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Decoding High Cholesterol: New Insights into Genetics and Your Health

Soraya Malik in Health & Wellness August 2025 • 5 min read.

"Unlocking the Secrets of HDL: Targeted Resequencing Reveals Key Genetic Variations"

For years, scientists have known that genetics plays a significant role in determining our cholesterol levels, particularly high-density lipoprotein cholesterol (HDL-C), often dubbed "good cholesterol." Genome-wide association studies (GWAS) have pinpointed numerous locations in our DNA linked to HDL-C, but understanding exactly how these genes work and identifying the specific variations that have the most impact has remained a challenge. Current methods often focus on common genetic variations with small effects, leaving many questions unanswered.

A new approach is needed to dig deeper and uncover the rarer, more impactful genetic variations that influence HDL-C levels. This is especially true for variations in the noncoding regions of our DNA, which are often overlooked but may hold crucial keys to understanding complex traits like cholesterol.

Now, a groundbreaking study has emerged, employing a technique called multiplexed targeted resequencing to analyze both coding and noncoding regions of genes associated with HDL-C. By focusing on individuals with extremely high or low HDL-C levels, researchers have been able to identify rare and novel genetic variations that could revolutionize our understanding and management of cholesterol.

Targeted Resequencing: A New Way to Find Hidden Genetic Clues

The research team utilized a molecular inversion probe (MIP) target capture approach. This allowed them to resequence specific areas of DNA in 797 individuals with extremely high HDL-C and compare them to 735 individuals with low-to-normal levels. The study focused on seven key locations in the genome already linked to HDL-C, including genes like GALNT2, APOA5, CETP, and LIPG, examining both the protein-coding regions and nearby noncoding regulatory features.

To ensure the accuracy of their findings, the researchers cross-referenced their results with existing exome-wide genotyping data from a subset of participants. This validation step confirmed a high level of agreement, with over 90% concordance between the two methods.

Rediscovering Known Associations: The targeted resequencing approach successfully rediscovered previously established links between certain genes (GALNT2, CETP, and LIPG) and HDL-C levels. This confirms the effectiveness of the method for identifying important genetic factors.
Pinpointing a Novel Noncoding Variant: The study identified a new, rare variation in a noncoding region of the CETP gene that was more common in individuals with extremely high HDL-C. This discovery highlights the potential of targeted resequencing to uncover previously unknown genetic influences.
Cost-Effective Strategy: By focusing on specific regions of interest and using a highly efficient technique, the researchers were able to achieve significant results with a relatively small sample size, demonstrating the cost-effectiveness of this approach.

These findings suggest that targeted resequencing of individuals at the extremes of the HDL-C spectrum is a valuable tool for identifying both rare coding and noncoding variations that influence cholesterol levels. This approach offers a novel and efficient way to uncover the genetic factors underlying complex traits and supports the rationale for applying this methodology to other complex conditions.

The Future of Cholesterol Management: Personalized Approaches

This research opens exciting new avenues for understanding and managing cholesterol. By identifying specific genetic variations that influence HDL-C levels, scientists and healthcare providers can move closer to personalized approaches to cardiovascular health.

Imagine a future where individuals can undergo targeted genetic screening to identify their unique risk factors for high or low HDL-C. This information could then be used to tailor lifestyle recommendations, dietary interventions, or even pharmacological treatments to optimize their cholesterol levels and reduce their risk of heart disease.

While more research is needed to fully understand the implications of these findings, this study represents a significant step forward in our quest to unravel the complex interplay between genetics and cardiovascular health. As technology advances and our understanding of the genome deepens, we can expect even more innovative approaches to emerge, paving the way for a healthier future for all.

About this Article -

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This article is based on research published under:

DOI-LINK: 10.1161/circgen.117.002070, Alternate LINK

Title: Multiplexed Targeted Resequencing Identifies Coding And Regulatory Variation Underlying Phenotypic Extremes Of High-Density Lipoprotein Cholesterol In Humans

Subject: General Medicine

Journal: Circulation: Genomic and Precision Medicine

Publisher: Ovid Technologies (Wolters Kluwer Health)

Authors: Sumeet A. Khetarpal, Paul L. Babb, Wei Zhao, William F. Hancock-Cerutti, Christopher D. Brown, Daniel J. Rader, Benjamin F. Voight

Published: 2018-07-01

Everything You Need To Know

What is HDL-C and why is it relevant to the research?

HDL-C, often called "good cholesterol," is a crucial component of cardiovascular health. The study investigates the genetic factors influencing HDL-C, as understanding these factors can pave the way for personalized health strategies. High levels of HDL-C are generally associated with a lower risk of cardiovascular diseases, because the protein helps to remove other forms of cholesterol from the bloodstream.

What is multiplexed targeted resequencing and how was it used in this study?

Multiplexed targeted resequencing is a cutting-edge technique employed in the study to analyze specific regions of DNA associated with HDL-C. The research team used a molecular inversion probe (MIP) target capture approach. The primary aim of this approach is to pinpoint both coding and noncoding genetic variations, focusing on individuals with extremely high or low HDL-C levels. This method is effective in identifying rare and novel genetic variations that influence HDL-C levels, offering a deeper understanding of cholesterol management.

Which genes were studied, and what key findings emerged?

The research focused on seven key locations in the genome already linked to HDL-C, including genes like GALNT2, APOA5, CETP, and LIPG. The focus on both protein-coding and noncoding regulatory features allowed for the identification of a new, rare variation in a noncoding region of the CETP gene. This variation was more common in individuals with extremely high HDL-C. It highlights the potential of targeted resequencing to uncover previously unknown genetic influences and the importance of noncoding regions.

Why are the study's findings significant?

The study's findings are significant because they underscore the importance of genetics in determining HDL-C levels and, by extension, cardiovascular health. The discovery of novel genetic variations, particularly in noncoding regions of the CETP gene, highlights the limitations of current methods. These findings pave the way for personalized health strategies. It allows a more targeted approach to cardiovascular health management based on individual genetic profiles.

What are the potential implications of this research?

The implications are far-reaching, suggesting that a deeper understanding of individual genetic profiles can lead to more effective cholesterol management strategies. By identifying specific genetic variations that influence HDL-C levels, healthcare providers can move closer to personalized approaches to cardiovascular health. The study's cost-effectiveness also suggests that this approach can be applied to other complex conditions, thus promoting better health outcomes through targeted genetic analysis.