DNA and Heart Network: Genetic Protection for your Heart

HDL Deficiency: Unmasking the Genetic Culprits Behind Low "Good Cholesterol"

Lena Voss in Health & Wellness December 2025 • 4 min read.

"Severe HDL deficiency isn't just a lifestyle issue; it often has deep genetic roots that significantly elevate cardiovascular disease risk. Are you at risk?"

For years, high-density lipoprotein (HDL), often dubbed “good cholesterol,” has been celebrated for its heart-protective qualities. It acts like a tiny vacuum cleaner, scooping up excess cholesterol from your arteries and ferrying it back to the liver for processing. But what happens when your HDL levels are stubbornly low? While lifestyle factors like diet and exercise play a significant role, sometimes, the real culprits are lurking in your genes.

A groundbreaking study published in the Journal of Lipid Research sheds light on the genetic and secondary causes of severe HDL deficiency. This research assessed over 258,000 subjects, pinpointing specific genetic mutations that contribute to alarmingly low HDL levels and a heightened risk of atherosclerotic cardiovascular disease (ASCVD).

This article dives deep into the findings, offering you a comprehensive guide to understanding the genetic underpinnings of HDL deficiency. We'll explore which genes are most frequently involved, how these mutations impact your heart health, and what steps you can take to mitigate your risk.

Decoding the Genetic Landscape of HDL Deficiency: What Genes Are Involved?

DNA and Heart Network: Genetic Protection for your Heart

The Journal of Lipid Research study meticulously sequenced 23 lipid-related genes in participants with severe HDL deficiency (defined as HDL-C levels below 20 mg/dL). The results revealed that a significant portion of these individuals carried mutations in key genes responsible for regulating HDL metabolism:

Here's a breakdown of the genes most frequently affected and their roles:

ABCA1 (ATP-binding cassette transporter A1): This gene plays a vital role in cholesterol efflux, the process by which cells release cholesterol to be picked up by HDL. Mutations in ABCA1 can impair this process, leading to a buildup of cholesterol in the arteries and low HDL levels. Approximately 26.9% of the study participants with HDL deficiency had mutations in this gene.
LCAT (Lecithin-cholesterol acyltransferase): LCAT is an enzyme that modifies cholesterol in HDL, helping it to mature and carry more cholesterol. Mutations in LCAT can lead to dysfunctional HDL particles, resulting in cholesterol buildup. 12.4% of the subjects showed mutation in this gene.
APOA1 (Apolipoprotein A1): APOA1 is the main protein component of HDL, providing its structural framework and facilitating cholesterol binding. Mutations in APOA1 can affect the stability and function of HDL, contributing to its deficiency. 5.0% of the participants showed mutation in this gene.
LPL (Lipoprotein Lipase): While primarily known for its role in breaking down triglycerides, LPL also indirectly influences HDL levels. Certain variants in LPL were found in 4.5% of participants and were associated with hypertriglyceridemia, which often accompanies low HDL.

It's important to note that almost 46.8% of the participants didn't have any mutations in the genes mentioned above, which indicates the involvement of other mutations, or that severe HDL deficiency sometimes arise from secondary causes, or lifestyle elements.

Take Control of Your Heart Health

If you have a family history of low HDL or premature heart disease, or you are looking for peace of mind, consult your doctor about genetic testing of the related genes to make sure your heart is in great condition. Knowing your genetic predisposition can empower you to make informed decisions about your lifestyle, diet, and potential medical interventions.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1194/jlr.m088203, Alternate LINK

Title: Genetic And Secondary Causes Of Severe Hdl Deficiency And Cardiovascular Disease

Subject: Cell Biology

Journal: Journal of Lipid Research

Publisher: Elsevier BV

Authors: Andrew S. Geller, Eliana Y. Polisecki, Margaret R. Diffenderfer, Bela F. Asztalos, Sotirios K. Karathanasis, Robert A. Hegele, Ernst J. Schaefer

Published: 2018-12-01

Everything You Need To Know

What role does ABCA1 play in maintaining healthy HDL levels, and what happens when this gene is mutated?

ABCA1, or ATP-binding cassette transporter A1, is crucial for cholesterol efflux. This is the process where cells release cholesterol to be picked up by HDL. When ABCA1 is mutated, this process is impaired, leading to a buildup of cholesterol in the arteries and consequently, low HDL levels. This impaired cholesterol efflux contributes significantly to the development of atherosclerotic cardiovascular disease (ASCVD).

How does LCAT influence HDL function, and what are the implications of LCAT mutations on cardiovascular health?

LCAT, or Lecithin-cholesterol acyltransferase, is an enzyme that modifies cholesterol within HDL, helping it mature and carry more cholesterol. When LCAT is mutated, it leads to dysfunctional HDL particles that cannot effectively manage cholesterol, resulting in cholesterol buildup and increased risk of cardiovascular issues. Reduced LCAT function impairs the ability of HDL to perform its protective role, exacerbating the risk of ASCVD.

Why is APOA1 important for HDL, and how do mutations in APOA1 contribute to HDL deficiency and potential heart problems?

APOA1, or Apolipoprotein A1, is the main protein component of HDL, providing its structural framework and facilitating cholesterol binding. Mutations in APOA1 can affect the stability and function of HDL, contributing to its deficiency. These mutations can impair HDL's ability to remove cholesterol from arteries, which raises the risk of heart disease. Deficiencies or dysfunction in APOA1 compromises the entire HDL particle's functionality.

Besides ABCA1, LCAT and APOA1, what is the role of LPL and how does it impact HDL levels and overall cardiovascular health?

LPL, or Lipoprotein Lipase, primarily breaks down triglycerides but also indirectly influences HDL levels. Certain variants in LPL are associated with hypertriglyceridemia, which often accompanies low HDL. While not directly involved in HDL production or function like ABCA1, LCAT, and APOA1, LPL's impact on triglyceride levels can affect HDL metabolism. Elevated triglycerides can lead to lower HDL levels, increasing the risk of cardiovascular disease.

If someone has severe HDL deficiency but tests negative for mutations in ABCA1, LCAT, APOA1 and LPL, what other factors might be contributing to their low HDL levels, and what steps should they consider next?

If mutations in ABCA1, LCAT, APOA1, and LPL are not identified, other genetic factors, secondary causes, or lifestyle elements could be contributing to the severe HDL deficiency. Other genes involved in lipid metabolism might be implicated. Secondary causes could include certain medications, underlying medical conditions (like diabetes or kidney disease), or lifestyle factors (such as smoking, poor diet, and lack of exercise). A comprehensive evaluation by a healthcare professional, including further genetic testing or investigation into secondary causes, is warranted. Making lifestyle adjustments focused on diet and exercise should be considered.