypertension. Among these, thePNPLA3gene and its common variants are particularly significant due to their strong association with lipid metabolism and liver fat accumulation. Thers738408 (I148M) variant in PNPLA3is a well-established risk factor for non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis. This single nucleotide polymorphism impairs the triglyceride hydrolase activity of thePNPLA3protein, leading to increased hepatic triglyceride content, which can initiate a cascade of inflammation and injury within the liver. Thers3747207 variant is also associated with liver fat content and disease progression, often in linkage disequilibrium withrs738408 . The chronic inflammation and collagen deposition characteristic of hepatic fibrogenesis are critical processes in the development of portal hypertension, making thesePNPLA3 variants important contributors to its risk.^[6]Ultimately, the genetic predisposition to liver fat accumulation and fibrosis can lead to cirrhosis, the primary cause of portal hypertension.

Other genes implicated in liver health and potentially portal hypertension includeHAPLN4, TRPC4AP, and PBX4. HAPLN4(Hyaluronan and proteoglycan link protein 4) is involved in organizing the extracellular matrix (ECM), a process critical to liver fibrosis where excessive collagen and other matrix components accumulate, increasing liver stiffness and resistance to blood flow.^[6] The rs72999033 variant in HAPLN4 could thus influence fibrotic progression. TRPC4AP (Transient Receptor Potential Cation Channel Subfamily C Member 4 Associated Protein) is linked to calcium signaling, a fundamental cellular process that regulates inflammation, cell proliferation, and migration. Alterations in these pathways, potentially influenced by the rs369517031 variant, could contribute to liver injury and fibrosis.PBX4 (Pre-B-cell leukemia transcription factor 4) is a transcription factor important in development and cell differentiation; its rs17217098 variant might affect liver regeneration or the inflammatory response, indirectly impacting the progression to portal hypertension.

Further genetic influences come from genes like EPHA7 and MAPT-AS1. EPHA7 (Ephrin Receptor A7) is a receptor tyrosine kinase that mediates cell-cell communication and tissue remodeling, processes vital for maintaining liver architecture and responding to injury. The rs543006888 variant in EPHA7could modify these cellular interactions, influencing the severity of liver inflammation and fibrosis.MAPT-AS1 (MAPT Antisense RNA 1) is a long non-coding RNA (lncRNA) known to regulate gene expression, including that of the MAPT gene. LncRNAs are increasingly recognized for their roles in complex diseases by affecting cellular stress responses, metabolism, and inflammation. The rs532403614 variant in MAPT-AS1might therefore modulate pathways relevant to liver disease pathogenesis, influencing the risk of conditions that lead to portal hypertension.^{[7], [8]}

Key Variants

RS ID	Gene	Related Traits
rs738408 rs3747207	PNPLA3	platelet crit hematocrit hemoglobin aspartate aminotransferase response to combination chemotherapy, serum alanine aminotransferase amount
rs72999033	HAPLN4	triglyceride , depressive symptom low density lipoprotein cholesterol low density lipoprotein cholesterol , lipid esterified cholesterol , low density lipoprotein cholesterol free cholesterol , low density lipoprotein cholesterol
rs369517031	TRPC4AP	portal hypertension
rs543006888	EPHA7	portal hypertension
rs17217098	PBX4	lymphocyte percentage of leukocytes diastolic blood pressure blood VLDL cholesterol amount esterified cholesterol , blood VLDL cholesterol amount free cholesterol , blood VLDL cholesterol amount
rs532403614	MAPT-AS1	portal hypertension

Causes of Portal Hypertension

Portal hypertension, characterized by an elevated pressure within the portal venous system, is a complex condition often arising from increased resistance to blood flow through the liver. Its etiology is multifactorial, involving a intricate interplay of genetic predispositions, environmental exposures, and the progression of various systemic comorbidities. Understanding these diverse causal pathways is crucial for comprehending the development and progression of this trait.

Genetic Susceptibility to Liver Pathology

Genetic factors play a significant role in predisposing individuals to liver conditions that are primary drivers of portal hypertension. Inherited variants can influence the susceptibility to nonalcoholic fatty liver disease (NAFLD), a common precursor to liver cirrhosis and subsequent portal hypertension. For instance, specific genetic loci, includingrs6487679 in PZP on chromosome 12, rs1421201 on chromosome 18, and rs2710833 on chromosome 4, have been identified through genome-wide association studies (GWAS) as being associated with the histologic features of nonalcoholic fatty liver disease.^[6] Such genetic variations can alter metabolic pathways, lipid accumulation, and inflammatory responses within the liver, accelerating the progression from simple steatosis to more severe forms of liver injury. Furthermore, genetic loci influencing concentrations of liver enzymes in plasma have been identified, indicating a polygenic risk for liver dysfunction.^[9] These genetic predispositions can determine an individual’s inherent vulnerability to liver damage, laying the groundwork for conditions that eventually lead to increased portal pressure.

Interplay of Genetics and Environmental Triggers

The development of liver diseases that culminate in portal hypertension is not solely determined by genetics but is significantly modulated by environmental and lifestyle factors, often through gene-environment interactions. While specific environmental exposures like diet and lifestyle choices can independently contribute to liver damage, genetic predispositions can amplify their effects. For example, individuals carrying genetic variants associated with an increased risk of fatty liver disease may be more susceptible to developing severe liver pathology when exposed to certain dietary patterns or sedentary lifestyles.^[6]This interaction can lead to a more rapid progression of conditions like NAFLD, where the genetic background lowers the threshold for environmental triggers to induce inflammation and fibrosis, ultimately increasing intrahepatic resistance and portal pressure. The presence of fatty liver is itself a significant trait influenced by multiple loci, reinforcing how environmental factors like diet interact with an individual’s genetic make-up to drive liver pathology.^[10]

Systemic Comorbidities and Age-Related Progression

Beyond primary liver pathology, several systemic comorbidities, often influenced by a combination of genetic and environmental factors, contribute to the development and severity of portal hypertension. Conditions such as hypertension and diabetes are frequently observed alongside liver disease and can exacerbate hepatic injury and fibrosis. Genetic variants in novel pathways can influence blood pressure and cardiovascular disease risk, while other loci are associated with albuminuria in diabetes, highlighting the genetic basis of these comorbidities.^[4]The presence of these systemic conditions places additional stress on the liver and vascular system, promoting inflammation, oxidative stress, and fibrogenesis, which in turn increase resistance to portal blood flow. Moreover, age-related changes, often accompanied by an increased prevalence of these comorbidities, contribute to the cumulative burden on liver health, making older individuals more susceptible to the progression of liver diseases and the subsequent development of portal hypertension.^[10]Genetic loci influencing kidney function and chronic kidney disease also represent another layer of systemic interaction that can indirectly impact liver health and portal hemodynamics.^[9]

Biological Background

Portal hypertension, characterized by elevated blood pressure within the portal venous system, is a complex condition influenced by a myriad of interconnected biological mechanisms. While the primary etiology often involves liver pathologies, the underlying molecular, cellular, and systemic processes that regulate vascular tone and blood pressure are critical to understanding its development and progression. These processes involve intricate signaling pathways, genetic predispositions, and systemic homeostatic controls that collectively determine the pressure dynamics within the circulatory system.

Molecular and Cellular Regulation of Vascular Tone

Blood pressure, including pressure within specific vascular systems, is tightly regulated by the contractile state of vascular smooth muscle cells (VSMCs).^[11] A critical molecular mechanism involves the balance between vasoconstrictive and vasodilatory signals, where angiotensin II, a potent vasoconstrictor, antagonizes cyclic guanosine monophosphate (cGMP) signaling in VSMCs, thereby promoting their contraction and increasing vascular resistance.^[11] Conversely, pathways that increase cGMP typically lead to vasodilation. The precise control of VSMC contraction also relies on calcium ion channels, such as the CaV1.2 calcium channel, whose activity can be modulated by subunits like CaVbeta2.^[2]impacting the influx of calcium essential for muscle contraction.

These molecular interactions dictate the tone of blood vessels. When these regulatory mechanisms are disrupted, either through increased vasoconstriction or impaired vasodilation, it can lead to elevated pressure within the circulatory system. The intricate interplay of these signaling molecules and ion channels within VSMCs ensures dynamic control over blood flow and resistance, which is fundamental to maintaining pressure homeostasis across various vascular beds.

Genetic Determinants of Cardiovascular Function

Genetic factors play a significant role in predisposing individuals to alterations in cardiovascular function and blood pressure regulation. Common genetic variants in genes such asNPPA and NPPB, which encode natriuretic peptides, are associated with circulating levels of these peptides and systemic blood pressure.^[1]Natriuretic peptides are crucial hormones involved in regulating blood volume and and pressure by promoting sodium and water excretion and vasodilation. Furthermore, mutations in genes likeTBX5, a transcription factor essential for cardiac development, can lead to conditions such as atypical Holt-Oram syndrome and paroxysmal atrial fibrillation.^[12]highlighting how genetic predispositions affecting heart structure and rhythm can influence overall cardiovascular dynamics and pressure.

The precise function and regulation of critical ion channels, such as the CaV1.2 calcium channel, are also under genetic influence, where variations in subunits like CaVbeta2 can alter the channel’s activity.^[2]These genetic mechanisms, through their impact on protein function and expression, establish a foundational susceptibility or resilience to pressure dysregulation within the body by affecting the contractile properties of vascular smooth muscle cells and cardiac muscle.

Signaling Pathways and Cellular Proliferation in Vascular Health

Beyond immediate contractile responses, long-term regulation of vascular health involves complex signaling pathways that influence cellular growth and remodeling. The c-Srcprotein, a non-receptor tyrosine kinase, is a key component in signaling cascades that drive vascular smooth muscle cell (VSMC) proliferation. Specifically, thec-Src and the Shc/Grb2/ERK2 signaling pathway are critical for angiotensin II-dependent VSMC proliferation.^[13] This proliferation contributes to the thickening of vessel walls, increasing resistance to blood flow and potentially exacerbating elevated pressure over time.

These pathways represent a regulatory network where external stimuli, such as angiotensin II, translate into cellular responses that alter vascular structure. The activation of such cascades can lead to maladaptive remodeling of blood vessels, disrupting normal homeostatic mechanisms and contributing to sustained increases in vascular resistance. Understanding these molecular and cellular functions is crucial for comprehending the progressive nature of conditions involving elevated vascular pressure.

Systemic Hormonal and Renal Contributions to Pressure Control

The maintenance of stable blood pressure involves intricate interactions between various organ systems, notably the renal and endocrine systems. The renal endothelin system plays a significant role in regulating blood pressure, as observed in models of spontaneous hypertension like the Prague hypertensive rat.^[14] Endothelins are potent vasoconstrictors produced by endothelial cells, and their dysregulation in the kidneys can profoundly impact systemic vascular resistance and fluid balance.

Hormones like natriuretic peptides, encoded by genes such as NPPA and NPPB, also exert systemic effects that counterbalance vasoconstrictive forces. These peptides promote vasodilation and natriuresis (excretion of sodium in the urine), contributing to the reduction of blood volume and pressure.^[1] Disruptions in these homeostatic mechanisms, whether through overactivity of vasoconstrictive systems or deficiencies in vasodilatory and volume-regulating hormones, lead to systemic consequences that manifest as elevated pressure throughout the circulatory system.

Cellular Signaling and Vascular Dynamics

The regulation of blood pressure and vascular tone involves complex cellular signaling networks that control vascular smooth muscle cell (VSMC) function and proliferation. Key among these are calcium channel modulations, such as theCaVbeta2 subunit’s influence on the CaV1.2 calcium channel, which can impact cellular excitability and contractility.^[2] Angiotensin II, a potent vasoconstrictor, promotes VSMC proliferation through the activation of the c-Src and the Shc/Grb2/ERK2signaling pathway, contributing to vascular remodeling associated with hypertension.^[2]Furthermore, altered phosphodiesterase 3-mediated cAMP hydrolysis can contribute to a hypermotile phenotype in aortic VSMCs, suggesting a role for aberrant intracellular signaling in diabetes-associated cardiovascular disease.^[11]

Hormonal and Endothelial Regulatory Systems

Several interconnected hormonal and endothelial systems play crucial roles in maintaining vascular homeostasis and are implicated in hypertension. The renal endothelin system, for example, is a significant contributor to blood pressure regulation and has been studied in models of spontaneous hypertension.^[2] Natriuretic peptides, encoded by genes like NPPA and NPPB, exert counter-regulatory effects by promoting vasodilation and natriuresis, and their circulating levels are associated with blood pressure.^[2]Additionally, the tissue kallikrein–kinin system is recognized for its involvement in hypertension and vascular remodeling, influencing local vascular responses and systemic blood pressure.^[15]

Lipid Metabolism and Vascular Health

Disruptions in lipid metabolism pathways are closely linked to cardiovascular health and can influence vascular function. The mevalonate pathway, regulated by hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is central to cholesterol biosynthesis and its regulation is critical for maintaining healthy lipid profiles.^[16] Genetic variants affecting alternative splicing of HMGCR exon13, for instance, are associated with varying LDL-cholesterol levels.^[16] Moreover, pathway-wide association studies have identified multiple genes involved in sterol transport and metabolism that are associated with HDL cholesterol regulation, highlighting the systemic impact of lipid homeostasis on vascular health.^[17]

Genetic and Post-Translational Regulatory Control

Genetic variations and post-translational modifications provide hierarchical regulatory control over pathways relevant to blood pressure and cardiovascular function. Genome-wide association studies (GWAS) have identified numerous genetic variants influencing blood pressure regulation, lipid metabolism, and cardiac structure, demonstrating the complex genetic architecture of these traits.^{[2], [18]} For example, a gain-of-function mutation in the TBX5 gene can lead to atypical Holt-Oram syndrome and paroxysmal atrial fibrillation, illustrating how specific genetic alterations can dysregulate cardiac development and function.^[2] Alternative splicing, such as that observed for HMGCR, represents a post-transcriptional regulatory mechanism that can modify protein function and contribute to disease-relevant phenotypes.^[16]

Frequently Asked Questions About Portal Hypertension

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

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1. My family has liver issues. Am I more prone to portal hypertension?

Yes, a family history of liver issues can increase your risk. Portal hypertension often stems from chronic liver diseases like viral hepatitis, alcoholic liver disease, or non-alcoholic fatty liver disease, all of which can have genetic predispositions. Your genes can influence how susceptible your liver is to damage or how quickly a condition progresses.

2. Can eating healthy really protect me from getting this condition?

Eating healthy can significantly reduce your risk, especially by preventing conditions like non-alcoholic fatty liver disease (NAFLD), a common cause of portal hypertension. While genetic factors influence susceptibility to liver diseases, lifestyle choices like diet play a crucial role in mitigating or exacerbating these risks. A healthy diet helps manage factors that contribute to liver damage.

3. Why do some people with liver disease get severe bleeding, but others don’t?

Individual differences in developing severe complications like variceal bleeding can be influenced by genetics. Genetic variants that affect vascular tone and blood flow dynamics might play a role in how readily collateral vessels form and become fragile in your body. The progression of liver fibrosis, which contributes to pressure, also varies genetically.

4. Does my ethnic background affect my chances of developing liver disease?

Yes, your ethnic background can influence your risk. Genetic studies often highlight differences across populations, and the prevalence of certain liver diseases like viral hepatitis or non-alcoholic fatty liver disease can vary. Research suggests that genetic findings need validation in diverse populations, implying that your ancestry might affect your specific genetic predispositions.

5. If I drink alcohol moderately, am I still increasing my risk for liver damage?

While moderate drinking generally carries less risk, individual susceptibility to alcoholic liver disease can vary due to genetic factors. Your genes can influence how your body processes alcohol and how vulnerable your liver is to damage, even from seemingly moderate consumption. It’s a complex interplay between lifestyle and genetic predisposition.

6. Could I have portal hypertension without any obvious symptoms?

Yes, it’s possible for chronic liver diseases to progress without immediate, overt symptoms, eventually leading to portal hypertension. The condition often arises from structural changes in the liver, like fibrosis, that develop over time. Early stages might be subtle, making regular check-ups important, especially if you have risk factors.

7. Is there a special test to know if I’m personally at high risk?

While there isn’t a single routine “portal hypertension risk” genetic test widely available, research is identifying genetic variants that contribute to overall blood pressure regulation and liver disease susceptibility. Understanding these genetic factors could one day help assess individual risk, but current diagnosis relies more on imaging and liver function tests.

8. Why do some people get fatty liver disease so easily, even if they’re not overweight?

Non-alcoholic fatty liver disease (NAFLD) can indeed have a strong genetic component, meaning some individuals are more predisposed to it regardless of their weight. Genetic variants can influence how your body processes fats and sugar, making your liver more susceptible to fat accumulation. This can then progress to more severe liver disease and portal hypertension.

9. Why do some people’s livers get damaged faster than others?

The rate of liver damage and disease progression varies significantly between individuals, and genetics play a role. Your genetic makeup can influence how effectively your liver repairs itself, its susceptibility to fibrosis, and how it responds to various stressors like viruses or toxins. This leads to differing rates of conditions like cirrhosis.

10. Can I completely avoid portal hypertension if I live a healthy lifestyle?

Living a healthy lifestyle significantly reduces your risk, but it might not completely guarantee avoidance, especially if you have strong genetic predispositions. While lifestyle choices are crucial in preventing conditions like alcoholic or non-alcoholic fatty liver disease, genetic factors can still influence your underlying susceptibility or the progression of liver damage.

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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

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[2] Levy, D, et al. “Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness.”BMC Med Genet, vol. 8, suppl. 1, 2007, p. S3. PubMed, PMID: 17903302.

[3] Arnett, DK, et al. “Genome-wide association study identifies single-nucleotide polymorphism in KCNB1 associated with left ventricular mass in humans: the HyperGEN Study.”BMC Med Genet, vol. 10, 2009, p. 48. PubMed, PMID: 19454037.

[4] Ehret, GB, et al. “Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.”Nature, vol. 478, no. 7367, 2011, pp. 103-09. PubMed, PMID: 21909115.

[5] O’Donnell, Christopher J. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.”BMC Medical Genetics, vol. 8, 2007, p. 77.

[6] Chalasani, N. et al. “Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease.”Gastroenterology, vol. 139, no. 5, 2010, pp. 1599-1609.

[7] Ferrucci, L. et al. “Common variation in the beta-carotene 15,15’-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study.” Am J Hum Genet, vol. 84, no. 1, 2009, pp. 123-133.

[8] Wallace, C. et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, vol. 82, no. 1, 2008, pp. 139-149.

[9] Chambers, John C., et al. “Genetic loci influencing kidney function and chronic kidney disease.”Nature Genetics, vol. 42, no. 5, 2010, pp. 445-50.

[10] Choe, Eun Kyoung, et al. “Leveraging deep phenotyping from health check-up cohort with 10,000 Korean individuals for phenome-wide association study of 136 traits.” Scientific Reports, vol. 12, no. 1, 2022, p. 1930.

[11] Vasan, R. S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, 2007.

[12] 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.

[13] 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. 339–49.

[14] 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.

[15] Temprano-Sagrera, Gema, et al. “Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations.”Journal of Thrombosis and Haemostasis, vol. 20, no. 5, 2022, pp. 1162–1177.

[16] Burkhardt, R. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, 2008, pp. 2070–2077.

[17] Sung, Yun J., et al. “Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat.” International Journal of Obesity, vol. 40, no. 5, 2016, pp. 883–892.