Important Genetic Markers in Cardiovascular Disease and CKD

DNA molecule, structure. Close-up of concept human genome. 3d

Are there important genes that, if you have a family history of heart disease or kidney disease you should know about? We think so! Below I cover the five top genes that we think are important to know in the prevention and management of heart and kidney disease.

From decades in clinical practice, we see the same root causes that trigger not only cardiovascular disease but also chronic kidney disease and even cancer and Alzheimer’s disease. So while I will focus on genes that are known to increase the risk of cardiovascular disease in great detail because it remains the number one killer in our country, any of these diseases are affected by the same root causes and can be mitigated by the same treatments.

We have the power to control our own health destiny if we recognize what tests we should be doing, what diets we should be following, and what exercise and fundamental health strategies we should be participating in.

I think that the greater understanding we have of some of the genes that we were born with and how that affects our cardiovascular and kidney disease risk, we can then make very small changes that have huge effects on the outcomes of our health.

So here are the five top genes that we know can increase the risk of CKD and CVD

APOE

The APOE gene, also known as the apolipoprotein E gene, is a crucial gene that plays a significant role in lipid metabolism and cholesterol transport in the body.

It is located on chromosome 19 and has three major alleles or subtypes: APOE2, APOE3, and APOE4.

Each subtype is determined by specific variations in the genetic sequence of the APOE gene.

APOE2 is considered the least common subtype and is associated with some potential protective effects against certain health conditions. The APOE2s are the lucky ones, about 11% of the population, as they are actually at a decreased risk compared to the average of developing Alzheimer’s, coronary disease, or heart attack. These individuals can tolerate and do better on a very high-fat diet, often consuming about 35% of their calories from fat. They do well on a ketogenic diet.

APOE3 is the most common subtype and is considered neutral, not significantly increasing or decreasing the risk for various diseases.

On the other hand, APOE4 is the most well-known subtype and is associated with an increased risk of developing Alzheimer’s disease, cardiovascular disease, and other neurological disorders. APOE4s, who make up about 25% of the population, do not do well on a ketogenic diet. It should be managed very carefully by someone with extreme experience in APOE genetics, oxidative stress, and inflammation. They should monitor their tolerance to these diets and be cautious about the potential negative effects on their health.

Understanding the different subtypes of the APOE gene is crucial in comprehending the variations in disease susceptibility and developing personalized approaches to healthcare.

If you have a family history of heart disease I highly recommend that you get tested for your APOE genetic status.

kinesin-like protein 6 – KIF6

The gene KIF6, also known as kinesin-like protein 6, is a protein-coding gene found in humans. It is located on chromosome 6q25.2 and is primarily expressed in tissues such as the liver, heart, and skeletal muscle. KIF6 encodes a member of the kinesin superfamily, which are motor proteins involved in intracellular transport and cellular processes such as mitosis, meiosis, and vesicle trafficking.

The KIF6 gene gained significant attention due to its potential association with cardiovascular disease risk. A specific variant of the gene, known as KIF6 719Arg, has been studied extensively in relation to coronary artery disease (CAD) and statin response. This variant refers to an amino acid change at position 719 from a tryptophan (Trp) to an arginine (Arg). The presence of the KIF6 719Arg variant has been proposed to influence the effectiveness of statin therapy and impact the risk of CAD.

Several large-scale studies have investigated the association between the KIF6 719Arg variant and cardiovascular outcomes. The most notable study was the JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin), which examined over 17,000 initially healthy individuals. The study found that carriers of the KIF6 719Arg variant had a higher risk of major cardiovascular events compared to non-carriers, and they derived greater absolute benefits from statin therapy.

https://www.sciencedirect.com/science/article/abs/pii/S0002914905020321

The KIF6 gene affects the way cholesterol medication works in our bodies. The most commonly prescribed drug for high cholesterol is Lipitor, but if you have the normal KIF6 gene, Lipitor will not prevent cardiovascular disease effectively. It will lower cholesterol, giving a false sense of doing its job, but it does not provide the reduction in cardiovascular events that we see with the gene variant present in 60% of patients. This is true for other drugs like Simvastatin or Rosuvastatin (Crestor) as well. Only KIF6 genetic mutants respond to Lipitor, so it’s important to have your KIF6 gene checked before taking any cholesterol medication or to ask your doctor to prescribe Rosuvastatin or Simvastatin instead if you don’t have the gene variant.

Lipitor and genetics in cardiovascular disease and statin drugs

If you have elevated cholesterol it is imperative to check this gene to make sure any medications prescribed will actually be effective or not.

If you are one of the people who will actually respond to a statin drug like Lipitor then I always recommend that CoQ10 is taken at the same time.

The same pathway that statin drugs work on, the HMG COA reductase pathway, lower cholesterol, simultaneously lower coenzyme Q10 levels, and CoQ10 is one of our best antioxidants, and remember we talked about oxidative stress is one of the major drivers of vessel disease, high blood pressure, and inflammation.

So we don’t want less CoQ10, we want more CoQ10, and if this drug class reduces it, you want to make sure that you protect your kidneys by taking the two (statin drug and CoQ10) together, this will also mitigate many of the side effects.

Coenzyme Q10 and kidney disease

MTHFR Genes

We have covered methylation and MTHFR genes in a previous post, but I want to cover it again quickly here, as mutations on this gene increase something called homocysteine which in turn increases the risk of many diseases including cardiovascular disease and kidney disease.

MTHFR stands for methylene tetrahydrofolate reductase, any word that ends in a-s-e is an enzyme most of the time, and this enzyme is responsible for the methylation pathway of turning folate to methyl folate. And in this pathway, we’re converting homocysteine into methionine, and if our bodies cannot do this effectively, our homocysteine levels build up.

Why is that important?

If we have high homocysteine levels, we get thick and sticky blood, and that increases the risk of blood clots. Not only blood clots in our legs but blood clots in our lungs, if we’re pregnant, blood clots in our uterus, can lead to miscarriage and premature birth or even fetal demise.

Homocysteine is also important in detoxification. So if you have high homocysteine levels, you don’t detox very well. The ability to detox in this modern world is one of the most protective function our bodies can perform, so it is critical to prevent any disease that we have the ability to adequately detox.

The third thing that methylation provides is the production of neurotransmitters. So neurotransmitters are made in our gut and made in our brain. If we don’t have these high levels of neurotransmitters, we’re at more risk to develop irritable bowel syndrome, anxiety, depression, OCD, bipolar, and dementia.

Haptoglobin 2 2 or 1 2 Gene gluten

Haptoglobin (Hp) is a glycoprotein that plays a crucial role in the immune system and the regulation of inflammation. It is primarily synthesized in the liver and released into the bloodstream, where it binds to free hemoglobin, a protein released from damaged red blood cells, preventing its oxidative and inflammatory effects.

The haptoglobin gene exists in two common allelic forms: Hp1 and Hp2. These allelic forms refer to genetic variations or mutations that occur in the DNA sequence of the haptoglobin gene. Specifically, the gene has two main alleles: Hp1 and Hp2, which can be further classified into three possible combinations: Hp1-1, Hp2-1, and Hp2-2.

The most common variant is Hp1, which has a shorter DNA sequence compared to Hp2. Hp1-1 individuals have two copies of the Hp1 allele, resulting in the production of haptoglobin consisting of two alpha chains and two beta chains. This variant is associated with higher haptoglobin levels in the blood and is considered the “normal” or wild-type form of haptoglobin.

On the other hand, Hp2 is a duplication of a specific DNA segment within the haptoglobin gene. Hp2-2 individuals have two copies of the Hp2 allele, resulting in the production of haptoglobin consisting of three alpha chains and three beta chains. This variant is associated with lower haptoglobin levels in the blood compared to Hp1-1 individuals.

The haptoglobin 1 2 gene (Hp1-2) refers to individuals who have one copy of the Hp1 allele and one copy of the Hp2 allele. Consequently, they produce haptoglobin consisting of two alpha chains and three beta chains. Hp1-2 individuals have intermediate haptoglobin levels compared to Hp1-1 and Hp2-2 individuals.

The variations in haptoglobin alleles can influence haptoglobin’s functional properties and its association with various health conditions. For example, the Hp2 allele has been associated with increased susceptibility to certain conditions, such as cardiovascular diseases, diabetes, and inflammatory disorders.

The Hp1 allele, on the other hand, is generally considered to confer some protective effects against these conditions.

Furthermore, there is an association of haptoglobin and the molecule called zonulin When someone has genetic sensitivity such as celiac disease or the haptoglobin 2 2 or 1 2 Gene, gluten activates zonulin. Gluten is that sticky protein that makes bread stretchy, makes the dough stretchy so that yeast can make it rise into that beautiful pizza crust that you like to eat so much, and zonulin can cause leaky cell membranes.

Instead of the cells of the intestines being held and glued tightly together, zonulin interferes with them and causes them to be leaky. Because of this gluten molecules can get inside the immune system, activate it, and then all kinds of antibodies can be made against gluten, triggering diseases such as type 1 diabetes and celiac disease.

In a haptoglobin 2-2, zonulin triggered by gluten causes leaky endothelial membranes. The blood vessels also become leaky.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943850/

Why is that important if you have Kidney Disease?

If it’s in your kidneys, it can lead to proteinuria. It can cause the kidneys to leak protein into the urine. If those endothelial cells are in your heart, inflamed oxidized cholesterol, can deposit itself behind the drywall and build up plaque.

zonulin, gluten sensitivity and kidney disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943850/

If you have leaky membranes in your endothelium, the mouth bacteria, gram-negative bacteria, that we will discuss in the next lesson, they cause lipopolysaccharides that can now get into your bloodstream. They can get now through that leaky membrane into your blood vessels and set up housekeeping inside the blood vessel walls where they can make their own plaque or they can make inflammation or they can drive cytokines, worsening the stability of the plaque and leading to plaque rupture.

The moral of this story? Nobody wants a leaky membrane. If you have the haptoglobin 2-2 genotype, you should treat yourself as if you’re allergic to wheat and gluten.

You should not consume any gluten. This haptoglobin 2-2 is basically acting as a type of genetic gluten sensitivity that can lead to long-term complications of increased risk of cardiovascular disease, heart attack, and stroke, yet you won’t know you have it as it may not cause any gut symptoms.

9p21 gene

The 9p21 gene, also known as CDKN2A or p16INK4a, is a tumour suppressor gene located on the short arm of chromosome 9 at position 21. This gene plays a crucial role in regulating the cell cycle and preventing uncontrolled cell division. Mutations or alterations in the 9p21 gene have been linked to various types of cancer, particularly melanoma, pancreatic cancer, and certain types of familial cancers.

Functionally, the 9p21 gene produces a protein known as p16INK4a, which acts as a negative regulator of the cell cycle. The protein p16INK4a inhibits the activity of cyclin-dependent kinases (CDKs) and prevents the phosphorylation of the retinoblastoma (RB) protein. This phosphorylation event is necessary for the cell cycle to progress from the G1 phase to the S phase, where DNA synthesis occurs. By inhibiting CDKs and preventing RB phosphorylation, p16INK4a helps to arrest the cell cycle and halt cell division.

Mutations or deletions in the 9p21 gene can disrupt the normal function of p16INK4a, leading to a loss of cell cycle regulation. This loss of regulation allows cells to divide uncontrollably, leading to the development of tumours.

Individuals with inherited mutations in the 9p21 gene have an increased risk of developing certain types of cancer, including melanoma, pancreatic cancer, and familial atypical mole and melanoma (FAMMM) syndrome.

This Gene is important, it is not as rare as you may think with 25 per cent of Caucasians and Asians being homozygous for this Gene. Apart from cancer, this gene increases your risk of having a heart attack or coronary artery disease by 102%. They also have a 56% increased lifetime risk of heart attack and coronary disease compared to the general population and a 74% increased risk of developing an abdominal aortic aneurysm.

If you have the 9p21 gene and you are a smoker, you significantly increase your risk of dying from an aneurysm, so if you knew at age 50 that you were a 9p21 carrier and you had smoked in your 20s and 30s you might go to your doctor at a much younger age than the usual recommendation and say I would like to be ultrasounded oh and by the way, I’m at really high risk for heart attack and stroke, so I really want your full corporation to do everything we can do to reduce my risk. If you have a good GP or cardiologist that understands the highly increased risk of carrying this gene then you should have no problem getting the support and tests that you require. If you don’t get that corporation I suggest you find a new GP that understands the implications of having this gene mutation.

Finally, if you’re a diabetic, have the 9p21 gene and you’re poorly controlled you have a 400% increased risk of coronary disease and a double risk of death. Scary I know, and this isn’t to scare anyone, but it is why if you have kidney disease or a family history of heart disease it is really important to know your genetic status. If we know if we’re at higher risk then we can be screened more carefully and work with a well-educated healthcare practitioner that can help mitigate a lot of these potentials through diet and lifestyle modifications.

Knowing your genetics means you can treat preventatively, and as I am sure we have said before here at the Kidney Coach – prevention is always better than cure.

I also want to acknowledge Dr Ellie Campbell for her wisdom and knowledge on this topic. To watch the interview between myself and Dr Cambpell please head to our YouTube site:

 

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