Heart disease is the leading cause of death in the US and around the world, and high LDL-cholesterol levels have been linked in many studies to increased heart disease. Standard medical advice on ideal cholesterol levels and cardiovascular disease is often confusing, ever-changing, and sometimes downright contradictory.
This article digs into the ways your genes can be involved in either high or low cholesterol levels. It includes evidence from research studies on the effects of high and low cholesterol, as well as the way that your diet and lifestyle interact with your genes and cholesterol.
When you read about cholesterol and heart disease, it is easy to get the idea that cholesterol is something terrible that you don’t want in your body. But that is far from the whole picture! Cholesterol is essential for your health and wellbeing.
Cholesterol is a type of lipid (fat) that is created by all animals and is an essential part of every cell as well as being important for the way your body digests foods and creates hormones.
Every cell in your body is surrounded by a membrane composed mainly of phospholipids. Cholesterol molecules make up part of that cell membrane, stabilizing the membrane to help maintain the integrity of it. Cholesterol keeps the membrane just firm enough to keep some very small water-soluble molecules out, but yet not too rigid.
In addition to being part of the structure of cells, cholesterol is also the precursor for bile acids, vitamin D, and steroid hormones. Bile acids are essential for digesting fats in the diet, and vitamin D plays a big role in calcium metabolism and in bone health. The steroid hormones include testosterone, estrogen, progesterone, cortisol, and aldosterone.
Like most things in the body, optimal health is a matter of having neither too much nor too little cholesterol. The right amount is personal to each of us, depending on our genes, diet, age, and lifestyle.
Here is an interesting chart plotting causes of death worldwide along with cholesterol levels. The chart shows a sharp increase in mortality with low cholesterol levels and with really high cholesterol levels. One reason for the high mortality rates with low cholesterol is that cholesterol plays a role in protecting against infectious diseases.[ref]
Don’t like charts? There is a large 10-year study out of Norway that found the lowest mortality rates occurred in people with cholesterol levels between ~190 to 270 mg/dl (5 and 7 mmol/l).[ref]
There are two sources of cholesterol: foods and endogenous production. In addition to the cholesterol that your body makes, cholesterol from food (animal products) is absorbed in the intestines. Eating foods that contain cholesterol causes a temporary increase in serum cholesterol levels, with levels drop to baseline in about seven hours.[ref]
Generally, eating cholesterol causes the body to produce less of it, and decreasing your cholesterol intake will trigger the body to make more of it. At least that is the way that it is supposed to work.
The majority of cholesterol in the body is synthesized in the liver, intestines, adrenals, and reproductive organs. It is a multi-step, complex process to make it. Cholesterol synthesis is regulated through several processes, with one of the main regulators being the SREBP protein, coded for by the SREBF1 and 2 genes. Other genes involved in your cholesterol levels include cholesterol transport and receptor genes.
Statins, one type of cholesterol-lowering medicine, is one of the most prescribed medications in the US and UK. It was estimated in 2014 that about 28% of Americans over age 40 are taking a statin. With prices for the prescription drugs ranging from $10 (generic) to over $700 for a month’s supply, the economic impact of taking statins can be extensive, especially when calculated over many years of use. [goodRx]
The Number Needed to Treat website has an extensive review of studies on statins, including the increased risk of diabetes and muscle pain. It is an interesting, well-crafted assessment of the risks and benefits which concludes that the risks from statins outweigh the benefits for most people. Everyone is unique. Talk with your doctor about your own specific risks and benefits.
Studies on both high and low LDL cholesterol show a variety of different effects:
A March 2018 study found that lung cancer patients with low cholesterol were at a 61% higher risk of death.[ref]
A study of over 100,000 people in Denmark found that having a lifeline lower LDL cholesterol level (1 mmol/L lower) reduced the risk of Alzheimers and dementia. [ref]
A review in the Journal of the American Medical Association in 2019 found that each “additional 300 mg of dietary cholesterol consumed per day was significantly associated with higher risk of incident” of cardiovascular disease. [ref]
A large review in Lancet recently found that reducing LDL cholesterol reduces the risk of ‘major vascular events’. [ref]
One well-studied gene related to cholesterol is CETP (cholesteryl ester transfer protein), which codes for a protein involved in exchanging triglycerides between LDL and HDL cholesterol.
Check your genetic data for rs708272 Taq1B (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs708272 is —.
Check your genetic data for rs5882 I405V (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs5882 is —.
Check your genetic data for rs3764261 (23andMe v4, v5):
Members: Your genotype for rs3764261 is —.
The PCSK9 gene codes for an enzyme involved in cholesterol transport. (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):
Members: Your genotype for rs11591147 is —.
Check your genetic data for rs28362286 (23andMe v4; AncestryDNA):
Members: Your genotype for rs28362286 is —.
Check your genetic data for rs67608943 (23andMe v4, v5;):
Members: Your genotype for rs67608943 is —.
Check your genetic data for rs72646508 (23andMe v4, v5):
Members: Your genotype for rs72646508 is —.
Genetic variants that increase PCSK9 are linked to higher LDL-c and a higher risk for heart disease.
Check your genetic data for rs505151 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs505151 is —.
Check your genetic data for rs28942112 (23andMe i5000370, v4; AncestryDNA):
Members: Your genotype for rs28942112 is <.
Check your genetic data for rs28942111 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs28942111 is —.
Apolipoprotein B is one of the main carriers of LDL cholesterol throughout the body and into the cells. Genetic variants in the APOB gene can lead to high LDL levels and an increased risk of heart disease.
Check your genetic data for rs693 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs693 is —.
There are also several fairly rare APOB mutations that are pathogenic for familial hypercholesterolemia, a genetic form of very high cholesterol. Familial hypercholesterolemia can significantly raise the risk of heart disease.
Check your genetic data for rs1444467873 (23andMe v4, v5 i4000339; AncestryDNA):
Members: Your genotype for rs1444467873 (i4000339) is .
Check your genetic data for rs5742904 (23andMe v4; AncestryDNA):
Members: Your genotype for rs5742904 is —.
Check your genetic data for rs12713559 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs12713559 is —.
Some relatively rare LDLR mutations also cause familial hypercholesterolemia. 23andMe data only covers a few of the over 400 mutations known, so you cannot use this data to rule out familial hypercholesterolemia.
Check your genetic data for rs6511720 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs6511720 is —.
A genetic variant in the HMGCR gene affects how well people respond to statins.
Check your genetic data for rs3846662 (23andMe v4, v5;):
Members: Your genotype for rs3846662 is —.
If you have high cholesterol and are trying to avoid going on a statin, here are some diet and supplement ideas to try:
A whole foods diet and moderate exercise are usually beneficial for keeping cholesterol levels in check. Yep – standard advice to cut out fast food and hit the gym a few times per week.[ref] [ref] While the old advice to give up eggs has been shown to be inaccurate[ref], cutting out the processed food should decrease inflammation and lower cholesterol levels a bit. A meta-analysis that combined the data from a bunch of studies found that fruit and vegetable intake of 3+ servings per day decreases triglyceride levels (a little) and marginally improves total cholesterol. (The study found no extra benefit from consuming 5 or more servings of fruits and vegetables per day.)[ref]
Berberine, which is an herbal supplement, has been shown in studies to reduce both LDL and triglyceride levels. Average LDL reductions ranged from 20 to 50 mg/dL. [ref] One study found that berberine upregulates the LDL receptor, which causes a decrease in serum LDL levels. For the 32 patients in the study who had high cholesterol, three months of berberine reduced LDL by 25% and also reduced triglycerides by 35%. [ref]
Fish oil: Omega 3 or fish oil supplements are often recommended for lowering cholesterol, but not all studies show that this is true. The jury seems to still be out on the topic, but adding fish to your diet may be beneficial. [ref]
A recent study found that pomegranate juice raised triglyceride and LDL levels, but lowered blood pressure. So you may want to skip the pomegranate juice right before a cholesterol test.
Resveratrol has been studied extensively, and the consensus seems to be that it doesn’t lower cholesterol.[ref]
High triglycerides are linked with an increased risk of cardiovascular disease. Both genetics and diet combine to elevate triglyceride levels. Learn how your genes interact with what you eat to lower your triglycerides.
High Lp(a) levels are a big risk factor for sudden heart attacks. Your Lp(a) levels are mainly controlled by your genetic variants. Check to see if you carry genetic variants that increase or decrease Lp(a).
Originally published 2/2015