Genetic Variants of Heart Disease

Anne Chhing and Anil Kumar, PhD
Dec 29 2020 21:27


Cardiovascular diseases (CVD) are chronic and complex multifactorial diseases of heart, resulting from both natural and hereditary elements. Because heart diseases are the leading cause of death, a variety of population studies, such as the Framingham Heart Study (FHS), have revealed numerous significant contributors to their development. This emerging evidence clearly shows the general risk factors for CVD include smoking, high body mass index, hypertension, lipid metabolism disorders, and diabetes, among several other factors. More specifically, after studying large group of people over several decades and multiple generations, the investigators of the FHS conclude that both environmental and genetic risk factors contribute towards heart diseases [1].

Aside from the general risk factors, population-based studies have demonstrated that genetic susceptibility accounts for approximately 50% of the risk for CVD, which further suggests that genetic factors play a significant role in the development of heart disease [2]. Here we look at some of the key genes known to modulate the risk of developing heart disease.

The importance of genetic factors in CVD have been supported by recent data provided by both genome-wide association studies (GWASs) and Framingham Heart Study (FHS). Over the past decade, the participants of the longitudinal cohort studies have gone through intensive genomic profiling and advanced genome-wide sequencing technologies to help facilitate scientific discoveries on the role of genes in heart health. Seventy years of data spanning three generation have now given insights into how the diseases are inherited from one generation to the next. For certain conditions, e.g., genetic cardiomyopathy and, more specifically, for Hypertrophic Cardiomyopathy, strong evidence now suggests more than one gene can modulate a given heart disease.

Genetic markers of heart health

A family history of premature CVD, in addition to traditional risk factors, are all interactive factors contributing to the occurrence and development of heart diseases. People who have a family history of heart disease tend to share common environments that contribute to specific risk factors that may increase their risk for heart disease [1]. These risks can increase even more when hereditary contributions combine with unhealthy lifestyle choices, such as cigarette smoking, an unhealthy diet, and a lack of exercise.

To analyze the role of genetics in heart disease, the FHS has been conducting genomic research over the past 15 years to investigate the several genotypic variants that have been associated with a range of phenotypic traits, such as blood pressure, body mass index, and other observed risk factors. Since 2014, the FHS has been obtaining whole-genome sequences of 4,100 individuals across three generations to improve our understanding of genetic contributions to common diseases such as CVD [1]. The investigators of the FHS recognized a wide range of variation among individuals in their cohorts, which made them hypothesize that CVD arises from multiple causes that work slowly within an individual. In other words, the biological basis of CVD is considered to be highly complex due to the interaction between hereditary and environmental factors.

Genetic vs phenotypic markers

Biological variation of diseases, such as CVD, can be described at two levels: phenotypic (i.e., physical characteristics) and genotypic (i.e., DNA characteristics). Many of the risk factors of CVD, for instance, high density lipoprotein cholesterol, blood pressure, among other numerous factors, can be described as quantitative phenotypic traits. Genotypes can vary as they are the combination of the set of genes responsible for a particular phenotypic trait.

Gene variants are common and normal as these variants are what make us unique by causing differences in physical traits, such as eye color, hair color, and blood type. However, genetic variants can also affect cardiac health by acting at different stages in the evolution of heart disease, such as in plaque formation and rupture in atherosclerosis or even subsequent blood clotting, which can further result in an increase of cardiac events [4]. Therefore, it’s crucial to understand each risk factor that contributes toward the development of the disease using genetic approaches.

Over the last decade, the discovery of genetic contribution to heart failure has evolved to investigate rare variants of certain genes through large-scale genome-wide association studies. The advancement in genome-wide sequencing technologies have led to an increased number of in-depth studies in the genetics of CVD, identifying a number of candidate genes that impact cardiac health [1]. A general overview of these genes and their effects on heart health can be identified in the table below.

Table: List of genes involved in heart disease and their impact [1]

Key Genes Relevant to Heart Disease

    1. APOE: Regulates lipoprotein (cholesterol) levels. Elevated levels of lipids and lipoproteins, which may result in:
      • Hypertension
      • Stroke
      • Heart Attack
    2. Factor II (Prothrombin): Regulates blood clotting process. Possible risk of
      • Thrombophilia (increased tendency for blood clotting)
      • Deficiency results in excessive or prolonged bleeding
      • Heart Attack
      • Stroke
    3. Factor V: Impacts body’s ability to form blood clots. Possible risk involve
      • Elevated chances of developing abnormal blood clotting
      • Thromboembolisms (obstruction of blood vessels)
      • Premature atherothrombotic events
    4. MTHFR: Regulates a metabolic enzyme that processes amino acids. Possible risk of
      • Inefficiency in recycling amino acids (specifically homocysteine)
      • Elevated levels of homocysteine in blood
      • Unwanted blood clots
      • Atherosclerosis
      • Hypertension
    5. 9p21: Involved in stopping tumor cell growth by modulating inflammation and cell proliferation. Possible risks are
      • Premature atherosclerosis
      • Coronary artery calcification (artery stiffness)
      • Heart attack
      • Impair artery integrity
    6. eNOS & NOS3: Regulates and synthesizes nitric oxide levels in vascular endothelium. Possible risk of
      • Endothelial dysfunction within heart
      • Promoting atherosclerosis
      • Hypertension
      • Stroke
    7. SLCO1B1*5: Provides instructions for a protein that transports compounds from the blood into liver. Possible risk of
      • Reduced ability to process certain drugs (specifically statins, which improve cholesterol levels)
      • Elevated levels of toxins, hormones, and drugs in blood
      • Cardiovascular events due to statin non-adherence/inability to process
    8. AGT: Provides instructions for angiotensinogen, which regulates blood pressure and balance of fluids and salts in the body. Possible risk of
      • Increased susceptibility to hypertension
      • Kidney disorders (i.e. renal tubular dysgenesis)

It is critical to discuss each of these markers in detail to understand the important role genes play in heart disease.


The ApoE gene is a known genetic risk factor for dementia, Alzheimer’s disease, and CVD [3]. It is responsible for coding a protein called apolipoprotein E, which is a key player in regulating lipid synthesis and metabolism [2]. The ApoE gene plays an important role in studying the genetic susceptibility to CVD as it determines lipoprotein levels–one of the traditional coronary risk factors. Variability within this gene leads to different levels of lipids and lipoproteins, risk for atherosclerosis, and premature CVD among individuals. This gene comes in three genetic variants: E2, E3, and E4.

The E2 variant provides more protection against heart disease as it regulates cholesterol at an optimal level. On the other hand, E4 is associated with higher total and low-density lipoprotein (LDL) cholesterol levels. Additionally, the risk of atherosclerosis and coronary heart disease appears to be higher in individuals with E4 variant and its effect on lipid metabolism [2]. Those with at least one copy of the E4 variant have increased risk for CVD while individuals with two copies have the highest risk of developing CVDs. Altogether, it’s been well-established that the presence of the E4 variant is linked to higher LDL levels, even at young ages [4]. However, the ApoE gene also interacts with environmental and traditional risk factors, which can unfortunately increase the risk of CVD. Diet, lifestyle, and other genes contribute to each individual’s cholesterol level, as well as to the population’s average level.

Those with two E2 copies have increased risk (below 10%) of a rare hereditary condition disease called hyperlipoproteinemia (III HLP) [5]. People with III HLP have high levels of total cholesterol, LDL and triglycerides, which increases the risk of atherosclerosis and cardiovascular disease. People with E2 pair should monitor cholesterol levels annually to check for III HLP.

Prothrombin (Factor II)

The prothrombin genotype, also called prothrombin G20210A mutation, is responsible for producing a protein (also known as Factor II) that affects the body’s ability to form blood clots. Typically, there’s a fine balance of Factor II within the body to ensure that there is not too much bleeding or blood clotting; however, irregular levels can cause a detrimental blood clot to occur, which can increase the risk of many cardiovascular-related heart conditions.

In 1986, it was discovered that a specific variant in the genetic code of the prothrombin genotype causes the body to produce too much of the Factor II protein [6]. This genetic variant can result in thrombophilia, a condition that’s defined by the imbalance in naturally occurring blood-clotting proteins such as Factor II. It’s possible to have one copy of this genetic variant in one of your prothrombin genes; however, it’s rare to have both copies [6]. Those with a copy of this genetic variant are more likely to have issues during the natural blood clotting process due to possessing Factor II in abnormal amounts; therefore, causing a detrimentally large blood clot to form. This can further result in cardiac events such as a heart attack or stroke, even at a young age.

Lung and vein clots

The prothrombin G20210A gene is present in 2-4% of US population and people of European ancestry have 5 to 10 times higher risk. Factor II protein may result in Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE). Symptoms of DVT include cramps in legs and arms, swelling, red or purple skin or a general feeling of warm skin. If the clot travels to lungs, Pulmonary Embolism or lung clot might result in chest pain, shortness of breath, unusually high heart rate. Lung clots are life threatening and should receive immediate medical attention.

Fortunately, there are treatments, such as blood thinning medications (i.e., anti-coagulants), for individuals who suffer from thrombophilia. Additionally, several lifestyle modifications can help reduce the risk of developing abnormal blood clots. Maintaining a healthy weight is one important way to reduce the risk while also refraining and or quitting smoking can help, as this factor often increases the risk for unwanted blood clots.

Factor V Leiden (FVL)

The Factor V gene provides instructions to produce a protein that helps with the conversion of clotting factors in the blood clotting process. This process is regulated by several proteins. A specific protein called activated protein C (APC) normally inactivates Factor V, which reduces the clotting process to prevent blood clots from growing too large. However, Factor V Leiden (FVL) is a genetic variant that results in an increased chance of developing abnormal blood clots that can be life-threatening as it cannot be inactivated normally by APC. As a result, the clotting process remains active for a longer period, increasing the chances of developing abnormal blood clots [7].

A detrimental consequence of inheriting this genetic disorder is thromboembolisms, which is the obstruction of blood vessels caused by abnormal blood clots [8]. The chances of developing an abnormal blood clot depends on whether an individual has one or two copies of the FVL variant. People who inherit two copies are typically at higher risk of developing an abnormal clot than people who inherit one copy of the mutation [9]. This condition occurs in approximately 5% of the U.S. population and is considered to be the most common inherited form of thrombophilia [9].

Approximately 2-8% of people with European ancestry carry one copy of the FVL variant while 1 in 5000 people carry two copies [7]. Furthermore, there have been recent studies that demonstrated that patients with FVL are at high risk of atherothrombotic events. Blood clotting is involved in the formation stage of an atherosclerotic plaque rupture; therefore, it’s been hypothesized in recent genomic studies that FVL may be a strong genetic risk factor in patients with established CVD [7].


5,10-methylene-tetra-hydrofolate reductase (MTHFR) genotype encodes for a key metabolic enzyme for processing amino acids, specifically homocysteine. Homocysteine is a chemical in the blood that’s naturally metabolized to be further recycled by our bodies to build other proteins. However, genetic variants are associated with 50% reduced MTHFR enzyme activity and an increased homocysteine concentration in the blood [10]. High levels of homocysteine in an individual’s blood can lead to severe cardiovascular diseases, affecting the heart and blood vessels, which can further cause unwanted blood clots in the arteries and veins [10]. These high homocysteine levels are considered to be another risk factor for cardiovascular disease. Genetic variants tend to be more common in some races and ethnicities than others, e.g., Hispanic individuals are more likely than non-Hispanic Whites and non-Hispanic Blacks to have the gene variant for MTHFR [10].

Approximately 85% of the general population carries a variant of the MTHFR gene while individuals who have both copies have an increased risk of developing some form of CVD [10]. However, genomic studies of MTHFR gene variations in individuals have had mixed results, with associations found in some studies but not in others. Therefore, the variation in the MTHFR gene and its effects in certain heart diseases still remains unclear. It’s likely that there are additional factors that influence the processing of homocysteine.


The 9p21 genotype is involved in stopping tumor cell growth by modulating inflammation and cell proliferation [11]. Through case-controlled studies, this gene has been recognized as a risk factor for CVD events. The GWAS revealed a highly significant association between the variation of this gene and the risk for heart disease, which has been validated by studies on different racial and geographic subgroups, independent of traditional risk factors [11]. Investigators concluded that the genetic variant of the 9p21 gene occurs in 75% of the population except for African-Americans and is associated with a 25% increased risk for CVD with 1 copy and a 50% increased risk for 2 copies [11].

Variance of the 9p21 gene has also been associated with coronary artery calcification, premature atherosclerosis, and cardiovascular events such as a heart attack or stroke. More specifically, there has been evidence that the gene variant detrimentally impacts the vascular structure within the heart, while leaving moderate effects on known CVD risk factors [11]. Calcification caused by the 9p21 gene variant can lead to hardening structure within the arterial wall, which ultimately leads to an active inflammatory response and initiating the development of atherosclerosis. Based on genomic studies, 9p21 demonstrates relevance as a risk factor, meaning variance within this gene can be a predictor of the severity of heart disease.

eNOS and NOS3

The NOS3 gene is responsible for encoding three different types of enzymes that synthesize nitric oxide (NO) in various regions of the body [12]. eNOS is an enzyme primarily responsible for the generation of NO within the vascular endothelium of the cardiovascular system, where it regulates endothelial integrity, cell production, and adhesion of white blood cells [12]. Additionally, eNOS has a protective function in cardiac health as it also possesses anti-inflammatory effects and promotes relaxation of cardiac vessels and arteries [13].

Overall, a functional eNOS is crucial for a healthy cardiovascular system. However, variation in the gene is associated with higher susceptibility to cardiac events by reducing NO synthesis, which can result in endothelial dysfunction [13]. As a result, individuals with the gene variant are more likely to have premature atherosclerosis as endothelial dysfunction is one of the major components associated with heart disease. Additionally, many reports have indicated the association of the NOS3 gene variance with increased occurrence of cardiovascular events, such as hypertension and strokes [12]. For instance, those with two copies of the gene variant are more likely to have ischemic strokes [13]. Altogether, alteration in NO levels due to genetic variation in the NOS3 gene and its impact on cardiac health make it a considerable and crucial genetic risk factor for cardiovascular disease.


The SLCO1b1*5 genotype is responsible for producing a protein called organic anion transporting polypeptide 1B1 (OATP1B1) [14]. This protein is found in liver cells, where it transports compounds, such as hormones, toxins, and certain drugs, from the blood into the liver. Drugs that are transported by this protein are typically statins, which are prescribed to individuals to prevent major cardiac events by reducing LDLs (i.e., bad cholesterol). However, genetic variations of this gene are considered to be a genetic risk factor of heart disease due to statin-induced side effects and premature drug discontinuation. More specifically, a specific variant causing changes in the OATP1B1 protein function results in reduced ability to process drugs like statins, leading to elevated levels of compounds in the body [14].

Approximately 25% of individuals carry either one or two copies of the SLCO1B1 variant, which increases their risk of developing statin-induced symptoms, such as muscle aches, pains or weaknesses [14]. However, there’s been research and testing for this gene to help healthcare providers to identify patients who are at higher risk for the negative side effects of statins. Discontinuation of statins for individuals who are more susceptible to CVD while simultaneously holding the genetic variant of the SLCo1B1*5 gene can lead to a higher rate of cardiovascular events. Fortunately, through testing, these individuals can be prescribed with the right type of statin and dose with the most minimal probability of causing the negative side effects.


The AGT genotype provides instructions for a protein called angiotensinogen, which helps regulate blood pressure and the balance of fluids and salts in the body [15]. Through a series of biochemical reactions, angiotensinogen converts to angiotensin II, which causes blood vessels to narrow and constrict, causing blood pressure to increase. This molecule further stimulates the production of a hormone called aldosterone, which also triggers the absorption of salt and water by the kidneys, resulting in a further increase in blood pressure [15]. However, variants of the AGT gene have been linked to heart disease. More specifically, through genetic linkage studies, genetic variation has been associated with susceptibility to high blood pressure (i.e., hypertension) due to higher levels of the angiotensinogen protein [15].

Recent studies have indicated that the kidney system contributes significantly to more severe forms of hypertension in individuals with the genetic variant of the AGT gene [15]. Those with two copies of the genetic variant of the AGT gene are more likely to develop a severe kidney disorder, such as renal tubular dysgenesis. Kidney disorders alter the levels of angiotensinogen production, preventing their main function to maintain and control blood pressure. Altogether, it’s been proposed that high levels of angiotensinogen due to genetic variation may contribute to renal hypertension, which can be an additional genetic risk factor for CVD.

Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy (HCM) involves thickening of the heart muscles [16]. These stiffer muscles affect the inner chambers of the heart reducing the amount of blood the heart can pump. This might appear as constant fatigue, shortness of breath, or chest pain. However, the genetic cardiomyopathy may go untreated for a long time as the symptoms may not appear until the late stage of disease, often resulting in weakness, palpitations, light-headedness, irregular heart beat or sudden heart failure [17].

Figure: Unlike a normal heart (left), an unusually thicker wall in Hypertrophic Cardiomyopathy (right) results in smaller ventricle that pumps much less blood.

Hypertrophic Cardiomyopathy is an inheritable disease involving several different gene mutations [16]. Children with a mother or father with history of HCM will have a 50% chance of inheriting the mutation and the risk of Hypertrophic Cardiomyopathy. Because of the dominant nature of the genes, one parent with the mutation is sufficient to cause the disease (unlike certain conditions where risk is lower with one parent than having two copies).

There is no single Hypertrophic Cardiomyopathy gene. The most commonly identified genes are: MYH7, MYBPC3, MYL2, MYL3, TTN, TNNI3, TNNT2, TPM1, PRKAG2, CSRP3, ACTC [16, 17]. Almost 50% of the mutations involve MYH7 and MYBPC3, and 20% cases involve the remaining genes for this heart disease.

Those with a family history of genetic cardiomyopathy might consider genetic testing to understand their risk, although new mutations might appear in certain cases without any family history. Research on HCM is still evolving despite 30 years of research and sometimes those with the risk gene might live long normal life without any symptoms. As of 2016, approximately 64 genes [16] have been identified to correlate with HCM, several might still be unknown. The American College of Medical Genetics has developed guidelines for genetic cardiomyopathy to minimize false positive results.


Genomic studies of heart disease have provided identification of certain genes that are directly related to CVD. There are some variants within genes that no one previously suspected had any effect on cardiovascular disease; however, the GWASs and FHS studies have illustrated that genes have a significant influence on the risk of heart disease.

Sampling for traditional CVD risk factors, such as cholesterol levels, requires patients to follow specific procedures and protocols to obtain results. However, these results may vary from patient to patient, which can prevent a thorough analysis of the risk factors for heart disease. In contrast, analyzing DNA variants provides several advantages over conventional risk factors. They do not change during an individual’s lifetime or vary with meals or drugs, and can be determined with a single blood test.

Diagnosis for genetic variation can analyze an individual’s DNA to reveal whether they carry one or two copies for a certain gene. The identification of these genes may lead to screening tests that allows individuals at risk for developing CVD to be identified early enough to allow lifestyle changes or prevention strategies to be implemented before the disease progresses in a detrimental manner. Additionally, a further understanding of genetic risk variants may ultimately contribute to the development of new therapies to help those who are most susceptible to CVD.

Altogether, there is hope for future genetic testing along with personalized medicine to help prevent the detrimental consequences associated with heart disease and genetic risk factors. In recent years, people have already started to benefit immensely from our understanding of genes in certain heart diseases, e.g., Hypertrophic Cardiomyopathy.


[1] Andersson, C., Johnson, A. D., Benjamin, E. J., Levy, D., & Vasan, R. S. (Nature Reviews 2019). 70-year Legacy of the Framingham Heart Study. In Epidemiology of CVD.

[2] Xu, M., Zhao, J., Zhang, Y., Ma, X., Dai, Q., Zhi, Wang, B. Wang, L. (BioMed Research International 2016). Apolipoprotein E Gene Variants and Risk of Coronary Heart Disease: A Meta-Analysis.

[3] APOE4 – Risks & Risk Management: A practical guide for those with the E4 variant of the APOE gene. (Forever Healthy 2020).

[4] Marrzoq, L., Sharif, F., & Abed, A. (J Cardiovasc Dis Res 2011). Relationship between ApoE gene polymorphism and coronary heart disease in Gaza Strip.

[5] Mahley RW; Rall SC. (Annual Reviews 2000). Apolipoprotein E: far more than a lipid transport protein.

[6] Elizabeth A., Moll, S., Moll, C. (Circulation 2004). Prothrombin 20210 Mutation (Factor II Mutation).

[7] Juul, K., Tybjærg-Hansen, A., Steffensen, R., Kofoed, S., Jensen, G., & Nordestgaard, B. (Blood 2002). Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses.

[8] Kujovich, J. (GeneReviews 2018). Factor V Leiden Thrombophilia.

[9] Factor V Leiden thrombophilia: MedlinePlus Genetics. (2020).

[10] MTHFR Gene, Folic Acid, and Preventing Neural Tube Defects. (CDC 2020).

Additional references…

[11] Gong, L., Chen, J., Lu, J., Fan, L., Huang, J., Zhang, Y., Lv, B., Hui, R., Wang, Y. (PLos One 2014). The 9p21 locus is associated with coronary artery disease and cardiovascular events in the presence (but not in the absence) of coronary calcification.

[12] Terzi, S., Emre, A., Yesilcimen, K., Yazıcı, S., Erdem, A., Sadik Ceylan, U., & Ciloglu, F. (Acta Cardiologica Sinica 2017). The Endothelial Nitric Oxide Synthase (NOS3-786TC) Genetic Polymorphism in Chronic Heart Failure: Effects of Mutant -786C allele on Long-term Mortality.

[13] Lee, C., North, K., Bray, M., Avery, C., Mosher, M., Couper, D., Coresh, J., Folsom, AR, Boerwinkle, E., Zeldin, D. (Pharmacogenet Genomics 2006). NOS3 polymorphisms, cigarette smoking, and cardiovascular disease risk: The Atherosclerosis Risk in Communities study.

[14] Li, J., Suchindran, S., Shah, S., Kraus, W., Ginsburg, G., & Voora, D. (Pharmacogenomics 2015). SLCO1B1 genetic variants, long-term low-density lipoprotein cholesterol levels and clinical events in patients following cardiac catheterization.

[15] Catt, KJ, Cran E, Zimmet PZ, Best JB, Cain MD, Coghlan JP. (Lancet 1971). Angiotensin II blood-levels in human hypertension.

[16] Mazzarotto, F., Olivotto, I., Boschi, B., Girolami, F., Poggesi, C., Barton, PJR, Walsh. R. (J Amer Heart Assoc 2020). Contemporary Insights Into the Genetics of Hypertrophic Cardiomyopathy: Toward a New Era in Clinical Testing?

[17] Konno T; Chang S, Seidman JG, Seidman CE (Curr Opin Cardiol 2011). Genetics of Hypertrophic Cardiomyopathy.

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