Lp(a): What is Normal vs. High + Genetic Factors

Lipoprotein (a), or Lp(a), has been the subject of greater attention from the lipid community in recent years, with physicians like Dr. Tom Dayspring, and Sam Tsimikas, MD leading the way.

We recently had the privilege of interviewing Dr. Dayspring and the subject of Lp(a) was discussed at length.

Because Lp(a) is determined by genetics, most physicians recommend everyone get tested at least once in their lives. I am in the process of writing the Lp(a) polygenic risk score for Gene Food based on the 45 markers outlined as determinative of elevated Lp(a) in JAMA.

Because I have been actively digging into the research on Lp(a), I wanted to offer this blog post to answer common questions from readers.

What is Lipoprotein(a) or Lp(a), and how is it related to cholesterol?

Lp(a), is a specific type of lipoprotein found in the bloodstream.

Lipoproteins are molecules made of protein and fats that transport cholesterol through your blood to various cells in your body. ¹

There are two primary groups of lipoproteins: HDL (high-density lipoprotein), often referred to as “good” cholesterol, and LDL (low-density lipoprotein), known as “bad” cholesterol.

Lp(a) belongs to the LDL category. It’s important to note that Lp(a) particles consist of two key protein components: apoB100 and apolipoprotein(a), connected by a disulfide bridge.

What is a “normal” level of Lp(a) and at what level does risk increase?

Dr. Sam Tsimikas, a physician studying Lp(a) at UC San Diego, published this helpful graphic which outlines risk tiers based on varying levels of Lp(a).

Dr. Tsimikas’ research shows three preliminary tiers for Lp(a) risk:

• < 30 mg/dl is considered normal in the US
• < 50 mg/dl is considered lower risk by the European Atherosclerosis Society
• > 60 mg/dl required in parts of Europe for Apheresis approval

We asked a friend of the podcast, Dr. Joel Kahn, a nationally recognized cardiologist in the Detroit area, what his perspective was on Lp(a) levels in the 30-50 mg/dl range meant.

Everyone can agree that Lp(a) from 30-50 mg/dl is in a grey area of risk.

Dr. Joel Kahn

How does high Lp(a) relate to heart health, and what are the associated risks?

Approximately one-fifth of the global population is believed to possess elevated levels of Lp(a), a condition linked to an increased likelihood of experiencing heart attacks, strokes or other severe cardiovascular incidents. ²

This heightened risk is attributed to the following effects of elevated Lp(a):

1. Atherosclerosis: Atherosclerosis is a condition characterized by the accumulation of fatty deposits within your arteries, causing them to narrow and lose flexibility. When your Lp(a) levels are elevated, it increases the likelihood of heart disease. The narrowing of arteries can obstruct blood flow, leading to various cardiovascular complications.
2. Thrombosis: Thrombosis is the formation of blood clots inside blood vessels. Elevated Lp(a) levels enhance the probability of these dangerous blood clots forming. These clots can impede blood flow, potentially causing serious health issues.
3. Aortic Valve Calcification: The aortic valve serves as a gateway in your heart, controlling the flow of blood. Calcification of this valve occurs when deposits cause it to become rigid and stiff. High Lp(a) levels can contribute to the formation of these deposits, affecting the proper functioning of the aortic valve and, subsequently, the overall performance of your heart.

The concentrations of Lp(a) in the bloodstream are predominantly under the influence of genetic factors. To be more precise, (). This means that a person’s Lp(a) concentration is primarily inherited from their biological parents. The genetic control of Lp(a) levels is mediated by a specific gene known as the LPA g

How do genetics affect Lp(a) levels?

Approximately 70% to over 90% of an individual’s Lp(a) levels are genetically determined. ³

The LPA gene, which encodes apolipoprotein (a), contains many different variations, or alleles, which can be inherited from one’s parents.

Some alleles are associated with higher Lp(a) levels, while others are associated with lower levels.

The specific combination of alleles a person inherits from their parents will determine their Lp(a) concentration.

The LPA gene in depth

The LPA gene is like a puzzle with ten similar pieces (called kringle IV or KIV domains). One of these pieces, KIV-2, can have lots of copies, from just one to more than 40 copies in some people. This big difference in the number of KIV-2 copies creates a lot of genetic diversity in populations. The size of KIV-2 affects how much Lp(a) you have in your blood. When you have more KIV-2 copies, your Lp(a) levels are usually lower, and when you have fewer copies, your Lp(a) levels tend to be higher.

This KIV-2 copy variation explains a big part of why Lp(a) levels are different between people, accounting for anywhere from 19% to 69% of the differences. ⁴

Additionally, a substantial number of single nucleotide polymorphisms (SNPs) located in the LPA gene region are strongly linked to variations in Lp(a) levels.

In a significant research study involving 3,100 individuals with coronary heart disease (CHD) and genetic testing for around 49,000 different genetic variations across 2,100 potential genes, researchers discovered two SNPs within the LPA gene (rs10455872 and rs3798220).

These two SNPs showed the most robust connection to an increased risk of CHD among all the studied genetic variations. ⁵

Are there any other genes besides LPA that affect Lp(a) levels?

APOE ε2 Gene: Besides the main LPA gene we talked about, there’s another gene called APOE ε2. If you have a specific version of this gene, it tends to make your Lp(a) levels lower. This APOE ε2 gene is responsible for only a tiny part (about 0.5%) of why Lp(a) levels can be different between people.

APOH Gene: Recent studies that looked at the entire genetic makeup of many people found more clues about how Lp(a) levels are connected to genes. One of these studies pointed to a gene called APOH. Inside this gene, there are instructions for making a protein called β2-glycoprotein 1. This protein is linked to another one called PCSK9 and sticks to a part of Lp(a) called apo(a) KIV2. By the way, β2-glycoprotein 1 is known to be involved in blood clotting, among other things.

Which genetic tests identify elevated Lp(a)?

There are genetic tests that can determine your Lp(a) levels by analyzing the LPA gene. I am in the process of designing a polygenic risk score to identify Lp(a) risk at Gene Food.

In addition, the LPA Aspirin Genotype is a genetic test offered by Berkeley HeartLab, a Quest Diagnostics service, which identifies the rs3798220 allele.

Individuals who test positive for rs3798220 are at an increased risk of developing blood clots, and as a result, they might experience greater advantages from the blood-thinning properties of aspirin.

However, the test has not been approved by by the U.S. Food and Drug Administration (FDA) and is considered not necessary.

Can lifestyle changes help manage high Lp(a) levels?

While genetics largely determine baseline Lp(a) levels, lifestyle changes can still have a positive impact on cardiovascular health. In our interviews with leading cardiologists, like Dr. Kahn and Dr. Dayspring, the consensus for those with elevated Lp(a) is to be even more hawkish about lowering APOB.

There are also drug trials underway for therapeutics designed to target and lower Lp(a) specifically.

Maintaining a healthy diet, engaging in regular physical activity, and avoiding smoking can help mitigate the overall risk of heart disease, even in individuals with genetically high Lp(a) levels. These lifestyle modifications are typically recommended alongside any medical interventions.

What about non-genetic factors?

•   Hormone replacement therapies involving androgens and estrogens have an impact on Lp(a) levels.
•   Both overactive (hyperthyroid) and underactive (hypothyroid) thyroid conditions have a slight effect on Lp(a) levels.
•    Lp(a) levels tend to rise in individuals with chronic kidney disease and nephrotic syndrome.
•   There is an association between Lp(a) levels and damage to the liver cells (hepatocellular damage)