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If it’s not cholesterol, what causes heart disease?

Heart Health Cholesterol Genetics

You may have heard a lot recently about the changing recommendations relating to dietary intake of cholesterol. Identifying the cause of increasing levels of obesity, diabetes and heart disease has become of interest, with much research occurring on the subject. As such, it can feel like you hear a different piece of conflicting dietary advice every day.

For example, the American Heart Association has recently come out against coconut oil as an unhealthy source of saturated fat.

So, what is the best practice when it comes to dietary cholesterol and saturated fat?

Well, as always, the best place to start is with a good understanding of the background and the key terms, so let’s dive in!

Cholesterol plays an important role in our bodies

Because of the various health guidelines, most people think of cholesterol as a fat similar to the triglycerides. However, whilst cholesterol is a lipid, it is not a triglyceride fat. Very different in structure, it contains carbon rings rather than long chains of carbon atoms which results in a very different activity in the body.

Indeed, cholesterol is essential for life, forming about 30% of all our cell membranes and providing flexibility in our cells. Additionally, cholesterol is the key component of many hormones including estrogen and testosterone, and is also required for the synthesis of vitamin D. Cholesterol also forms bile acids which facilitate the digestion of fats and oils in the intestine as well as aiding the absorption of the fat-soluble vitamins A, D and E.

Many of the features described above are specific to animals rather than plants and it is for this reason that cholesterol is typically associated with meat and dairy products, with plant based foods typically containing little, if any, cholesterol.

As with triglycerides, cholesterol is not soluble in water, and so to be transported around the circulatory system it requires assistance. 1

Lipoproteins – transporters of cholesterol

To transport the insoluble triglycerides and cholesterol around the body in the blood, lipoproteins are required. Lipoproteins are particles made up of thousands of molecules which encase the triglycerides and cholesterol allowing these insoluble molecules to be transported around the circulatory system.

There are several different types of lipoproteins, the most commonly known being low-density lipoproteins (LDL) and high-density lipoproteins (HDL). LDL delivers cholesterol to the tissues within the body. However, where there is an excess of LDL, harmful depositions of cholesterol, particularly in the blood vessels, can occur, contributing to the build-up of fatty plaques on blood vessel walls. This is why LDL is often referred to as ‘bad cholesterol’, even though LDL is not made of cholesterol, it just transports it! In contrast, HDL is responsible for transporting excess cholesterol from the tissues within the body (including removing cholesterol from the arteries) for disposal by the liver, and is referred to as “good cholesterol.” 2

See also: Why heart attack risk goes well beyond LDL-C

High cholesterol is bad… right?

By now I guess you’re wondering why, if cholesterol is so fundamental to life, does it have such a bad reputation?

Well the dietary advice surrounding cholesterol is an excellent example of correlation not equalling causation. Historical studies proposed that eating high levels of saturated fat, and cholesterol in foods like eggs, led to an increase in blood cholesterol levels, which congealed inside the blood vessels eventually resulting in poor heart health. And so, the idea that a high cholesterol diet is bad was born. 3

New studies challenge the traditional cholesterol paradigm

However, numerous studies have since pointed out several flaws with this hypothesis. 4

Firstly, whilst a high level of blood-borne cholesterol is associated with an increased risk of heart disease, most people who suffer from heart disease have normal blood cholesterol levels. 5 Secondly, as cholesterol is so fundamental to life, it is directly synthesized in the body, mainly in the liver. Excess dietary cholesterol is excreted, and any dietary cholesterol which is absorbed results in a decrease in cholesterol synthesis in the liver. 6 7 Together this means that even a diet very high in cholesterol has little, if any, impact on the cholesterol levels in the blood which are maintained at a steady state.

A side note: you get op-ed style articles like this one, which appeared in the Guardian, discussing “cholesterol deniers.” There are two things to point out here:

  1. Yes, some people, tend to hyper-absorb cholesterol and plant sterol. These people may need to keep a closer eye on cholesterol than others.
  2. The article lumps saturated fat in with cholesterol, but as we’ve learned, the two are very different. Especially in some genotypes, saturated fat may indeed increase the risk for heart disease, but let’s not conflate these two separate issues.

See also our articles on TMAO, which is a metabolite of the gut produced when we eat cholesterol, and which has been linked to heart disease. Not everyone produces the same amount of TMAO, and notably, eating fish causes the same reaction, so the likelihood is that genetic differences, as well as differences in the microbiome, play the key role in driving TMAO production.

As a result of this disconnect between the advice and the science, the USDA Dietary Guidelines Advisory Committee in 2015 reversed the long-standing recommendation that people limit dietary cholesterol intake. 8

So, if not cholesterol, what is responsible for the ever-increasing occurrence of heart disease?

There are several hypotheses.

Source and type of dietary fat

The source and type of dietary fat ingested has also been investigated. Early work proposed that saturated animal fats were bad for health as they caused the blood vessel plaques associated with heart disease. Together with cholesterol, saturated fats were the bad guy and we were supposed to phase them out of our diet. 3

More recently however, the role of polyunsaturated fats in disease has been investigated. Of primary concern are vegetable oils. The process of extracting these oils from the source plants damages the structure of the finished product, causing us to ingest free radicals. It has been proposed that these polyunsaturated lipids can do huge amounts of damage to the linings of blood vessels. This damage results in inflammation and narrowing of the blood vessel and potential development of blood clots.9

It is key to point out here that this area remains very controversial, and may hinge on the degree to which a given individual absorbs the oxidized fats found in vegetable oils and processed foods. One of the drivers here are the ABCG8 genes, which play the role of “kicking out” sterol and cholesterol from the gut wall before it reaches the blood stream. When ABCG8 function is impaired, as it can be when certain polymorphisms are present, more of the damaged oil is absorbed, and therefore the risk to heart health is greater.

I’ve linked to evidence which offers a different perspective on fat intake. However, the majority of dietary guidelines still recommend a reduction in saturated fat intake, replacing it with unsaturated fat equivalents.

The food industry replaces dietary fat with sugar…

A lot of the controversy arising above may be due to the choice of what to replace saturated fat with. An interesting emerging hypothesis is that the recommendation for a low saturated fat diet, rather than leading to us replacing them with alternative fats, instead led to a massive increase in the amount of carbohydrates and sugars we eat. Fat is responsible for a lot of the taste in food, as we’ve demanded its reduction suppliers have had to find other means to maintain flavor and settled on carbohydrates and especially refined sugars. An excessive intake of these sugars has been linked to the development of diabetes, but also more recently the development of obesity and poor heart health.10 The topic is too complex to get into here but for an excellent overview of the controversy see the following article.

Trans fats – you won’t find them in nature, but you will in the grocery aisles

Whilst saturated fats and cholesterol were the bête noires of healthy eating for the past half-century, have they been masking the true culprits? With the industrialisation of our food industry there has been a steady increase in the use of processed and preserved ingredients.

Trans-fats are rare in nature but are often introduced when polyunsaturated fat is treated to improve shelf-life and character (by standardising fatty acid length giving a constant melting temperature) by breaking double bonds. This long shelf life of trans-fats has made them desirable for use in numerous pre-prepared meals and foods. Additionally, deep fried foods can contain high levels of trans-fats which are generated during the frying procedure. This is especially true if the frying oil is used multiple times. It is thought that trans-fats can increase the levels of LDL in the blood, with the resulting impact on heart health.11

Current Advice

The scientific understanding is complex and in flux, but that doesn’t help you right now. So what’s the best practice right now?

  1. Stop worrying about cholesterol, unless you have a specific cholesterol-related disease your dietary intake will be having little if any impact on your blood cholesterol levels.
  2. Try and reduce LDL, and in particular, sdLDL levels, whilst increasing HDL levels. Certain genotypes will see a “hyper-response” when consuming saturated fat, meaning their LDL-C, and LDL-P levels will rise significantly. Analyzing genetics is one way to determine whether you are a hyper responder, and gauging LDL response to saturated fat is one of the things we try to do with our custom nutrition plans.
  3. The debate about which form of fat is the best for good health is still underway. Until then, a balanced diet with perhaps a preference for natural monounsaturated fats, such as olive oils.
  4. Avoid highly processed trans-fat rich foods, or fat-free foods which have replaced fat with sugar. Trans-fats along with excessive sugar are strongly linked to poor heart health, as well as with obesity and diabetes.

I hope I’ve given you a good overview of the current scientific consensus on dietary intake, but this blog is interested in the interaction between your genes, diet and health and wellbeing. Below I’ve focused on SNPs associated with LDL levels, but in the future may loop back to cover some of the other topics discussed.

LDL levels and genetics – which genes influence LDL?

There are a number of SNPs in different genes which have been associated with an increase in the detected levels of LDL. It is important to understand the methods used to associate these these SNPs with increased LDL levels, as this is key to understanding outcomes. The association has been made through the use of genome wide association studies (GWAS), a method which allows researchers to analyse many hundreds of thousands of SNPs across the entire genome and compare the results between cases (in this example people with increased LDL levels) and controls (people with normal LDL levels).

Those SNPs which are significantly associated with the case group, but not the control group, can then be associated with increased LDL levels. This of course has its limitations – GWAS provides associations between SNPs and disease but not the specific cause of the disease, once again correlation but not causation. Therefore, the allele at a given SNP position is not necessarily causing LDL levels to increase, the allele is just more often present in individuals with increased LDL levels than with those who have normal LDL levels. This is also why SNPs which are not in a gene (‘intragenic’) or are described as near a gene (‘upstream’) can be associated with a trait such as increased LDL levels.

SNPs which have been associated with an increase in the levels of LDL are tabulated below. Remember, the alleles called can change depending on who is providing you with the data.

SNP IDGene(s) of interest within or near associated intervalMajor allele, Minor allele
rs6544713ABCG8C, T
rs515135APOBC, T
rs12740374CELSR2G, T
rs3846663HMGCRC, T
rs2650000HNF1AC, A
rs1501908TIMD4-HAVCR1C, G
rs6511720LDLRG, T
rs6102059MAFBC, T
rs10401969NCANT, C
rs11206510PCSK9T, C

Table adapted from:

There is no doubt in the literature that the SNPs above have been shown through GWAS to associate with changes in LDL levels. Similarly, others have been shown to associate with changes in HDL or triglyceride levels. However, as mentioned above, these SNPs do not explicitly cause these changes to lipoprotein levels through a known functional mechanism (for example, changing the allele is not known to cause the function of a resulting protein to change), rather they are likely to be close to a gene or causative change that does. Therefore, individuals who have ‘at risk’ alleles may be ideal candidates for further investigation into their true risk of heart disease by healthcare professionals, through sequencing of key genes known to contribute at a functional level.1213141516

Further research into how the SNPs in the genes listed above subsequently effect protein function is required before we can begin to understand their role in controlling LDL levels.

Dr. Aaron Gardner, BSc, MRes, PhD

Dr. Aaron Gardner, BSc, MRes, PhD is a life-scientist with a strong background in genetics and medical research, and the developing fields of personalized medicine and nutrition. Read his full bio here.

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