The role of heredity in the development of cardiovascular diseases

The role of heredity in the development of cardiovascular diseases

I. Introduction: genetic landscape of cardiovascular risk

Cardiovascular diseases (SVD) is a group of diseases that affect the heart and blood vessels, remaining a leading cause of mortality around the world. The complex interaction of genetic factors and environmental factors determines the receptiveness of a person to the SVD. Although modified risk factors, such as diet, physical activity and smoking, play an important role, more and more data emphasizes the significant influence of heredity on the development of the SVD.

II. Family aggregation and risk of SVD: epidemiological evidence

Numerous epidemiological studies sequentially demonstrate that the presence of SVD in close relatives significantly increases the risk of developing similar diseases in an individual. This family aggregation indicates a likely genetic component of the RISS risk.

  • Studies on Gemini: Studies on twins, especially on monozygous (single -eating) and dizigate (bilingual) twins, are a powerful tool for evaluating the heredity of signs. Higher concordantity (similarity) of the SVD in monozygous twins compared to dizigate twins implies a significant genetic effect. For example, studies have shown that the inheritance of coronary heart disease (IBS) is approximately 40-60%.

  • Family research: Family studies can trace the presence of SVD in several generations of the same family. These studies have identified families with a high risk of developing early SVDs, which suggests the presence of dominant or recessive genes that increase susceptibility.

  • Research for adoptive children: Studies of adoptive children, which compare the health indicators of adopted children with the indicators of the health of their biological and adoptive parents, can help separate genetic influences from environmental influences.

III. Genetic mechanisms underlying the SSZ

Genetic factors can affect various aspects of the physiology of the cardiovascular system, including:

  • Structure and function of blood vessels: Genes can affect the structure and function of the walls of the arteries, their elasticity and a tendency to the formation of atherosclerotic plaques.

  • Regulation of blood pressure: Genetic options can affect the activity of the renin-angiotensin-aldosterone system (RAS), the sympathetic nervous system and other mechanisms that regulate blood pressure.

  • Lipid metabolism: Genes play an important role in the metabolism of lipoproteins, such as LDL cholesterol (low density lipoproteins) and HDL cholesterol (high density lipoproteins), and triglycerides, which affects the risk of atherosclerosis.

  • Inflammation: Inflammation plays a decisive role in the development and progression of the SSZ. Genetic options can affect the inflammatory paths and the level of circulating inflammatory markers.

  • Coagulation and thrombosis: Genes can affect blood coagulation and a tendency to form blood clots, which can lead to myocardial infarction and stroke.

  • Cardiomyocyte function: Genes can affect the structure and function of cardiomyocytes (cells of the heart muscle), which can lead to cardiomyopathy and heart failure.

IV. Specific genetic variants associated with the CVD

The numerous genetic variants associated with an increased risk of development of the CVD are identified. These genes are involved in various physiological processes related to the cardiovascular system.

  • Lipid metabolism genes:

    • LDLR (low density lipoproteins receptor): Mutations in the LDLR gene are the most common cause of family hypercholesterolemia (FG), a hereditary disease characterized by a high level of LDL cholesterol and an increased risk of early SVDs.

    • APOB (apolipoprotein b): Apob gene encodes the main LDL protein. Mutations in the APOB gene can also cause FG.

    • PCSK9 (subtilizine-biscuit-biscuits 9): PCSK9 regulates the number of LDL receptors on the surface of the liver cells. Variations in the PCSK9 gene are associated with the level of LDL cholesterol and the risk of SVD. PCSK9 inhibitors are a new class of drugs that reduce the level of LDL cholesterol.

    • LPL (Lipoproteinlipaz): LPL is an enzyme that hydrolyzing triglycerides in lipoproteins. Mutations in the LPL gene can lead to hypertriglyceridemia and increased risk of pancreatitis and SSZ.

    • CETP (protein, carrying ethers of cholesterol): CETP transfers cholesterol from HDL to other lipoproteins. Variations in the CETP gene are associated with the level of HDL cholesterol and the risk of SVD.

  • Genes associated with the regulation of blood pressure:

    • Agt (angiotensinogen): AGT is the predecessor of angiotensin II, a powerful vasoconstrictor. Variations in the AGT gene are associated with high blood pressure.

    • ACE (angiotensinoproting enzyme): Ace turns angiotensin I into angiotensin II. Variations in the ACE gene are associated with high blood pressure and the risk of SVD.

    • Add1 (Adducin 1): ADD1 is involved in the regulation of sodium transport in the kidneys. Variations in the ADD1 gene are associated with high blood pressure.

  • Genes associated with inflammation:

    • IL6 (Interlayykin 6): IL6 is a pro -inflammatory cytokine. Variations in the IL6 gene are associated with an increased IL6 level in the blood and an increased risk of SVD.

    • TNF (tumor necrosis factor): TNF is a pro -inflammatory cytokine. Variations in the TNF gene are associated with an increased TNF level in the blood and an increased risk of SVD.

    • CRP (C-reactive protein): CRP is a marker of inflammation. Although CRP itself is not genetically encoded, genetic factors can affect the CRP level in the blood.

  • Coagulation genes and thrombosis:

    • F5 (Factor V): LEIDEN LEIDEN Mutation V is a common genetic risk factor for thromboembolism.

    • F2 (prothrombin): The G20210A option is associated with an increased risk of thromboembolism.

    • ITGA2 (integral alpha-2): ITGA2 encodes the alpha-2 indigrine subunit, collagen receptor on platelets. Variations in the ITGA2 gene affect platelet adhesion and thrombosis risk.

  • Genes associated with the function of cardiomyocytes:

    • Myh7 (beta-miozin of a heavy chain): Mutations in the MyH7 gene are the most common cause of hypertrophic cardiomyopathy (GKMP).

    • Mybpc3 (protein C, connecting myosine, heart): Mutations in the MyBPC3 gene are also a common cause of GKMP.

    • LMNA (lamine A/C): Mutations in the LMNA gene can cause various forms of cardiomyopathy and conductivity disorders.

V. Polygenic risk and genomic research of associations (GWAS)

Most of the CVD are polygenic, that is, the risk of the disease is determined by a combination of many genetic options, each of which has a slight effect. GWAS is an approach that allows scanning the entire genome for genetic options associated with the disease.

  • GWAS revealed numerous loci related to the CVD: GWAS identified hundreds of genetic loci associated with the risk of SVD. These loci are often in genes involved in lipid metabolism, regulation of blood pressure, inflammation and other processes related to the cardiovascular system.

  • Polygenic risk assessments (PRS): PRS is estimates that summarize the effects of many genetic options to assess the genetic risk of the disease. PRS for SSZ can help identify people with high genetic risk and direct preventive measures.

VI. Epigenetics and SV

Epigenetics is a study of changes in genes expression that are not associated with changes in the DNA sequence. Epigenetic mechanisms, such as DNA methylation, modifications of histones and micrord, can affect the development of SVD.

  • Epigenetic changes under the influence of environmental factors: Environmental factors, such as diet, smoking and the effects of toxins, can cause epigenetic changes that affect the risk of CVD.

  • Epigenetic changes are inherited: In some cases, epigenetic changes can be transmitted from generation to generation, which can affect the risk of SVD for descendants.

VII. Genetic testing and clinical application

Genetic testing can be used to identify people with a high genetic risk of CVD and to manage clinical solutions.

  • Family hypercholesterolemia screening: Genetic testing can be used to identify people with FG, which can benefit from the early start of treatment with statins.

  • Assess the risk of cardiomyopathies: Genetic testing can be used to identify people with genetic mutations that increase the risk of cardiomyopathy.

  • Pharmacogenetics: Genetic testing can be used to predict a person’s response to drugs used to treat SVDs, such as statins and anticoagulants.

  • Specification Diagnosis: Genetic testing can help clarify the diagnosis with unclear clinical paintings.

VIII. Genetic testing restrictions and ethical considerations

Genetic testing has restrictions, and it is necessary to take into account ethical considerations.

  • Incomplete penetrance: Not all people with a genetic mutation will develop the disease. Penetrandity is the likelihood that a person with a genetic mutation will show a disease.

  • Various expressiveness: In people with the same genetic mutation, the disease can manifest themselves in different ways.

  • Psychological impact: The results of genetic testing can have a psychological effect, such as anxiety and depression.

  • Discrimination: There is a risk of genetic discrimination by employers and insurance companies.

  • Confidentiality: It is necessary to protect the confidentiality of genetic information.

IX. Interaction of genes and the environment (GXE)

The risk of SVD is determined by the complex interaction between genes and environmental factors.

  • Environmental factors can modulate the effect of genes: For example, a high content of saturated fats can increase the risk of SVD in people with a genetic predisposition to hypercholesterolemia.

  • Genes can affect susceptibility to environmental effects: For example, some people can be more susceptible to the harmful effects of smoking than others, depending on their genetic composition.

  • Epigenetic mechanisms play a role in the interaction of GXE: Environmental factors can cause epigenetic changes that affect the expression of genes and the risk of SVD.

X. Prospects for genetic research of the CVD

Genetic studies of the CVD continue to develop, and it is expected that in the future they will lead to new discoveries and improve the results of the treatment of patients.

  • Increasing accuracy PRS: In the future, an increase in PRS accuracy for the SSZ is expected, which will more effectively identify people with high genetic risk.

  • Development of new drugs based on genetic targets: Genetic studies can identify new medicinal targets for the treatment of SSZ.

  • Personalized medicine: Genetic information can be used to personalize preventive and therapeutic strategies for individual patients.

  • A deeper understanding of the biological mechanisms of the SVD: Genetic studies can help us better understand the biological mechanisms underlying the SVD, which will lead to the development of more effective treatment methods.

XI. Specific SPZ and their genetic component

  • Corny heart (coronary heart disease): IBS, characterized by atherosclerotic damage to the coronary arteries, has a significant genetic component. Genes affecting lipid metabolism (LDLR, APOB, PCSK9), inflammation (IL6, CRP), coagulation (F5, F2) and vascular function, play an important role. GWAS revealed numerous locals associated with the IBS, including 9P21.3, containing the CDKN2A/B gene, which is involved in the regulation of the cell cycle.

  • Stroke: A stroke caused by a violation of blood supply to the brain also has a genetic predisposition. Distinguish ischemic and hemorrhagic stroke. Genetic factors affecting blood coagulation, blood pressure and blood vessels can increase the risk of stroke. Mutations in the Notch3 gene are associated with cerebral autosomal-dominant arteriopathy with subcortical heart attacks and leukoencephalopathy (Cadasil), a form of hereditary stroke.

  • Arterial hypertension: Arterial hypertension (high blood pressure) is an important risk factor in the CVD. Genetic factors affecting the renin-angiotensin-aldosterone system (RAS), sodium transport and vascular function can increase blood pressure. Variations in the AGT, ACE, ADD1 and GNB3 genes are associated with hypertension. GWAS also revealed numerous loci associated with blood pressure.

  • Heart failure: Heart failure, a state in which the heart cannot pump blood enough to meet the needs of the body, may have genetic causes. Cardiomyopathy, diseases of the heart muscle, are often hereditary and can lead to heart failure. Mutations in the MyH7, Mybpc3, LMNA and TTN genes are associated with various forms of cardiomyopathy.

  • Congenital heart defects (VPS): Higher School of Economics, structural anomalies of the hearts present at birth often have a complex etiology, including both genetic and environmental factors. Mutations in genes involved in the development of the heart, such as NKX2-5, GATA4 and TBX5, can cause VPS. Di George syndrome, caused by a deletion in the field of 22Q11.2, is a common genetic cause of the Higher Superior.

  • Aortic aneurysm: Aortic aneurysm, the expansion of the aorta, can lead to a break and death. Genetic factors affecting the structure and function of the walls of the aorta can increase the risk of aneurysm. Mutations in the genes TGFBR1, TGFBR2, SMAD3 and Acta2 are associated with family aortic aneurysms and Loyes-trunis syndrome. Marfan syndrome, caused by mutations in the FBN1 gene, is also associated with the aneurysm of the aorta.

  • Arrhythmias: Arrhythmias, heart rhythm disturbances can be caused by genetic factors. The elongated QT interval syndrome, a hereditary disease characterized by an extension of the QT interval on the ECG can lead to sudden heart death. Mutations in the KCNQ1, KCNH2 and SCN5A genes are common causes of suiqt. Brugada syndrome, another hereditary disease associated with arrhythmias, caused by mutations in the SCN5A gene.

XII. Key genes and their functions in more detail

  • LDLR (low density lipoproteins receptor): This gene encodes the LDL receptor located on the surface of the cells, especially in the liver. LDL receptor binds to LDL, allowing them to enter the cells for metabolism. Mutations in LDLR lead to family hypercholesterolemia, a state characterized by a high level of LDL cholesterol in the blood. This increased content of LDL contributes to the development of atherosclerosis, since LDLs are deposited in the walls of the arteries, forming plaques.

  • APOB (apolipoprotein b): APOB is the main protein found in LDL and LOPP (very low density lipoproteins). It is necessary for the assembly and secretion of these lipoproteins. APOB also plays a role in connecting LDL with LDL receptor. Apob mutations, especially those that affect the link in the LDL receptor, can lead to family hypercholesterolemia.

  • PCSK9 (protein converting subtilizine / biscuits type 9): PCSK9 is a protein that contacts the LDL receptor and causes its degradation in lysosomes. Thus, PCSK9 reduces the number of LDL receptors on the surface of the cells, which leads to a decrease in the capture of LDL from the blood and an increase in the level of LDLC cholesterol. Variations in PCSK9, which lead to an increased PCSK9 function, are associated with an increased risk of CVD. PCSK9 inhibitors, a class of drugs that reduce the activity of PCSK9 are used to reduce the level of LDLC cholesterol and reduce the risk of SSZ.

  • Agt (angiotensinogen): AGT is the predecessor of angiotensin II, a powerful vasoconstrictor, which plays a key role in the regulation of blood pressure. AGT is produced in the liver and turns into angiotensin with renin. Angiotensin I then turns into angiotensin II angiotenzinzinoprofing enzyme (ACE). Genetic variations in Agt, such as M235T polymorphism, are associated with high blood pressure.

  • ACE (angiotensinoproting enzyme): ACE is a key enzyme in a renin-angiotensin system (RAS). It turns angiotensin I into angiotensin II, which causes narrowing of the blood vessels and increases the retention of sodium and water, which leads to an increase in blood pressure. ACE Polymorphism (Inersion/Deletion (I/D) Polymorphism) is associated with arterial hypertension and the risk of SVD.

  • Myh7 (myosin, heavy chain 7, heart beta): Myh7 encodes beta-miozin heavy chain, the main protein of the contractile apparatus of the heart muscle. Mutations in MyH7 are the most common cause of hypertrophic cardiomyopathy (GKMP), a hereditary disease characterized by a thickening of the heart muscle. GKMP can lead to heart failure, arrhythmias and sudden heart death.

  • Mybpc3 (protein C, connecting myosine, heart): Mybpc3 encodes a protein that is associated with both myosin and actin in the sarrotomer of the heart muscle. He plays a role in the regulation of the contraction of the heart muscle. Mutations in Mybpc3 are also a common cause of GKMP.

  • LMNA (Lamine A/C): LMNA encodes Lamin A and C proteins, which are components of nuclear lamine, a structural network inside the cage nucleus. LMNA mutations can cause various forms of cardiomyopathy, including dilatation cardiomyopathy (DKMP) and atrioventricular blockade.

  • TGFBR1 and TGFBR2 (receptor transforming growth factor beta 1 and 2): TGFBR1 and TGFBR2 encode receptors of the transforming factor of beta growth (TGF-β), cytokine, which plays the role in the development and maintenance of blood vessels. Mutations in TGFBR1 and TGFBR2 are associated with Loyes-Titting syndrome, a hereditary disease of connective tissue, which is characterized by aortic aneurysms and other anomalies.

  • FBN1 (Fibrillin 1): FBN1 encodes fibrillin-1, the main component of microfibrils, which are important for the strength and elasticity of connective tissue, especially in the aorta. Mutations in FBN1 cause marfan syndrome, a genetic disease of connective tissue, which is characterized by aortic aneurysms, a lens dislocation and other skeleton abnormalities.

XIII. Problems and future directions of genetic research

  • Sample size and diversity: Many genetic studies are mainly focused on European population populations. To improve the generalization and identify genetic options specific for the population, it is necessary to expand research by including more diverse population groups.

  • Functional abstract of genetic options: Many genetic options detected as a result of GWAS are located in the non -encoding areas of the genome, which complicates the determination of their functional value. Further research is needed to understand how these options affect the expression of genes, protein structure or other cell processes.

  • Interaction Gen-Gen (GXG): SSZ probably depend on complex interactions between several genes. Studies studying the interaction of GXG can help identify combinations of genetic options that have a disproportionate effect on the risk of the disease.

  • Integration of ohmic data: The integration of genomic data with other ohmic data, such as transcriptomics, proteomics and metabolomics, can give a more complete idea of the biological paths that underlie the CVD.

  • Development of more effective PRS methods: PRS is currently limited by their prognostic accuracy. Further studies are needed to develop more effective PRS methods, which include more genetic options, take into account the interaction of the gene-Gen and the gene-converting medium, and also take into account genetic effects specific to the population.

  • Ethical use of genetic information: As genetic testing is becoming more and more common, it is important to solve ethical issues related to confidentiality, discrimination and interpretation of the results. Clear recommendations are needed to ensure that genetic information is used responsible for the benefit of patients.

XIV. The effect of genetics on the prevention and treatment of SVD

  • Primary prevention: Genetic testing can be used to identify persons with a high genetic risk of development of the SVD, allowing more purposeful preventive measures. For example, persons with a genetic predisposition to hypercholesterolemia can benefit from the early start of changes in lifestyle and drug therapy to reduce cholesterol.

  • Secondary prevention: In persons with the existing SSZs, genetic information can be used to select the most suitable treatment options and monitor the response to therapy. For example, pharmacogenetic testing can help determine which statins are most effective for a particular patient.

  • Development of new drugs: The identification of genetic targets can lead to the development of new drugs for the treatment of SVD. For example, PCSK9 inhibitors were developed on the basis of genetic studies of cholesterol metabolism.

  • Stratification Risk: Genetic information can be used to stratify the risk of patients with SVD, allowing a more personalized approach to treatment. For example, faces with a high genetic risk of sudden heart death can be beneficial from implantation of the cardioverter defibrillator (ICD).

XV. The future of cardiovascular genetics

The future of cardiovascular genetics looks promising. As we learn more about the genetic foundations of the SVD, we will have more opportunities for identifying people with high risk, developing new methods of treatment and personalization of preventive and therapeutic strategies. Key areas of future research include:

  • Further study of the genome: Further research is needed to identify all the genetic options related to the SVD, and to understand how these options interact with each other and with environmental factors.

  • Development of more effective PRS: Further research is needed to develop more effective PRS, which can accurately predict the risk of SVD in individuals.

  • Study of the influence of epigenetics: Further studies are needed to understand the role of epigenetics in the development of SVD and for the development of methods that allow you to influence the epigenetic mechanisms for the prevention and treatment of SVD.

  • Broadcast of genetic discoveries into clinical practice: It is important to translate genetic discoveries into clinical practice so that patients have access to the best possible treatment.

XVI. Genetic consultation and family history

  • Family history collection: The collection of a detailed family history of the CVD is an important step in assessing a genetic risk in humans. The anamnesis should include information about the age of the SVD for relatives of the first and second degree of kinship, as well as any cases of sudden heart death.

  • When should be directed to genetics: Persons with the family history of the early development of the SVD, several affected family members or a rare hereditary disease should be directed to the genetics. A genetic consultant can evaluate the genetic risk of a person, prescribe appropriate genetic testing and provide advice on prevention and treatment.

  • Discussion of genetic testing results: It is important to discuss the results of genetic testing with a genetic consultant or other medical worker in order to understand their meaning and consequences for health.

XVII. Genetics and remedy therapy in SSZ

  • Pharmacogenetics: Pharmacogenetics studies how genes affect a person’s reaction to medicines. Pharmacogenetic testing can be used to predict a person’s response to medicines used to treat SVD, such as statins, clopidogrel and warfarin.

  • Statin: Statins are drugs that are used to reduce LDL cholesterol. Genes affecting the metabolism of statins, such as SLCO1b1, can affect the efficiency and side effects of statins.

  • Clopidogrel: Clopidogrel is an antiplatelet that is used to prevent blood clots. The CYP2C19 gene affects the activation of Clopidogen. Persons with certain genetic options CYP2C19 can have a reduced reaction to clopidogrel.

  • Varfarin: Warfarin is an anticoagulant that is used to prevent blood clots. Vkorc1 and CYP2C9 genes affect the metabolism of warfarin. Persons with certain genetic options VKORC1 and CYP2C9 may need a different dose of warfarin.

XVIII. Genetics and lifestyle

Although genetics plays an important role in the risk of SSZ, lifestyle factors are also important. The adoption of a healthy lifestyle can help reduce the risk of CVD, even in people with a genetic predisposition.

  • Diet: A balanced diet with a low content of saturated fats, trans fats, cholesterol and sodium can help reduce the risk of SVD. It is recommended to consume a lot of fruits, vegetables and whole grains.

  • Exercise: Regular physical exercises can help improve the health of the cardiovascular system, reduce blood pressure, reduce cholesterol and control weight. It is recommended to engage in moderate aerobic exercises for at least 150 minutes a week or intense aerobic exercises of at least 75 minutes a week.

  • Smoking: Smoking is the main risk factor in the SSZ. The cessation of smoking can significantly reduce the risk of the CVD.

  • Weight control: Excess weight or obesity increase the risk of SVD. Weight control with a diet and physical exercises can help reduce the risk of SVD.

  • Stress control: Chronic stress can increase the risk of CVD. Stress control methods, such as yoga, meditation and deep breathing, can help reduce the risk of CVD.

XIX. Ethical, legal and social consequences of the genetics of the SVD

Genetic studies of the SVD have serious ethical, legal and social consequences.

  • Confidentiality: Genetic information is personal and must be protected from unauthorized access.

  • Discrimination: There is a risk of genetic discrimination by employers and insurance companies.

  • Justice: It is important to ensure that genetic testing and genetic information are available to all, regardless of race, ethnicity or socio-economic status.

  • Informed consent: Before conducting genetic testing, faces should be informed about the risks and advantages of testing, as well as how their genetic information will be used.

  • Public education: It is important to educate the public about the genetics of the SVD and how genetic information can be used to improve health.

XX. Resources for patients and families

There are many resources for patients and families who want to learn more about the genetics of the SVD.

  • Medical workers: Contact your doctor or another medical worker to learn more about the genetics of the SVD.

  • Genetic consultants: A genetic consultant can evaluate your genetic risk, prescribe appropriate genetic testing and provide advice on prevention and treatment.

  • National Health organizations: Many national healthcare organizations, such as the American Cardiological Association and the National Institute of Heart, Light and Blood, provide information about the genetics of the SVD.

  • Online resources: There are many resources on the Internet about the genetics of the SVD, including websites of medical institutions and healthcare organizations.

Studying the genetics of the SPZ is a continuous process that changes our understanding of these complex diseases. The development of technology and the deepening of scientific knowledge allow us to use genetic information for more accurate diagnosis, the development of effective methods of treating and introducing personalized prophylaxis approaches. The continuation of research and their use in clinical practice promise a significant improvement in the health of the cardiovascular system and a decrease in the burden of these diseases around the world.

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