APOB gene: Apolipoprotein B Levels and Health Risks

Key takeaways:
~ ApoB is a protein found in LDL, VLDL, Lp(a), and chylomicrons, with one ApoB per particle.
~ ApoB is a better predictor of heart disease risk than LDL-C or total cholesterol.
~ Genetic variants can increase or decrease ApoB levels. Understanding your genetic variants can help you to prioritize diet and lifestyle factors, which also play a strong role in ApoB levels.

What is ApoB?

Lipids, such as cholesterol, are packaged up into lipoproteins in order to be transported through the body and delivered to their target tissues.

ApoB (Apolipoprotein B) is a component of:

• LDL (low-density lipoprotein)
• VLDL (very-low-density lipoproten)
• Lipoprotein (a) – Lp(a)
• Chylomicrons

There is one ApoB particle per lipoprotein, meaning there is one in each LDL particle and in each Lp(a). This makes it a direct marker of the number of lipoprotein particles in circulation.[ref][ref]

ApoB enables the various-sized LDL particles to bind to LDL receptors on cells, which then facilitates the clearance of cholesterol from the bloodstream.

Why is ApoB important?

Newer research directly ties ApoB numbers to the risk of atherosclerosis and cardiovascular disease. Research shows that it is a better marker than LDL, VLDL, triglycerides, or total cholesterol for understanding your risk of heart disease.[ref]

The mass of cholesterol within ApoB particles is variable, but in the walls of the artery, the number of ApoB particles is thought to equally contribute to atherosclerosis. Thus, many cardiologists now look at ApoB levels as a simple and unified measure of cardiovascular risk.[ref]

While LDL-C and ApoB levels are often concordant for people, sometimes the levels don’t line up — some people have higher ApoB without elevated LDL. In these cases, the high ApoB is a better predictor of the risk of heart disease. Thus, many cardiologists are moving toward measuring ApoB to better understand risk.

What is a normal ApoB level?

While a normal ApoB level is generally considered >100 mg/dL, the expert consensus of the National Lipid Association sets target ApoB levels to be lower than that if you have other risk factors for atherosclerotic cardiovascular disease. The target for borderline to intermediate risk is ApoB of 90 mg/dL or less, while those at a higher risk (high cholesterol or type 2 diabetes) have a target ApoB of below 70 mg/dL.[ref]

A meta-analysis of 25 drug trials found that “each 10-mg/dl decrease in apoB was associated with a 9% decrease in coronary heart disease”.[ref]

APOB gene and forms of ApoB:

A single APOB gene encodes two forms of ApoB – a longer one called ApoB-100 and a shorter version called ApoB-48.[ref] ApoB-100 is synthesized in the liver and incorporated into each lipoprotein particle. ApoB-100 acts as a ligand to bind to the LDL receptor. ApoB-48 is synthesized in the intestines and incorporated into chylomicrons, which transport triglycerides and cholesterol from food to the rest of your body (muscle, liver, adipose tissue, etc).

Genetic variants in APOB alter your levels:

Mutations and polymorphisms in the APOB gene can affect its function in multiple ways. The common polymorphisms alter ApoB and LDL levels a little bit, while rare mutations have a large effect size, either increasing or decreasing ApoB and LDL levels significantly.[ref]

Studies in twins show that genetics accounts for 50-60% of ApoB levels, while diet and lifestyle account for the rest.[ref]

High cholesterol:
Some mutations cause ApoB to have a harder time binding to the LDL receptor, which moves LDL particles out of the bloodstream and into the appropriate tissues. Thus, more LDL stays in the bloodstream and circulates. This causes a type of familial hypercholesterolemia, or high cholesterol in the blood, resulting in atherosclerosis and xanthomas.[ref]

Low cholesterol:
Other mutations cause low levels of ApoB to be produced. This causes familial hypobetalipoproteinemia. The defective synthesis and export of ApoB then causes very low LDL cholesterol test levels, but it can also lead to the accumulation of triglycerides in the liver. People with hypobetalipoproteinemia are at a significantly higher risk of developing fatty liver disease. [ref]

Individuals who carry one copy of an APOB hypobetalipoproteinemia mutation often show levels of ApoB to be about a third to half of normal. Even with just one copy of an APOB mutation and low ApoB, there is still an increased risk of developing fatty liver disease.[ref]

APOB and CYP27A1: Reverse Cholesterol Transport

Early genetic studies on ApoB levels identified that CYP27A1 polymorphisms affected ApoB. CYP27A1 encodes sterol 27-hydroxylase, an enzyme that converts cholesterol to 27-hydroxycholesterol, which is used primarily for the synthesis of bile acids.

APOB and Alzheimer’s Disease:

While ApoE has long been known to play a role in Alzheimer’s disease, recently, several studies have linked lifelong higher levels of ApoB to an increased relative risk of Alzheimer’s disease. Animal models show that excess ApoB throughout life increases amyloid beta levels in the brain.[ref]

In the brains of people who died at different stages of Alzheimer’s, APOB protein levels correlate with the extent of Alzheimer’s pathology and amyloid beta levels. Interestingly, the mRNA levels of APOB didn’t correlate, and the researchers think there is a link between blood-brain barrier dysfunction and the excess of APOB protein. Essentially, circulating levels of ApoB add to the problems in Alzheimer’s at later stages of the disease.[ref]

A Mendelian randomization study was used to determine whether ApoB levels are likely to play a causal role. A multivariable Mendelian randomization showed that high ApoB, rather than LDL, is likely to play a causal role in decreasing healthspan and possibly increasing Alzheimer’s risk.[ref]

ApoB interacts with diabetes and heart disease:

Insulin is released by the pancreas to promote the uptake of glucose into cells. Diabetes involves insulin resistance – cells are less responsive to insulin’s signals, so more insulin is released.

Insulin normally promotes the degradation of ApoB in the liver and decreases ApoB secretion. In insulin resistance, the insulin signaling is impaired, resulting in a decreased clearance of ApoB.[ref]

In people with diabetes, ApoB levels are significantly higher on average. This may be why cardiovascular disease is more often a problem in people with diabetes.[ref]