The genetics of high triglycerides

Triglycerides are the main type of fat in your blood. Triglyceride is a general term for a type of lipid-containing three fatty acids (tri) bound to a glycerol. Most importantly, triglycerides are used by the body as energy and are stored in adipocytes (fat cells that compose adipose tissue).

Most of the time, when you go to the doctor for a lipids test, they are worried about higher LDL or lower HDL levels. These are classically linked to cardiovascular disease risk. However, triglycerides also play a causal role in heart disease.[ref]

People are starting to take note of triglyceride levels as a marker of metabolic syndrome. The defining factors for metabolic syndrome include abdominal obesity, high blood pressure, high blood sugar, low HDL, and high triglycerides.

The immediate response to ‘why do I have high triglycerides’ is to blame the diet and assume you are eating donuts and drinking lots of soda. While diet does play a role (of course), your genetic variants are also very important in basal triglyceride levels.

Digging deeper into triglycerides

Triglycerides – three fatty acids and glycerol – can contain either saturated or unsaturated fatty acids. Most triglycerides contain different types of fatty acids in them.

Saturated fats are carbon-hydrogen chains that have single bonds between the carbons. Unsaturated fats have either one double bond (monounsaturated) or multiple double bonds (polyunsaturated). The double bonds cause a bend in the molecule, keeping it from packing together as tightly. Thus polyunsaturated fats are usually liquids and saturated fats can be solids at room temperature.

Triglycerides from food cannot be directly absorbed. Instead, they are emulsified by lipase, an enzyme secreted by the pancreas, to break down fats. In the enterocytes ( an intestinal cell that absorbs) of the small intestines, the fatty acids from triglycerides are packaged into chylomicrons (like a glob of fat). Picture how oil clumps together into droplets when you try to stir it into water.

Chylomicrons contain mostly triglycerides, along with a smaller percentage of cholesterol, phospholipids, and proteins. They are secreted into the lymphatic system first, so they don’t initially go through the liver’s first amino acids and sugars.

Testing triglyceride levels:

Testing of triglyceride levels is usually done in a fasted state because the blood levels of triglycerides can rise quite a bit after eating.

Plasma triglyceride tests measure the very low-density lipoproteins (VLDL) and chylomicrons.

Triglyceride level ranges[ref]:

  • Normal: Less than 150 mg/dl
  • Borderline high: 150-199 mg/dl
  • High: 200 – 499 mg/dl
  • Very high: 500 and up

To convert mg/dl triglyceride levels into mmol/L, multiply by .01129.

In studies, hypertriglyceridemia is usually defined as being higher than 150 mg/dl or higher than 2 mmol/L (175mg/dl). About 25% of adults in the US meet this criterion.[ref][ref] Other studies call levels from 150-999 mg/dl mild to moderate hypertriglyceridemia. Levels over 1,000 mg/dl are severe and can cause pancreatitis.[ref]

Disease risk:

High triglycerides are linked to atherosclerosis and stroke. Is this a big increase in risk? That is a hard question to quantify since every study seems to have different endpoints and biases.
Here are some study results:

  • High fasting triglycerides have links to a 24% increase in the risk of mortality from cardiovascular disease.[ref]
  • All-cause mortality also increases as triglyceride levels increase.[ref – open access]
  • One study states that slightly elevated triglyceride levels in people with metabolic syndrome or prediabetes are more likely to cause atherosclerosis than the really high levels found in people with genetic mutations.[ref – open access]
  • Other studies point to elevated non-fasting triglyceride levels being linked to an increased risk of heart attack and death.[ref]

Fructose and high triglycerides:

Several studies show that high fructose intake increases triglycerides. As a result, this may lead you to assume that drinking the periodic soda is causing your high triglycerides…

Animal studies pretty clearly show that fructose increases triglyceride levels. In rats, replacing water with fructose water increases blood pressure, liver fat, and triglycerides pretty significantly.[ref][ref]

Human studies on fructose and triglycerides show similar trends but much less dramatic results.

A study using normal-weight adults looked at the difference between consuming 150g/d of fructose or 150 g/day of glucose for four weeks. They did this by substituting fructose or glucose for other calories in the diet, so overall calories weren’t affected. After four weeks, there was no increase in visceral fat, muscle fat, or liver fat and no changes to blood pressure. The only change after four weeks was that triglycerides in the fructose group went up by 35 mg/dl (still in the normal range, though). There was no change in triglycerides in the glucose group.[ref]

Studies in humans where fructose is added on top of their regular caloric intake show a more considerable increase in triglyceride. One study that added fructose for a 35% increase in calories showed triglyceride levels rising 75%.[ref] But it is hard to differentiate between suddenly adding that many calories vs. those calories being from fructose.[ref]

A meta-analysis concluded there is no difference in triglyceride levels from fructose vs. sucrose vs. glucose.[ref]

Triglycerides, leptin, and obesity:

Leptin is the hormone that signals to the brain that you are full and don’t need to eat. In people who are overweight or obese, there is usually a high level of leptin, but that signal isn’t being received in the brain (leptin resistance). The question is ‘why?’… For example, one theory is that elevated triglyceride levels interact with leptin in the brain, causing leptin resistance.

Triglyceride levels rise when you are in a state of starvation as your body activates fat from adipose tissue. A recent study recently looked at the connection between triglyceride levels and leptin resistance. The study found that triglycerides cross the blood-brain barrier and can induce leptin resistance.[ref – open access]

Theoretically, it makes sense that high triglycerides would block the leptin signal in times of starvation, driving people to need more food. But in our modern epidemic of metabolic syndrome and high triglyceride levels, this is causing leptin resistance and increasing the desire to eat even when overweight.

HDL and triglyceride levels:

High triglyceride levels usually correspond to lower HDL levels. Certainly, this is part of what makes research on cardiovascular disease risk and triglycerides difficult — is it the low HDL or high triglycerides that cause the increase in risk?[ref – open access]


Triglycerides Genotype Report

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Below are some of the more common genetic variants that affect triglyceride levels. Most studies now point to the additive effect between these variants. For example, if you carry a couple of variants that raise your triglyceride levels, it may be (partly) causing your high triglycerides. But carrying a couple of variants that lower your triglycerides, along with one that raises them, could give you a normal triglyceride level (depending on diet).

APOA5 gene:

The APOA5 gene codes for apolipoprotein A5, a lipoprotein involved in triglyceride levels, possibly through activating lipoprotein lipase (LPL).

Check your genetic data for rs662799 (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: increased triglyceride levels, 16% increase in triglyceride levels[ref]
  • G/G: increased triglyceride levels[ref][ref][ref], a 32% increase in triglyceride levels[ref]

Members: Your genotype for rs662799 is .

Check your genetic data for rs2075291 G185C (23andMe v4; AncestryDNA):

  • C/C: typical
  • A/C: high triglyceride levels, especially in Asian populations[ref][ref][ref]
  • A/A: very high triglycerides, especially in Asian populations.

Members: Your genotype for rs2075291 is .

Check your genetic data for rs3135506 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • C/G: increased triglyceride levels, increased risk of coronary artery disease
  • C/C: increased triglyceride levels, increased risk of coronary artery disease[ref][ref][ref]

Members: Your genotype for rs3135506 is .

Check your genetic data for rs651821 (23andMe v4, v5; AncestryDNA):

  • T/T: normal or lower triglycerides (good)
  • C/T: increased triglyceride levels
  • C/C: higher triglyceride levels[ref][ref][ref]

Members: Your genotype for rs651821 is .

LPL gene:

The lipoprotein lipase (LPL) enzyme releases fatty acids for fuel. It does this by hydrolyzing the triglycerides in plasma lipoproteins. Genetic variants that decrease this enzyme can raise triglyceride levels.

Check your genetic data for rs328 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/G: lower triglycerides
  • G/G: lower triglycerides[ref][ref]

Members: Your genotype for rs328 is .

Check your genetic data for rs320 (23andMe v4, v5):

  • T/T: typical
  • G/T: slightly lower triglycerides
  • G/G: slightly lower triglyceride[ref][ref]

Members: Your genotype for rs320 is .

Check your genetic data for rs268 (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: higher triglycerides
  • G/G: higher triglycerides[ref]

Members: Your genotype for rs268 is .

GCKR gene:

Glucokinase regulatory protein regulates glucose kinase, a sensor that regulates glucose from glycolysis.

Check your genetic data for rs780094 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: slightly higher triglycerides[ref]
  • T/T: higher triglycerides[ref][ref] but possibly no increase in heart disease risk[ref]

Members: Your genotype for rs780094 is .

 

APOE gene:

The APOE E4 variant is also tied to a risk of increased triglyceride levels. If you want to know your APOE status, read through the article on Alzheimer’s disease and APOE. 

 

What are we missing here? Rare mutations…  

Here are a few mutations covered in 23andMe or AncestryDNA. But this is just the tip of the iceberg for rare variants that could greatly impact high triglycerides. What does ‘rare’ mean — usually that the mutation is found in less than 1 in 1000 people.

Check your genetic data for rs5126 (23andMe v5 only):

  • A/A: typical
  • A/C: carrier of pathogenic APOC2 variant
  • C/C: 2 copies of pathogenic APOC2 variant[ref][ref]

Members: Your genotype for rs5126 is .

Check your genetic data for rs120074114 (AncestryDNA only):

  • A/A: typical
  • A/C: carrier of pathogenic APOC2 variant
  • C/C: 2 copies of pathogenic APOC2 variant[ref][ref]

Members: Your genotype for rs120074114 is .

Check your genetic data for rs199673455 (23andMe v5 only):

  • G/G: typical
  • A/G: carrier of pathogenic mutation for transient hypertriglyceridemia
  • A/A: 2 copies of pathogenic mutation for transient hypertriglyceridemia[ref]

Members: Your genotype for rs199673455 is .

 


Lifehacks:

If you have high triglycerides, carrying some of the variants (above) that raise your triglyceride levels is part of the problem. The other half of the equation is diet and lifestyle.

Diet:

Some research indicates that high fructose corn syrup increases triglyceride levels, while other research shows that increased calories (whether from high fructose corn syrup, sugar, etc.) increase trigs. Either way, cutting out the soda and switching to unsweetened drinks may help to lower triglyceride levels.

Even more noteworthy, a (small) study showed that the ketogenic diet, which is a low carbohydrate diet, reduced triglyceride levels fairly significantly.[ref]

The Mediterranean diet, consisting of plenty of fresh fruits, vegetables, and fish, reduced triglycerides (a little) in a clinical trial.[ref]

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About the Author:
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.