Cardiovascular disease (CVD) is the most common cause of mortality worldwide, affecting around 17.9 million individuals each year. CVDs are an umbrella term used to describe the disorders of the heart and vascular system that mainly include coronary heart disease, cerebrovascular disease, and rheumatic heart disease.1,2 According to World Health Organization (WHO) surveys, cardiovascular disease-related deaths are expected to exceed 23 million globally by 2030. CVD death rates in developed as well as developing countries have increased in recent decades.3 According to a WHO estimate, low- and middle-income countries account for more than three-quarters of CVD mortality, which has become a serious epidemic in recent years.4,5 Ischemic Heart Disease (IHD) and cerebrovascular diseases constitute two of the top five main causes of increased Disability Adjusted Life Years (DALYs).6 A biomarker is defined a distinct biological substance present in body fluids or tissues that is analysed to indicate normal biological processes, pathological processes, or a response to an exposure or treatment, including pharmacological therapies. They are also known as molecular markers or signature molecules. These markers can be chemical elements like proteins, DNA, RNA, or metabolites, as well as physical signs like blood pressure and heart rate. These are useful in medical practice, clinical research, and drug development because they can signal illness prevalence, progression, severity, or therapeutic responsiveness. They offer useful insights into diagnosis and progression of disease, pharmacological therapy evaluation, and patient outcome prediction.7 By looking into the complex relationship between gene mutations and cardiovascular health, this review hopes to shed more light on the potential clinical utility of genetic markers for stratification of risk, personalized medicine, and targeted pharmaceutical care in cardiovascular disease management.

Genetic markers are quantitative measures of DNA and or RNA sequence which is an indicator of normal biologic and pathogenic processes and or response to curative or other therapeutic interventions.8 As it is derived from genetic variation, it can provide a detailed clarity about a person's predisposition to disease progression, development and response to treatment. Genetic markers in cardiac disorders play a major role in understanding the genetic vulnerability to heart diseases, risk analysis and personalized medicine.9 A family history of cardiac disease, as well as genetic anomalies, may increase the likelihood of illness progression.10 Changes in DNA sequence and epigenetic profile have been linked to heart disease. These genetic biomarkers are present at birth but are only triggered when subjected to specific activities, such as co-morbid conditions, environmental factors, and lifestyle behaviours.11,12 The identification of genetic cardiac markers helps to understand the complex relationship between genetics and cardiovascular health. Apolipoprotein genes, TTN genes, Troponin genes, KCNQ1 & KCNH2 genes, MYBPC3 genes, MYBPC3 genes, PLIN1 genes, ACE genes, LDLR genes and LMNA genes are some key genes associated with cardiovascular disorders.

Apolipoproteins are proteins found in the blood that attach to fats and produce lipoproteins, which transport cholesterol and other lipids throughout the bloodstream.13 Apolipoproteins have other activities such as enzyme cofactors and cell-surface receptor ligands. It is mostly produced in the liver and partially in the small intestine.14 Apolipoproteins are classified into six categories (Apolipoprotein A1, Apolipoprotein B, Apolipoprotein C-1, Apolipoprotein C-2, Apolipoprotein C-3, Apolipoprotein E), each encoded by a specific gene. Among different types of apolipoproteins, the apolipoprotein E (APOE), and Apolipoprotein A1(APOA1) genes are the most widely studied genetic indicators of cardiovascular disease as it is the principal element of high-density lipoprotein and low-density lipoprotein. Higher ApoB and lower ApoA1 levels are linked to an increased risk of cardiovascular disease.15 The Apolipoprotein E (APOE) gene encodes instructions for producing a protein known as apolipoprotein E. There are at least three different alleles of the APOE gene. The primary alleles are ε 2, ε 3, and ε 4. ε 3 is the most prevalent allele, accounting for more than half of the general population. Variations in these alleles specially ε4 and ε2 allele have been reported with higher incidence of atherosclerosis, and acute coronary syndrome by promoting atherogenic lipoprotein levels and LDL levels.16 This indicates the role of genetic factors in fat metabolism and cardiovascular disease risk. Apolipoprotein A1 (APOA1) is a protein component of in good cholesterol (High-Density Lipoprotein). HDL cholesterols transfer cholesterol from peripheral tissues to the liver, where it is processed through metabolism and removed by excretion, an activity referred to as reverse cholesterol transport. APOA1 is encoded by the APOA1 gene on chromosome 11q23-q24. Variants in the APOA1 gene can impact APOA1 levels and HDL cholesterol levels, affecting a person's vulnerability to cardiovascular disease.17

The TTN gene encodes instructions for producing titin.18 Titin, commonly known as connectin, is a large protein that is essential for the growth and development of striated muscle, especially cardiac and skeletal muscle.19 It is the largest known protein in human beings, having a molecular weight of over 3-4 million Dalton's. TTN protein chains are coloured: Z-disc (red), I-band (blue), A-band (green), and M-band (purple).20 The titin gene is found on the short arm of chromosome two. It has 363 coding exons and an extra initial non-coding exon. Titin works as a molecular spring, adding elasticity and stiffness to muscle fibres. Titin is an essential component of muscle cell structures known as sarcomeres.21 Titin has multiple functions within sarcomeres. One of the protein's primary functions is to provide structure, flexibility, and stability to the cell structures. Titin interacts with other muscle proteins, such as actin and myosin, to keep sarcomere components in place during muscular contraction and relaxation.22 Titin also has a spring-like structure that permits muscles to stretch. TTN gene variations play an important role in the etiology of many cardiac disorders like Dilated Cardio Myopathy, Hypertrophic Cardio Myopathy (HCM) and Arrhythmogenic Cardio Myopathy (ACM). Genetic screening for TTN gene variations may be utilized to assess people with suspected cardiomyopathies or a family history of cardiac disease.23 Understanding these variations may assist in risk assessment, prompt diagnosis, and individualized treatment for affected people and their families.

The Troponin T gene is situated at 1q32 in the mammalian chromosomal genome encodes instructions for producing a protein called cardiac Troponin T which is found only in cardiac muscles.24 Heart troponin T is one of three proteins that form the troponin protein complex in heart muscle cells. The troponin system is a fundamental component of muscle contraction. Sarcomeres are composed of thick and thin filaments. The overlapping or binding of thick and thin filaments to each other and then their release, allowing the filaments to move one another, causes muscles to contract.25 Together with calcium, the troponin complex regulates heart muscle contraction. Mutations or variants of the TNNT2 gene can impair the normal structure and function of troponin T, causing various heart diseases. Polymorphisms in TNNT2 have been linked with a variety of cardiomyopathies, including hypertrophic cardiomyopathy, dilated cardiomyopathy, and other types of cardiomyopathy.26 Genetic testing for TNNT2 gene variants can aid in the diagnosis of inherited cardiac disorders, predicting the likelihood of complications such as congestive cardiac failure or sudden cardiac death, and guiding personalized treatment plans.27,28 Recognizing the significance of the TNNT2 gene in cardiac muscle function is essential for understanding the hereditary basis of heart disease and developing targeted treatments for those who are affected.

The KCNQ1 (potassium voltage-gated channel subfamily Q member 1) gene is one of a large family of genes that provide instructions for building potassium channels.29 These channels, which transport positively charged potassium ions out of cells, are essential for a cell's ability to generate and transfer electrical impulses, particularly in the regulation of cardiac electrical activity.30 The KCNQ1 gene also known as KVLQT1 gene situated on chromosome 11q15.5 (long arm (q) of chromosome 11 at position 15.5).31 The KNCQ1 protein channels are mainly located in the inner ocular region and cardiac muscles; they help in normal hearing and maintain proper cardiac rhythm. The gene mutations change the properties of ion channels generated with the KCNQ1 protein, enhancing their capacity to function.32 As a result, more potassium ions exit cells of the cardiac muscle, eventually resulting in an abnormal cardiac rhythm. Alterations in these genes also lead to Romano-Ward Syndrome also known as long QT syndrome 1 (LQT1) and Jervell and Lange-Nielsen syndrome.33 LQT1 is a cardiac rhythm disorder characterised by prolong QT interval on ECG. Whereas Jervell and Lange-Nielsen syndrome is a rare condition characterised primary by congenital deafness and QT prolongation.34 Mutations in the KCNQ1 genes can cause Sudden Infant Death Syndrome (SIDS). The KCNH2 (potassium voltage-gated ion channel subfamily H member 7) gene encodes voltage gated potassium channel present in the nerve cells, heart muscle cells and macrophages of brain.35 The primary function of these ion channels is regulating the flow of potassium ion (K+) across the membrane especially in the cardiac muscles. KCNH2 also known as hERG (Human ether-a-go-go-related gene). This voltage gated ion channel is playing a major role in the repolarization phase of the cardiac action potential, since it aids in the restoration of the cell's resting membrane potential following depolarization.36,37 Therefore, proper function of this channel is important for regulation of normal heart rhythm and preventing arrhythmias. Variations or mutation in this gene lead to Long QT syndrome type 2 (LQTS2). Long QT syndrome type 2 (LQTS2) is a type of long QT syndrome (LQTS), a cardiac arrhythmia characterized by a prolonged QT interval on an electrocardiogram (ECG). Individuals with LQTS2 may develop life threatening ventricular arrythmias, palpitations, syncope, seizures, or abrupt cardiac arrest, especially after physical activity or emotional stress. KCNQ1 & KCNH2 genes serves as a biomarker in cardiac diseases especially in the context of heart rhythm abnormalities.38,39 Therefore, genetic testing these markers helps in early detection and management of diseases.

The MYBPC3 gene is located on the chromosome 11p11.2, it encodes cardiac myosin binding protein C (CMYBPC3), a protein that is essential for heart muscle contraction. CMYBPC3 is also called as cardiac myosin-binding protein C and is exclusively expressed in cardiac system.40 CMYBPC is largely found in sarcomeres. Within the sarcomere, CMYBPC interacts with a protein called myosin. By binding to myosin, CMYBPC regulates the interaction of myosin with another protein involved in muscle contraction called actin.41 This kind of regulation is necessary for the normal contraction of heart muscle. MYBPC3 gene mutations can affect the structure and function of the CMYBPC protein, resulting in inadequate control of heart muscle contraction and relaxation. Abnormal CMYBPC protein can cause abnormal thickening of the heart muscle, which is indicative of hypertrophic cardiomyopathy (HCM).42 This may hinder the heart's capacity to pump blood correctly. This can result in dyspnoea, angina, palpitations, fainting, and in severe cases, heart failure and abrupt cardiac death. MYBPC3 gene mutations have also been related to a number of genetic cardiac conditions, including dilated cardiomyopathy and restrictive cardiomyopathy.43 These illnesses are characterized by cardiac muscle abnormalities, which can lead to cardiac failure and other cardiovascular problems.44 Screening individuals with MYBPC3 mutations allows for early risk assessment and individualized treatment plans for the patients, which help enhance their quality of life.

The perilipins are a family of protein located on the outer surface of intracellular lipid droplets present in the adipocytes. This protein family has five members each of which plays a major role in storage and metabolism of lipids with in the cells. Perilipin – 1 (PLIN1), PLIN2 (adipose differentiation-related protein or adipophilin), PLIN3 (TIP47), PLIN4 and PLIN5 are the members of perilipin family.45 Perilipin family of proteins are necessary for the growth, development and maturation of lipid droplets, the storage of triglycerides, and the release of free fatty acids from them. PLIN regulates a critical role in the storage and release of triglycerides, playing a key role in energy regulation. Phosphorylation of perilipin plays a vital role in the mobilization of lipids.46 Phosphorylation of perilipin stimulate the release of fatty acids from lipid droplets, allowing them to be utilized for energy production. In humans perilipin encoded by the PLIN gene.47 Mutation in the perilipin gene especially PLIN1 gene have been associated with significant implications in the metabolism of lipids especially dephosphorylation can suppress lipolysis results in an increased the risk of cardiovascular disease such as atherosclerosis, acute coronary syndrome and myocardial infarction. Polymorphism of perilipin genes causes an increase the levels of triglycerides and other lipid mediators in the body can promote the development of lipodystrophy like Familial Partial LipodystrophyType 4.48 The impact of gene mutation on lipid metabolism and health outcome deepens on other genetic and environmental factors.

The ACE gene provide directions for the synthesis of Angiotensin Converting Enzyme (ACE) which is a basic component of Renin Angiotensin Aldosterone System (RAAS). Angiotensin converting enzyme is well known for its bifunctional actions, which include converting inactive angiotensin I to active angiotensin II in RAAS system and degrade active bradykinin (BK) in Kinin Kallikrein system.49 RAAS and Kinin kallikrein system plays major role in maintain vascular tone and regulation of normal blood pressure. In human, ACE gene is located on chromosome 17q23.50 Mutations in the ACE genes such as single nucleotide polymorphism and ACE insertion or deletion can cause the occurrence to different cardiovascular diseases including high blood pressure, myocardial infarction and coronary artery diseases.51

The low-density lipoprotein receptor (LDLR) gene provides an instruction for making a protein called the low-density lipoprotein helps to regulate normal cholesterol level in the body. These receptors are present on the surface of the cells especially in the liver. The prime role of LDL receptors is to remove bad cholesterol (LDL) from the blood. The quantity of low-density lipoprotein receptors on the surface of liver cells determines how quickly cholesterol is removed from the bloodstream.52 The LDLR gene are located on the short arms of chromosome 19. Genetic variations in the LDL receptors can cause a condition called familial hypercholesterolemia (FH) characterised by an elevated levels of LDL cholesterol in the circulation. FH increases the risk of occurrence of different cardiovascular and cerebrovascular disorders at a young age.53

Lamins are the protein produce from LMNA gene. There are two types of lamin proteins ie Lamin A and Lamin C. These two proteins play an important role in maintaining structural integrity of nucleus and different cellular processes like cell division and DNA replication.54 Variations in the LMNA genetic material, which generates lamin A and C isoforms, result in a wide spectrum of conditions known as laminopathies, including dilated cardiomyopathy, which has a poor prognosis and a high probability of sudden death due to conduction deficiency and early ventricular arrhythmia. LMNA mutations can also cause other cardiovascular manifestations including Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and familial partial lipodystrophy (FPLD).55

The SCN5A (Sodium voltage gated channels alpha subunit 5) gene provides a major role in the generation and propagation of action potential in the cardiomyocytes. These sodium channels are responsible for depolarization phase of the cardiac action potential, which is required for the normal function of the cardiac electrical conduction system.56 Mutations in the SCN5A gene cause cardiac electrical conduction system-related abnormalities, including arrhythmias. Variations in SCN5A genes can cause a variety of cardiovascular disorders, including long QT syndrome, brugada syndrome, sick sinus syndrome (SSS), atrial fibrillation (AF), and progressive cardiac conduction defects.57