Does heart disease run in your family? I bet that most of us can think of at least one older relative who died from heart disease. It is the number one cause of death worldwide…
Coronary artery disease is what most people think of as heart disease. It’s a huge topic and one that is vaguely understood by most people (and often poorly explained by doctors).
I’m going to dive in and explain the recent research on coronary artery disease. I’ll cover how your genetic variants influence your risk for coronary artery disease and then give multiple solutions. If you have heart disease, I encourage you to read the research studies, talk with your cardiologist, and make informed decisions on what is the best path for you.
Research shows us that coronary artery disease is about 50-60% heritable. This means that genetics is important, but so are lifestyle factors. For some of us, a ‘heart healthy’ lifestyle is really important for preventing heart attacks and death.
Coronary Artery Disease (CAD): Genes, diet, lifestyle
Often called heart disease, coronary artery disease (CAD) is defined by doctors as developing when the major blood vessels to the heart become damaged. In general, atherosclerotic plaques in the arteries along with inflammation are blamed for CAD.[ref] As plaques build up, there is a narrowing of the arteries that bring blood flow into the heart. Coronary artery disease develops over the years, and it can take decades to become significant enough to notice.
Symptoms of CAD:
- Angina – pressure or tightness in the chest.
- Fatigue and/or shortness of breath
- Heart attack
If you think the symptoms apply to you, talk with your doctor or go to the ER (for a heart attack). Your doctor can run tests such as an echocardiogram, stress test, or coronary artery calcium scan.
Prevalence: Cardiovascular disease, a category that includes coronary artery disease, is the number one cause of death in the US and worldwide. About 18 million adults have coronary artery disease in the US, according to 2019 CDC data.[ref]
Interestingly, cholesterol levels have declined from 1999 to 2016 across all the subgroups that are measured (gender, race, etc).[ref]
Myocardial infarction, or heart attack, can be mild or it can kill you. About 50% of sudden deaths are due to myocardial farctions, with an average age of about 65 for men and 72 for women.[ref]
Lifestyle factors: Always discussed with CAD are risk factors including smoking, diabetes, high blood pressure, and high cholesterol. These are the big ones, but as you’ll see below, other factors can also increase CAD.
Genetic factors: Researchers estimate that 50-60% of CAD risk is hereditary. Breaking this down, the research points to genetic factors that influence hypertension, diabetes, obesity, dyslipidemia, high homocysteine levels, coagulation, and systemic inflammation. Additionally, the genetic influence on pollution detoxification is likely involved as well.[ref]
What exactly is happening in coronary artery disease?
Health websites talk vaguely about CAD being caused by high LDL cholesterol from a bad diet along with inflammation. For example, the Cleveland Clinic website explains “If your cholesterol is too high, it builds up on the walls of your arteries. Over time, this buildup is known as atherosclerosis.”[ref]
You may be picturing fat from a cheeseburger sticking to the inside of your arteries and clogging them up.
But… this isn’t what actually happens. A lot of what is written about high cholesterol and coronary artery disease is based on observations from over a hundred years ago noting that the arteries had yellow streaks that looked like fat in them.
Enough of the generalities; let’s get to the heart of this issue (pun intended :-).
What’s going on in your arteries?
Blood vessels are made up of several layers, and the innermost layer is the endothelium.
Between the endothelium and the outer wall of the blood vessel is where fatty, cholesterol-rich deposits can build up. This is called the sub-endothelium space.
Coronary artery disease is caused by the buildup of these cholesterol-rich plaques (atherosclerosis) in the arteries that supply the heart muscles with blood. When the heart muscle doesn’t get enough blood and oxygen, it cannot function well. This can result in angina (chest pain), fatigue from exertion, or even a heart attack.
The questions are ‘why’ and ‘how’ does this area enlarge with cholesterol-rich deposits — and what else in addition to cholesterol is in these plaques.
While it sometimes gets a bad rap, cholesterol is essential for your body to function. Cholesterol is a type of fat made in your body or consumed when eating animal-based foods.
- Cholesterol is an essential part of the membrane that surrounds the cell, and it is especially important in neurons in the brain. (Fun fact: 20% of your body’s cholesterol is in the brain.)[ref]
- Cholesterol is also essential for the synthesis of hormones (testosterone, estrogen, cortisol, and vitamin D) and for the creation of bile acids.
We all know that oil (fat) and water don’t mix. The same is true for cholesterol in the blood. Thus, cholesterol is packaged up with proteins and carried in the blood in molecules called lipoproteins.
Players in the CAD game:
Research shows us four “principal and interdependent processes”:[ref]
- Inflammation in the endothelium of the arteries
- lipoprotein handling (LDL cholesterol and more)
- endothelial integrity
- thrombosis (clot)
These four processes are individually important and also intertwined.
Starting with inflammation in the endothelium:
The endothelium is the layer of cells that line blood vessels (and lymphatic vessels).
It is a single layer of cells, and doctors used to think of the endothelium as just a lining, like a cellophane wrapper inside the blood vessels.
Research over the last couple of decades, though, shows that the endothelium has many important functions including secreting hormones, reacting to pathogens, controlling platelet activation, and regulating vascular tone.[ref]
In other words, it is nothing like a cellophane wrapper – instead, the endothelium runs the show.
When the endothelium is healthy, such as in younger people, the cells are tightly joined, forming a barrier that LDL-cholesterol cannot cross.
As one research paper puts it:
“endothelial cells (ECs) serve as multifunctional biosensors that coordinate vascular responses to environmental stress of which hypoxia, oxidative stress, acidosis, and inflammation are especially prominent in myocardial disease and cancer “[ref]
Let’s dig into these endothelial stressors:
- Acidosis is when your blood pH is off balance – too much acid or too little base (bicarbonate). It can occur when you have too much glucose and not enough insulin, especially in people with diabetes. Additionally, acidosis can be due to respiratory disease, tumors, or inflammation.[ref]
- Hypoxia is a lack of oxygen in cells. This can occur when blood vessels are narrowed and not enough oxygen is carried through to meet demand.
Research shows that hypoxia along with acidosis triggers an inflammatory response in endothelial cells that includes HIF-1a and HMGB1.[ref] HIF-1a (hypoxia-inducible factor 1a) is a regulator of hundreds of other genes that act in response to low oxygen. Activating HIF-1a in the short term causes some protective pathways to be initiated. But long term activation of HIF-1a leads to cardiovascular dysfunction. HMGB1 is another protein that activates other genes – specifically, it amplifies an inflammatory response.[ref]
Research from June of 2021 explains that HMGB1 (activated by hypoxia and acidosis) causes LDL-cholesterol transcytosis. When the endothelium is healthy, the LDL cholesterol can’t pass between the cells to get to the area between the endothelium and the arterial wall. The only way that LDL-c can get into that space with a healthy endothelium is via transcytosis – being taken into the endothelial cell and then deposited back out the other side. Thus, the HMGB1 alarmin causes the initiation of cholesterol moving into the area between the endothelium and the arterial wall, without the endothelial junctions being loosened.[ref]
Other causes of endothelial inflammation include exposure to toxicants and pathogens. Your blood circulates everything you’re exposed to and thus the endothelial cells are exposed. Smoking is an easy example here: Smoking cigarettes dumps toxicants such as benzene, formaldehyde, and toluene into the lungs, which then transfers the harmful substances into the bloodstream. Similarly, viruses, bacteria, or parts of the pathogen, can circulate in the bloodstream and interact with the endothelium.[ref] (More on this below)
Resolving Inflammation: Doctors and researchers used to think that an inflammatory state resolved back to normal when the inflammatory markers just passively went away. This is why so many anti-inflammatory drugs, such as COX2 inhibitors, target the initial inflammatory cytokines.
But it turns out that inflammation resolution is an active process, not a passive one. The resolution of inflammation involves anti-inflammatory mediators called lipoxins, resolvins, maresins, and protectins.[ref] The inflammation resolution molecules are derived from DHA and EPA (omega 3 fatty acids found in fish oil).[ref]
The buildup of plaques in the walls of blood vessels is called atherosclerosis. It is at the root of coronary artery disease as well as other common cardiovascular disorders.
Classically, the cholesterol hypothesis of atherosclerosis explains that elevated LDL is directly associated with atherosclerosis. The literature on this states that infiltration of apoB particles that contain LDL-cholesterol is the initial cause of atherosclerosis. This is thought to start with arterial injury, which causes the endothelium to be infiltrated by monocytes and apoB particles into the artery wall.[ref]
For atherosclerosis to occur, you need increased cellular adhesion molecules, which are found on endothelial cells that are activated by inflammatory cytokines. Increased cellular adhesion allows for immune system molecules, such as macrophages, to adhere to endothelial tissue.[ref]
Inflammation is, of course, a natural and completely necessary response to injury or toxic insult. The key is that there needs to be a balance between the inflammatory process and the resolution of inflammation.
In atherosclerosis, there is an inadequate resolution of the inflammation in a timely fashion.[ref]
Macrophages, foam cells, and plaques:
The imbalance of too much inflammation or too little resolution is the heart of coronary artery disease and atherosclerosis.
The body’s immune response is key, and several immune system cell types are important here. (Interestingly, mice bred to have immunodeficiency never get atherosclerosis.[ref])
Macrophages are immune cells that colonize tissues in the body. Being ’tissue-resident immune cells’ means that they aren’t roaming around your whole body, but rather specific forms of macrophages are on patrol in different tissues (lung, brain, liver, etc.).
Macrophages engulf and digest cells that don’t seem to be healthy. This includes cancer cells, foreign substances, viruses, bacteria, and cellular debris. In addition to defending our body against pathogens, macrophages also increase inflammation, stimulate other parts of the immune system, and encourage tissue repair.
Foam cells form when macrophages internalize ApoB containing lipoproteins. The macrophage infiltration then increases oxidative stress and cytokine production, resulting in more endothelial cell activation, cellular adhesion, and recruitment of more macrophages.[ref]
This results in a build-up of macrophages and entrapment in the atherosclerotic plaque.[ref]
Dual role: While macrophage infiltration is inflammatory, macrophages also play a role in resolving inflammation. Using DHA as a substrate, macrophages can biosynthesize maresin, a pro-resolvin, from DHA.[ref]
Macrophages can be divided into groups:[ref]
- M1 macrophages are classically activated (e.g. by pathogens) and sustain inflammation
- M2 macrophages are alternatively activated and resolve inflammation
- Mox macrophages are a proatherogenic subset responding to oxidized phospholipids
Plaques to Clots to Heart Attacks: Excessive inflammation due to macrophages that are entrapped and sustaining inflammation can lead to the formation of atherosclerotic plaques. The atherosclerotic plaque can eventually rupture, causing essentially a little tear in the blood vessel, which then is repaired by the body’s clotting cascade. The clot, if it is large enough, can block the blood vessel and restrict blood flow — not good when you are talking about blood flow to the heart muscle.
While macrophages and inflammation are at the heart of atherosclerosis, macrophages are also the solution. Animal studies dating back decades show that changing diet from a high-fat, high-cholesterol diet to one that is low-fat, low-cholesterol can reduce the thickness of the coronary artery plaques. Human studies show that lowering cholesterol helps, but perhaps not to the same degree seen in animal studies.[ref] More on this in a bit…
The role of LDL cholesterol in cardiovascular disease:
Cholesterol hypothesis of heart disease: One thing that most people ‘know’ is that high LDL cholesterol causes cardiovascular disease. But what does LDL cholesterol have to do with endothelial inflammation? And why does it end up in the wall of the blood vessel?
Essentially, the hypothesis is that either:
- Too much LDL causes it to end up in the arterial wall -or-
- Excessive oxidation of LDL causes the inflammatory cycle
Macrophages identify oxidized LDL-c and also LDL-cholesterol bound to glycosaminoglycans as ‘foreign’, causing the macrophage to initiate an immune response.[ref]
As I mentioned above, research from 2019 on inflammation in the endothelial cells shows that an increase in HMGB1, an alarmin that increases other inflammatory cytokines, causes LDL cholesterol to be taken up by endothelial cells via endocytosis and then moved to the space between the endothelium and the arterial wall.[ref]
While these may seem contradictory – is it high LDL-c? or oxidized LDL-c? or endothelial inflammation? – I think all this can be true. Endothelial inflammation moves the LDL-c, and higher levels of LDL-c would then result in more of it being moved. LDL-c is oxidized by exposure to higher oxidative stress in the area of inflammation. To compound the issue, oxidized LDL-c is recognized by macrophages as ‘foreign’ and initiates an inflammatory response – driving the process of more inflammation, more cholesterol deposited, and more macrophages activated.
Thus, lowering really high LDL-c levels means that there is less of it to move across the endothelial cells by transcytosis. Lower levels of LDL-c mean that there is less of it available to be oxidized. Additionally, antioxidant therapy such as vitamin E or Vitamin C may help to reduce oxidized LDL-c. Finally, reducing inflammation along with increasing the resolution of inflammation (e.g. aspirin therapy) also helps.
Cholesterol and lipoproteins:
Is there more to this cholesterol thing? Well, yes.
Cholesterol is a general term, and there are different lipoprotein particles, different sizes of LDL particles, etc. that all interact here.
- The different lipoprotein particles play different roles in cholesterol transport. For example, lipoprotein(a) is strongly linked to an increased risk of heart attacks. Lp(a) consists of LDL-c along with apo(a) and apoB100 particles. The apo(a) in Lp(a) block the resolution of clots and increases proinflammatory events in the cell wall.[ref]
- APOA5 gene variants link high triglycerides and higher ox-LDL levels to increased risk of CAD.[ref]
- Receptors for oxidized LDL are important, such as LOX-1[ref]
- Other receptors, such as the apoE2 receptor, are important in reducing clotting and increasing blood vessel dilation.
Let me go into a little more detail on a couple of important regulators of cholesterol levels so that the genetics part (below) makes more sense:
1) APOE and receptors:
Apolipoprotein E (ApoE) is well studied in relation to Alzheimer’s risk. The APOE E4 variant significantly increases the risk of Alzheimer’s disease. ApoE is a lipoprotein that binds to and transports cholesterol. It is present in several different classes of lipoproteins.
A receptor for apoE, called the apolipoprotein E receptor-2, was identified in a genome-wide association study as being important in developing premature CAD. This prompted research into why an apoE receptor would influence the development of coronary artery disease. The receptor is found abundantly in the brain (important in memory formation) and testes (important in selenium uptake and fertility). At lower levels, the receptor was also found in platelets, endothelial cells (lining the blood vessels), and monocytes/macrophages. Animal research shows that when apoE binds to the apoE2 receptor, it stimulates nitric oxide (a vasodilator) and inhibits cellular adhesion. In other words, it makes the blood vessels dilate and prevents stickiness, such as found in a clot. The receptor also modulates macrophage activation and influences the formation of atherosclerosis.[ref]
PCSK9 and atherosclerosis:
One way that cells regulate the amount of LDL cholesterol is through taking in LDL-c through an LDL receptor. PCSK9 is a protein that causes fewer LDL receptors to be available on the surface of cells. Higher PCSK9 levels lead to higher LDL-c levels. Genetics plays a big role in PCSK9 levels, with some variants leading to high LDL-c and other variants causing lifelong lower LDL-c.
While most PCSK9 is produced in the liver and kidney, the endothelial cells lining blood vessels also produce PCSK9. Additionally, macrophages can produce PCSK9. This makes PCSK9 (along with LDL-c) an important player in the formation of atherosclerotic plaques. Animal studies show that PCSK9 has pro-inflammatory behavior in macrophages, increasing the formation of foam cells and plaque. When the PCSK9 gene is deleted in mice, it is protective even in animals that normally would have atherosclerosis.[ref]
Calcium and hardening of the arteries:
In addition to inflammation and cholesterol infiltration, calcium also plays a role in heart disease.
In atherosclerosis, the thickening of the artery wall is a problem only when the blood vessel can no longer expand. As long as the artery can expand and compensate for the fatty deposits, blood flow is not reduced.
The problem of reduced blood flow comes when the blood vessel flexibility is reduced. This is where calcium comes in. Calcification of the vascular smooth muscle cells reduces flexibility, but it also stabilizes the atherosclerotic plaque, hardening it and making it less likely to rupture and cause a heart attack.
You may have heard of a coronary calcium score, which measures calcium-containing plaques in your arteries.
Researchers have found two seemingly contradictory findings: highly calcified lesions are less likely to rupture, but a high calcium score is linked to a greater risk of future coronary events. Both seem to be true. Higher levels of calcification can stabilize large plaques, but calcium is also linked to fragmented or microcalcifications, which also cause coronary events.[ref]
Genetic variants linked to higher serum calcium levels are also linked to an increased risk for CAD.[ref]
Triggers of endothelial injury:
I want to circle back to the inflammation of the endothelium. What causes it?
There are a lot of causes of endothelial inflammation: bacteria, viruses, toxic substances, high blood glucose levels, hypoxia, autoimmune responses, shear stress from high blood pressure, and hyperlipidemia (high cholesterol, oxidized cholesterol, or really high triglycerides).[ref]
Keep in mind that endothelial injury isn’t a one-time event. You don’t end up with CAD or atherosclerosis from being just once to something that inflames the endothelium. Your cells are resilient, inflammation occurs and then resolves. It is the repeated and sometimes constant barrage of insults that causes long-term damage.
Let’s dig into a couple of these triggers:
Autoimmune disease: Systemic sclerosis and Raynaud’s disease are both linked to endothelial injury that can lead to long-term changes in the blood vessels.[ref]
High blood glucose: Diabetes and cardiovascular disease go together for a reason. Severely high blood glucose levels alter pH, causing damage response and inflammation. But for most people with higher blood glucose levels, the damage to endothelial cells comes from the long-term accelerated degradation of nitric oxide (NO). NO is important in protecting cells from inflammation as well as relaxing the blood vessels.[ref]
Toxicants: We are exposed to all kinds of chemical toxicants daily, and our body does a good job of dealing with these insults by breaking them down and excreting them. But chronic exposure can also damage endothelial cells. Cigarette smoking is an excellent example, and several substances in cigarette smoke are well known for their ability to injure endothelial cells. Heavy metal exposure can also damage the endothelium, and certain medications (e.g. chemotherapy drugs) also cause damage.[ref]
Pathogens: Viruses and bacteria can invade endothelial cells. For example, dengue virus can disrupt the barrier that protects the endothelial cells (called the glycocalyx) and cause havoc with the endothelium. Severe dengue fever causes ‘vascular leakage’.[ref] Ebola and other hemorrhagic fever viruses also disrupt endothelial function, but these are short-term events (often ending abruptly in death) and are not the cause of your atherosclerosis. Periodontal disease, though, is linked to endothelial dysfunction and cardiovascular disease. Chronic, low-grade inflammation due to gingivitis downregulated nitric oxide, eventually leading to coronary endothelial dysfunction.[ref][ref] The bacteria that cause periodontal disease, P. gingivalis, has also been found in atherosclerotic plaque.[ref]
Spike protein (from SARS-CoV-2) causes endothelial dysfunction:
In the news recently is research showing that the spike protein alone increases endothelial cell ROS triggering autophagy and apoptosis. Recent research shows that the spike protein alone can also induce cell death in vascular endothelial cells by triggering an inflammatory response.[ref]
One study found that the spike protein was more likely to cause endothelial injury “under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-α)”.[ref] Men, especially younger men, have higher overall androgen levels, but as men age, DHT tends to increase compared to testosterone.[ref]
While there are still a lot of unknowns with the SARS-CoV-2 spike protein, thrombocytopenia and thrombosis is a rare side effect, especially in the adenoviral vector vaccines.[ref]
Coronary Artery Disease Genotype Report:
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the member’s only information in the Lifehacks sections.
How can you use this information: The genetic variants below will explain some of your relative risk for coronary artery disease. If you have a higher than normal risk of CAD, lifestyle factors (healthy diet, exercise, sleep) will be important for you in keeping your heart healthy.
CDKN2B-AS1 gene: long-coding RNA that impacts transcription of other genes.
Check your genetic data for rs2383206 (23andMe v4; AncestryDNA):
- G/G: increased risk for CAD[ref]
- A/G: increased risk for CAD
- A/A: typical
Members: Your genotype for rs2383206 is —.
Check your genetic data for rs10757274 (23andMe v4, v5; AncestryDNA):
- G/G: increased risk for CAD[ref]
- A/G: increased risk for CAD
- A/A: typical
Members: Your genotype for rs2383206 is —.
TCF7L2 gene: encodes a protein that is linked to an increased risk of diabetes and CAD in people without diabetes.
Check your genetic data for rs7903146 (23andMe v4, v5; AncestryDNA):
- T/T: increased risk of diabetes, decreased beta-cell function, higher nocturnal glucose[ref][ref][ref] in non-diabetic individuals, increased risk and severity of coronary artery disease and cardiovascular events.[ref]
- C/T: increased risk of diabetes[ref] T allele is associated with diabetes and, in non-diabetic individuals, with a higher prevalence and severity of coronary artery disease and cardiovascular events.[ref]
- C/C: typical
Members: Your genotype for rs7903146 is —.
ALOX5AP gene: arachidonate 5-lipoxygenase-activating protein – an enzyme for the production of proinflammatory lipid mediators (leukotrienes)
Check your genetic data for rs17222842 (23andMe v4; AncestryDNA):
- A/A: significantly decreased risk of heart attack[ref]
- A/G: typical risk of heart attack
- G/G: typical
Members: Your genotype for rs17222842 is —.
Check your genetic data for rs4769874 (23andMe v4; AncestryDNA):
- A/A: increased risk of CAD[ref]
- A/G: increased risk of CAD
- G/G: typical
Members: Your genotype for rs4769874 is —.
ACE gene: angiotensin-converting enzyme important in blood pressure regulation
Check your genetic data for rs4343 (23andMe v4, v5; AncestryDNA):
- A/A: ACE insertion/insertion, lower ACE enzyme activity
- A/G: ACE deletion/insertion, increased risk of CAD
- G/G: ACE deletion/deletion, higher ACE enzyme activity, increased risk of CAD.[ref]
Members: Your genotype for rs4343 is —.
LRP8 gene: low-density lipoprotein receptor (APOE receptor), important in platelet activation
Check your genetic data for rs5174 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs5174 is —.
LOX1 gene: encodes the oxidized LDL receptor 1
Check your genetic data for rs11053646 (AncestryDNA):
- G/G: increased risk of CAD
- C/G: increased risk of CAD[ref]
- C/C: typical
Members: Your genotype for rs11053646 is —.
NOS3 gene: encodes nitric oxide synthase, important in helping blood vessels stay healthy.
Check your genetic data for rs891512 G24943A or IVS25+15 (23andMe v5; AncestryDNA):
- G/G: typical (more common allele)
- A/G: higher blood pressure, increased risk of coronary artery disease
- A/A: higher blood pressure[ref][ref], increased risk of coronary artery disease[ref]
Members: Your genotype for rs891512 is —.
Check your genetic data for rs1800779 (23andMe v4, v5; AncestryDNA):
- A/A: typical
- A/G: decreased NOS3 expression (compared to AA); increased risk of high blood pressure and cardiovascular disease
- G/G: decreased NOS3 expression (compared to AA); increased risk of high blood pressure and cardiovascular disease[ref] increased risk of primary open-angle glaucoma (women)[ref]
Members: Your genotype for rs1800779 is —.
PCSK9 Gene: encodes an enzyme involved in cholesterol transport, interacting with the LDL receptors. (Learn more here).
Genetic variants that decrease PCSK9 cause lower LDL-C and lower risk of heart disease.
Check your genetic data for rs11591147 R46L(23andMe v4, v5; AncestryDNA):
- G/G: typical
- G/T: decreased LDL-cholesterol, 30% lower risk of heart disease[ref][ref]
- T/T: decreased LDL-cholesterol, > 30% lower risk of heart disease
Members: Your genotype for rs11591147 is —.
Check your genetic data for rs28362286 (23andMe v4; AncestryDNA):
- A/A: decreased LDL-cholesterol, lower risk of heart disease[ref][ref], decreased fasting glucose levels[ref]
- A/C: decreased LDL-cholesterol, lower risk of heart disease, decreased fasting glucose levels
- C/C: typical
Members: Your genotype for rs28362286 is —.
Check your genetic data for rs67608943 (23andMe v4, v5;):
- G/G: decreased LDL and decreased risk of heart disease[ref]
- C/G: decreased LDL and decreased risk of heart disease
Members: Your genotype for rs67608943 is —.
Check your genetic data for rs72646508 (23andMe v4, v5):
- T/T: decreased LDL and decreased risk of heart disease[ref]
- C/T: decreased LDL and decreased risk of heart disease
- C/C: typical
Members: Your genotype for rs72646508 is —.
Genetic variants that increase PCSK9 have links to higher LDL-c and a higher risk for heart disease.
Check your genetic data for rs505151 (23andMe v4, v5; AncestryDNA):
- G/G: increased LDL, increased risk of coronary artery disease[ref][ref][ref]
- A/G: increased LDL, increased risk of coronary artery disease
- A/A: typical
Members: Your genotype for rs505151 is —.
Check your genetic data for rs28942112 (23andMe i5000370, v4; AncestryDNA):
- C/T: greatly increased LDL, considered pathogenic for familial hypercholesterolemia[ref]
- T/T: typical
Members: Your genotype for rs28942112 is —.
Check your genetic data for rs28942111 (23andMe v4, v5; AncestryDNA):
- A/T: greatly increased LDL, considered pathogenic for familial hypercholesterolemia[ref]
- T/T: typical
Members: Your genotype for rs28942111 is —.
LPA gene: encodes lipoprotein(a)
Check your genetic data for rs3798220 (23andMe v4, v5, AncestryDNA):
- C/C: risk of elevated Lp(a), increased risk for heart disease – 3.7x risk of aortic stenosis[ref][ref][ref]
- C/T: risk of elevated Lp(a), increased risk for heart disease, increased risk of aortic stenosis
- T/T: typical
Members: Your genotype for rs3798220 is —.
Check your genetic data for rs10455872 (23andMe v4, v5; AncestryDNA):
- G/G: likely elevated Lp(a), increased risk for heart disease – 2x risk of aortic stenosis[ref][ref][ref]
- A/G: likely elevated Lp(a), increased risk for heart disease
- A/A: typical
Members: Your genotype for rs10455872 is —.
ABCA1 gene: encodes a protein important in the reverse transport pathway of cholesterol. ABCA1 plays a role in the efflux of cellular cholesterol to HDL and also affects inflammatory cytokine activation.[ref]
Check your genetic data for rs2230806 (23andMe v4, v5; AncestryDNA):
- C/C: typical
- C/T: decreased risk of CAD (slightly decreased risk in Caucasians; more protection in Asians)
- T/T: decreased risk of CAD (slightly decreased risk in Caucasians; more protection in Asians)[ref]
Members: Your genotype for rs2230806 is —.
Rare mutations and CAD:
About 0.4% of the population carries rare mutations that cause a high risk of CAD. Most of these variants impact cholesterol levels.[ref] Below are a few of these mutations that can be found in your 23andMe or AncestryDNA data. Keep in mind that your raw data shouldn’t be used for medical diagnosis, so talk with your doctor about getting a clinical-grade test to confirm.
LDLR Gene: LDL Cholesterol Receptor
- G/G: typical
- G/T: decreased LDL, lower risk of heart disease
- T/T: decreased LDL, lower risk of heart disease[ref]
Members: Your genotype for rs6511720 is —.
LDLRAP1 gene: LDL-R adaptor protein 1 gene
Check your genetic data for rs121908324 (23andMe v5):
Members: Your genotype for rs121908324 is —.
Check your genetic data for rs121908325 (23andMe v5; AncestryDNA):
Members: Your genotype for rs121908325 is —.
MEF2A gene: Myocyte Enhancer Factor-2A
Check your genetic data for rs121918529 P279L (AncestryDNA) or i5003637 (23andMe v4):
- C/C: typical
- C/T: rare, significantly increased risk of CAD.[ref]
Members: Your genotype for rs121918529 is —.
APOB gene: encodes of lipoprotein important in cholesterol
Check your genetic data for rs144467873 (23andMe i4000339 v4, v5; AncestryDNA):
- A/A: risk of familial hypercholesterolemia[ref]
- A/G: carrier for familial hypercholesterolemia
- G/G: typical
Members: Your genotype for i4000339 is — and for rs144467873 —.
Check your genetic data for rs5742904 (23andMe v4; AncestryDNA):
- T/T: familial hypercholesterolemia, increased risk of heart attack[ref][ref]
- C/T: carrier for familial hypercholesterolemia
- C/C: typical
Members: Your genotype for rs5742904 is —.
Lifehacks for preventing heart disease:
Doctors tell you that heart health comes from eating a good diet, exercising, being at the right weight, and not smoking.
All good things to do… But what does it mean to eat a good diet? How much does an extra 20 pounds matter? Are there other changes or supplements that can give you the most bang for your buck?
Below is information on recent research studies on CAD and atherosclerosis. As always, talk with your doctor for specific medical advice.
To me, the prevention of CAD and atherosclerosis comes down to a few key factors:
- Avoiding excess inflammation in the endothelium
- Reducing chronic inflammation throughout the body
- Promoting the resolution of inflammation (not just reducing inflammation, but promoting the active processes involved in resolving inflammation)
Stop smoking. Clear and abundant research shows that smoking cigarettes is terrible for your vascular system.
Avoid BPA: In animal studies, exposure to low levels of BPA (bisphenol-A) increased atherosclerotic lesions significantly. Human studies do show a link between higher urinary levels of BPA and various cardiovascular disease types. It isn’t completely clear, though, whether the correlation in humans is causal (although animal studies suggest it is).[ref]
Related article: BPA and Detoxification
Oral health: P. gingivalis is a bacteria that causes gingivitis and periodontal disease. It also is linked to atherosclerosis, both through increasing chronic inflammation and also directly being incorporated into atherosclerotic plaque.[ref] If your gums are bleeding when you brush or floss, bacteria and viruses can get into the bloodstream. Recommendations include regularly going to the dentist for cleanings and brushing your teeth daily.[ref] You may also want to look into oral probiotics, which may help balance out the microbiome in your mouth. Oil pulling is another option.
Interestingly, killing off all the microbes in your mouth may be the wrong path to take. Antiseptic mouthwash use is linked to increased mortality in hospitalized patients. One study showed that antiseptic mouthwash was associated with a >2-fold increase in mortality. Researchers think this is due to killing off the good oral bacteria that help to produce nitric oxide.[ref]
Stop eating ultra-processed foods: A recent study showed that people who consumed higher amounts of processed foods were at an increased risk of cardiovascular disease. The increase in relative risk wasn’t as much as I expected (13% increased risk for highest quartile vs lowest quartile). But this is one dietary change that should improve metabolic health also.[ref]
Eat your veggies? Most health websites recommend a high intake of fruits and vegetables for a heart-healthy diet. The problem is that conventionally grown fruits and vegetables have residue from pesticides on them. A large study that looked at this topic found that a higher intake of fruits and vegetables with low pesticide residue (aka organic, or the types of veggies not grown with a lot of pesticides) was associated with a decreased risk of heart disease (about 25% decreased relative risk). But eating a lot of fruits and vegetables (4+ servings a day) that are higher in pesticide residue did not decrease the risk of heart disease. The conclusion was that exposure to pesticide residue negated the cardiovascular benefits of fruit and vegetable intake.[ref]
Your best bet may be to eat mostly organic fruits and vegetables — or just avoid the dirty dozen.
The resolution of inflammation is an active process. This means that inflammatory cytokines don’t just fade away – there is a huge, complicated active process by with inflammation is ended and tissue is restored back to normal.
Read lots more about this: Specialized Pro-Resolving Mediators and the process of resolving inflammation.
Aspirin: For decades, low-dose aspirin has been recommended for preventing heart attacks, but more recently, the American Heart Association has changed its recommendation.[ref]
Aspirin acts to inhibit the inflammation in the arteries as well as helping with the resolution of inflammation. In addition to blocking the formation of inflammatory molecules (COX2 inhibitor), aspirin also promotes the formation of resolvins. This is what makes aspirin unique and different from other drugs that just block inflammation.[ref]
Talk with your doctor, of course, before beginning daily aspirin therapy. Aspirin isn’t right for everyone. People at a higher risk of bleeding (medical issues, medications, etc) shouldn’t take aspirin. If you don’t have any contraindications, the question then becomes: Will you benefit from aspirin? Genetic research fills in some of the answers on whether aspirin is likely to give you benefits for preventing heart attacks.
DHA and EPA are the fatty acids used to create the pro-resolving mediators in atherosclerosis.
- Fish oil: DHA and EPA help with the resolution of inflammation via promoting the formation of resolvins.[ref] If you don’t eat fish regularly, decide whether a good quality DHA and EPA supplement may be right for you. Consider that fish oil can act as a blood thinner (important if you are already on blood-thinning medications). Keep in mind that fish oil supplements can contain oxidized or damaged fatty acids, so high quality is important.
- Should you take flaxseed instead of fish oil? The answer likely lies in your genes: FADS1, the omega 3 conversion gene
- Alternative source of DHA/EPA: While egg yolks do contain cholesterol, pasture-raised eggs are also a good source of DHA and EPA. If you aren’t regularly eating fish, an easy way to increase your DHA and EPA is to include pasture-raised eggs in your diet (especially if you don’t have really high cholesterol levels). Find a local source for eggs from chickens that are out running around, eating bugs and grass.
Nose breathing: While this may sound a bit crazy, there is good evidence that breathing through your nose (instead of your mouth) increases nitric oxide. Don’t be a mouth-breather.
Sleep apnea: Hypoxia is a trigger of endothelial dysfunction. If you have sleep apnea, talk to your doctor about what it will take to cure it.
Reducing high cholesterol:
Statins? The first drug that most doctors recommend for higher LDL cholesterol is a statin. Genetics plays a big role in whether you will have side-effects, such as muscle pain, from statins. Read about statins and your genes.
Saturated fat: Your body can convert saturated fat into LDL cholesterol. An excessive amount of saturated fat in the diet can increase LDL and throw it out of balance with HDL cholesterol (for some people.) The best way to know whether saturated fat is increasing your cholesterol is to test it: get your cholesterol level checked; then cut your saturated fat (butter, coconut oil, lard, fatty beef) intake by half for a month; test again.
A randomized controlled trial showed that butter increases LDL-c more than coconut oil or olive oil. But coconut oil didn’t increase LDL significantly compared to olive oil.[ref]
This members-only section includes additional information on natural supplements for CAD along with a recap of your genotypes. Consider joining today to see the rest of this article.
Supplements for inflammation and endothelial dysfunction:
Related Articles and Genes:
Berberine: Research studies, absorption, and genetics
Berberine is a natural supplement with some amazing research on it for reducing high blood glucose levels and reducing high cholesterol. The drawback, though, is poor absorption in the intestines, decreasing its effectiveness.
Boosting NAD+ to Reverse Aging? Overview of NR and NMN
Explore the research about how nicotinamide riboside (NR) and NMN are being used to reverse aging. Learn about how your genes naturally affect your NAD+ levels, and how this interacts with the aging process.
Hypertension Risk Factor: CYP11B2 Variant
Hypertension risk can be modifiable in terms of diet and exercise. However, genetics can play a part in risk. Learn more about how the CYP11B2 variant can increase the risk of hypertension.
Abraham, David, and Oliver Distler. “How Does Endothelial Cell Injury Start? The Role of Endothelin in Systemic Sclerosis.” Arthritis Research & Therapy, vol. 9, no. Suppl 2, 2007, p. S2. www.ncbi.nlm.nih.gov, https://doi.org/10.1186/ar2186.
—. “How Does Endothelial Cell Injury Start? The Role of Endothelin in Systemic Sclerosis.” Arthritis Research & Therapy, vol. 9, no. Suppl 2, 2007, p. S2. www.ncbi.nlm.nih.gov, https://doi.org/10.1186/ar2186.
Anderson, Jeffrey L., et al. “Genetic Variation at the 9p21 Locus Predicts Angiographic Coronary Artery Disease Prevalence but Not Extent and Has Clinical Utility.” American Heart Journal, vol. 156, no. 6, Dec. 2008, pp. 1155-1162.e2. PubMed, https://doi.org/10.1016/j.ahj.2008.07.006.
Barale, Cristina, et al. “PCSK9 Biology and Its Role in Atherothrombosis.” International Journal of Molecular Sciences, vol. 22, no. 11, June 2021. www.ncbi.nlm.nih.gov, https://doi.org/10.3390/ijms22115880.
Barrett, Tessa J. “Macrophages in Atherosclerosis Regression.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 40, no. 1, Jan. 2020, p. 20. www.ncbi.nlm.nih.gov, https://doi.org/10.1161/ATVBAHA.119.312802.
Benjamin, Emelia J., et al. “Heart Disease and Stroke Statistics—2019 Update: A Report From the American Heart Association.” Circulation, vol. 139, no. 10, Mar. 2019, pp. e56–528. ahajournals.org (Atypon), https://doi.org/10.1161/CIR.0000000000000659.
Bilotta, Clio, et al. “COVID-19 Vaccine-Related Thrombosis: A Systematic Review and Exploratory Analysis.” Frontiers in Immunology, vol. 12, 2021. www.ncbi.nlm.nih.gov, https://doi.org/10.3389/fimmu.2021.729251.
“Coronary Artery Disease – Symptoms and Causes.” Mayo Clinic, https://www.mayoclinic.org/diseases-conditions/coronary-artery-disease/symptoms-causes/syc-20350613. Accessed 19 Jan. 2022.
Dai, Xuming, et al. “Genetics of Coronary Artery Disease and Myocardial Infarction.” World Journal of Cardiology, vol. 8, no. 1, Jan. 2016, p. 1. www.ncbi.nlm.nih.gov, https://doi.org/10.4330/wjc.v8.i1.1.
Dong, Lixue, et al. “Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells.” International Journal of Molecular Sciences, vol. 18, no. 2, Jan. 2017, p. E278. PubMed, https://doi.org/10.3390/ijms18020278.
Duvall, Melody G., and Bruce D. Levy. “DHA- and EPA-Derived Resolvins, Protectins, and Maresins in Airway Inflammation.” European Journal of Pharmacology, vol. 785, Aug. 2016, p. 144. www.ncbi.nlm.nih.gov, https://doi.org/10.1016/j.ejphar.2015.11.001.
Enas, Enas A., et al. “Lipoprotein(a): An Underrecognized Genetic Risk Factor for Malignant Coronary Artery Disease in Young Indians.” Indian Heart Journal, vol. 71, no. 3, June 2019, p. 184. www.ncbi.nlm.nih.gov, https://doi.org/10.1016/j.ihj.2019.04.007.
Guionaud, Silvia. “The Far Side of Vascular Injury: Nonconventional Vasoconstrictors, DNA-Targeting Agents, and Agents Toxic to Vascular Smooth Muscle.” Toxicologic Pathology, vol. 43, no. 7, Oct. 2015, pp. 945–58. SAGE Journals, https://doi.org/10.1177/0192623315601905.
Herrero-Fernandez, Beatriz, et al. “Immunobiology of Atherosclerosis: A Complex Net of Interactions.” International Journal of Molecular Sciences, vol. 20, no. 21, Nov. 2019. www.ncbi.nlm.nih.gov, https://doi.org/10.3390/ijms20215293.
“High Cholesterol Diseases: Conditions & Outcome.” Cleveland Clinic, https://my.clevelandclinic.org/health/articles/11918-cholesterol-high-cholesterol-diseases. Accessed 19 Jan. 2022.
Hussain, Mehak, et al. “P. Gingivalis in Periodontal Disease and Atherosclerosis – Scenes of Action for Antimicrobial Peptides and Complement.” Frontiers in Immunology, vol. 6, 2015. www.ncbi.nlm.nih.gov, https://doi.org/10.3389/fimmu.2015.00045.
Interactive Atlas of Heart Disease and Stroke Tables. https://nccd.cdc.gov/DHDSPAtlas/Reports.aspx. Accessed 19 Jan. 2022.
Jin, Uram, et al. “Cholesterol Metabolism in the Brain and Its Association with Parkinson’s Disease.” Experimental Neurobiology, vol. 28, no. 5, Oct. 2019, p. 554. www.ncbi.nlm.nih.gov, https://doi.org/10.5607/en.2019.28.5.554.
Jinnouchi, Hiroyuki, et al. “Calcium Deposition within Coronary Atherosclerotic Lesion: Implications for Plaque Stability.” Atherosclerosis, vol. 306, Aug. 2020, pp. 85–95. PubMed, https://doi.org/10.1016/j.atherosclerosis.2020.05.017.
Kasikara, Canan, et al. “The Role of Non-Resolving Inflammation in Atherosclerosis.” The Journal of Clinical Investigation, vol. 128, no. 7, July 2018, p. 2713. www.ncbi.nlm.nih.gov, https://doi.org/10.1172/JCI97950.
Kim, Minjoo, et al. “A Promoter Variant of the APOA5 Gene Increases Atherogenic LDL Levels and Arterial Stiffness in Hypertriglyceridemic Patients.” PLoS ONE, vol. 12, no. 12, 2017. www.ncbi.nlm.nih.gov, https://doi.org/10.1371/journal.pone.0186693.
Kohli, Payal, and Bruce D. Levy. “Resolvins and Protectins: Mediating Solutions to Inflammation.” British Journal of Pharmacology, vol. 158, no. 4, Oct. 2009, p. 960. www.ncbi.nlm.nih.gov, https://doi.org/10.1111/j.1476-5381.2009.00290.x.
Kumar, Nitin, et al. “SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism.” Viruses, vol. 13, no. 11, Nov. 2021, p. 2209. PubMed, https://doi.org/10.3390/v13112209.
Larsson, Susanna C., et al. “Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction.” JAMA, vol. 318, no. 4, July 2017, pp. 371–80. PubMed, https://doi.org/10.1001/jama.2017.8981.
Li, Bowei, et al. “Infection and Atherosclerosis: TLR-Dependent Pathways.” Cellular and Molecular Life Sciences, vol. 77, no. 14, 2020, p. 2751. www.ncbi.nlm.nih.gov, https://doi.org/10.1007/s00018-020-03453-7.
Li, Fei, et al. “SARS-CoV-2 Spike Promotes Inflammation and Apoptosis through Autophagy by ROS-Suppressed PI3K/AKT/MTOR Signaling.” Biochimica Et Biophysica Acta. Molecular Basis of Disease, vol. 1867, no. 12, Dec. 2021, p. 166260. PubMed, https://doi.org/10.1016/j.bbadis.2021.166260.
Linton, MacRae F., et al. “The Role of Lipids and Lipoproteins in Atherosclerosis.” Endotext, edited by Kenneth R. Feingold et al., MDText.com, Inc., 2000. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK343489/.
—. “The Role of Lipids and Lipoproteins in Atherosclerosis.” Endotext, edited by Kenneth R. Feingold et al., MDText.com, Inc., 2000. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK343489/.
Liu, Jinxue, et al. “MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis.” Disease Markers, vol. 2021, 2021. www.ncbi.nlm.nih.gov, https://doi.org/10.1155/2021/4933194.
—. “MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis.” Disease Markers, vol. 2021, 2021. www.ncbi.nlm.nih.gov, https://doi.org/10.1155/2021/4933194.
Liu, Minxuan, et al. “Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1.” Frontiers in Physiology, vol. 11, 2020. Frontiers, https://www.frontiersin.org/article/10.3389/fphys.2020.00774.
—. “Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1.” Frontiers in Physiology, vol. 11, 2020. Frontiers, https://www.frontiersin.org/article/10.3389/fphys.2020.00774.
Malavige, Gathsaurie Neelika, and Graham S. Ogg. “Pathogenesis of Vascular Leak in Dengue Virus Infection.” Immunology, vol. 151, no. 3, July 2017, pp. 261–69. PubMed, https://doi.org/10.1111/imm.12748.
Moore, Kathryn J., et al. “Macrophage Trafficking, Inflammatory Resolution, and Genomics in Atherosclerosis: JACC Macrophage in CVD Series (Part II).” Journal of the American College of Cardiology, vol. 72, no. 18, Oct. 2018, p. 2181. www.ncbi.nlm.nih.gov, https://doi.org/10.1016/j.jacc.2018.08.2147.
Rajendran, Peramaiyan, et al. “The Vascular Endothelium and Human Diseases.” International Journal of Biological Sciences, vol. 9, no. 10, 2013, p. 1057. www.ncbi.nlm.nih.gov, https://doi.org/10.7150/ijbs.7502.
Serhan, Charles N., et al. “Maresins: Novel Macrophage Mediators with Potent Antiinflammatory and Proresolving Actions.” The Journal of Experimental Medicine, vol. 206, no. 1, Jan. 2009, p. 15. www.ncbi.nlm.nih.gov, https://doi.org/10.1084/jem.20081880.
Silva, Grazielle Caroline, et al. “Experimental Periodontal Disease Triggers Coronary Endothelial Dysfunction in Middle-Aged Rats: Preventive Effect of a Prebiotic β-Glucan.” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, vol. 76, no. 8, July 2021, pp. 1398–406. PubMed, https://doi.org/10.1093/gerona/glab066.
Topol, Eric J., et al. “Genetic Susceptibility to Myocardial Infarction and Coronary Artery Disease.” Human Molecular Genetics, vol. 15 Spec No 2, Oct. 2006, pp. R117-123. PubMed, https://doi.org/10.1093/hmg/ddl183.
Waltmann, Meaghan D., et al. “Apolipoprotein E Receptor-2 Deficiency Enhances Macrophage Susceptibility to Lipid Accumulation and Cell Death to Augment Atherosclerotic Plaque Progression and Necrosis.” Biochimica et Biophysica Acta, vol. 1842, no. 9, Sept. 2014, p. 1395. www.ncbi.nlm.nih.gov, https://doi.org/10.1016/j.bbadis.2014.05.009.
Xu, Lang-Biao, et al. “Rs10757274 Gene Polymorphisms in Coronary Artery Disease: A Systematic Review and a Meta-Analysis.” Medicine, vol. 99, no. 3, Jan. 2020, p. e18841. PubMed, https://doi.org/10.1097/MD.0000000000018841.
Yamamoto, Yasuhiro, et al. “Intermittent Local Periodontal Inflammation Causes Endothelial Dysfunction of the Systemic Artery via Increased Levels of Hydrogen Peroxide Concomitantly with Overexpression of Superoxide Dismutase.” International Journal of Cardiology, vol. 222, Nov. 2016, pp. 901–07. PubMed, https://doi.org/10.1016/j.ijcard.2016.08.099.
Zhang, Yefei, et al. “Resveratrol Prevents TNF-α-Induced VCAM-1 and ICAM-1 Upregulation in Endothelial Progenitor Cells via Reduction of NF-ΚB Activation.” The Journal of International Medical Research, vol. 48, no. 9, Sept. 2020. www.ncbi.nlm.nih.gov, https://doi.org/10.1177/0300060520945131.
Zhao, Zi-Wen, et al. “Circulating Soluble Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor‐1 Levels Are Associated With Angiographic Coronary Lesion Complexity in Patients With Coronary Artery Disease.” Clinical Cardiology, vol. 34, no. 3, Mar. 2011, p. 172. www.ncbi.nlm.nih.gov, https://doi.org/10.1002/clc.20847.
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.