Understanding Hidden Heart Risk: How Genetics Can Inform Your Lp(a) Levels

Lipoprotein(a), or Lp(a), is a type of cholesterol particle that is gaining increasing attention from researchers and clinicians. Unlike LDL ("bad") cholesterol, which is largely influenced by diet and lifestyle, Lp(a) levels are shown to be 70-90%+ heritable.¹ Elevated Lp(a) is a significant, and often unmeasured, predictor of future Atherosclerotic Cardiovascular Disease (ASCVD), independently of traditional risk factors like LDL. This means many individuals may be unaware that they have this risk factor for heart disease.

Here are 5 major topics from the recent paper by Helix researchers titled, "A novel method for predicting Lp(a) levels from routine outpatient genomic testing identifies those at risk of cardiovascular disease across a diverse cohort" that shed light on this important risk factor and how genetic testing might help identify those at risk:

1. Lp(a): A Stealthy Contributor to Heart Disease Risk

Lp(a) is composed of LDL cholesterol and a protein called apolipoprotein(a), encoded by the LPA gene. Circulating Lp(a) levels can vary dramatically, up to a hundred-fold between individuals. Elevated Lp(a) levels, typically defined as around 120 nmol/L (50 mg/dL) or above, are found in approximately 20% of the population. Studies consistently show that higher levels of Lp(a) are associated with an increased risk of ASCVD at the population level, regardless of ethnicity, gender, or baseline ASCVD status.¹ ² This includes conditions like coronary artery disease (CAD), peripheral artery disease (PAD), and aortic stenosis (AS).

2. Why Isn't Lp(a) Routinely Measured, and How Can Genetics Help?

Despite its importance, Lp(a) is not typically measured during routine clinical care. One reason is that accurate measurement can be difficult due to the variation in Lp(a) particle size. Because that Lp(a) levels are highly heritable, research is exploring whether genetic estimation could help identify individuals at risk. Previous research has independently identified genetic contributions from single nucleotide variants (SNVs) as well as a major contribution from a copy number variant (CNV) in the kringle-IV subtype 2 exon (KIV-2) in the LPA gene. However, these two genetic factors have seldom been studied together in large groups.

3. A Novel Genetic Method for Predicting Lp(a) from Exome Data

Helix researchers developed a novel method to quantify the total number of KIV-2 repeats directly from exome sequencing data. KIV-2 copy number is highly variable and significantly impacts Lp(a) levels, but it's challenging to measure accurately from standard sequencing data. By combining this new KIV-2 quantification method with a previously established SNV-based GRS, the researchers created a comprehensive genetic predictor for estimated Lp(a) levels.

4. The Predictor Works Across Diverse Genetic Backgrounds

A key finding of this study is that the combined genetic strategy significantly improved the prediction of clinically-elevated Lp(a) measurements across a genetically diverse cohort. Specifically, for individuals not genetically similar to European reference populations (non-EUR), the combined method's predictive power (r2 = 0.34) was much higher than using the GRS alone (r2 = 0.04). While the GRS performed reasonably well in individuals genetically similar to Europeans (EUR), its poor performance in non-EUR groups highlights the challenge of applying genetic predictors equitably. The KIV-2 copy number estimation (CNE) itself showed a strong negative correlation with Lp(a) levels in both EUR and non-EUR groups, meaning a lower KIV-2 CNE is associated with higher Lp(a). Individuals with a low KIV-2 CNE were 5-fold more likely to have elevated Lp(a) levels (80% vs 16%). The combined model, incorporating either a high GRS or a low KIV-2 CNE, showed similar performance in identifying individuals with clinically elevated Lp(a) in both the EUR and non-EUR cohorts, addressing the ancestry bias seen with GRS alone.

5. Genetically Predicted High Lp(a) Risk is Linked to Increased ASCVD, Even in "Low-Risk" Individuals, Pointing to Future Directions

The study found that individuals with a "high combined genetic risk" for high Lp(a) had a higher incidence of ASCVD diagnoses. This association was observed for several ASCVD phenotypes including:

• Coronary artery disease (CAD)
• Peripheral artery disease (PAD)
• Myocardial infarction (MI)
• Aortic stenosis (AS)
• Major Adverse Cardiovascular Event (MACE) index

This increased risk was evident when comparing high-risk individuals to both average and low combined genetic risk groups. Importantly, among individuals identified as having a lower risk based on traditional factors like age, BMI, and LDL levels, those with a high combined genetic risk of high Lp(a) still showed a 2-fold enrichment for ASCVD diagnoses compared to those with low genetic risk. This suggests that genetic prediction of Lp(a) could be a way to identify individuals at increased risk, including some who may not be flagged by traditional risk assessments, though more research is needed to determine its clinical application.

Currently, Lp(a) measurement is primarily used for ASCVD risk stratification. However, several novel nucleic acid therapies designed to lower Lp(a) are currently in phase III clinical trials. These include Pelacarsen, Olezarsen, and Lepodisiran, which have shown promise in reducing Lp(a) levels. If these medications prove effective in reducing cardiovascular events, there will be even greater clinical interest in identifying patients with elevated Lp(a).

As genetic screening becomes more common in diagnosis and care, researchers are exploring whether genetically predicting Lp(a) levels could help identify individuals at risk for cardiovascular disease, including those without traditional risk factors. However, more evidence is needed before this approach can be widely adopted.

If your health system is already performing exome sequencing, partner with us! We welcome the opportunity to conduct a prospective analysis to provide your patients with genetically estimated Lp(a) levels, which may help inform future research on cardiovascular risk assessment and prevention strategies. Let's collaborate to further study how this genetic risk factor could be incorporated into patient care as the evidence base evolves.

To learn more about this research, read the full publication here. To work with us further, please fill out the contact us form below.

1. Reyes-Soffer G, et.al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022 Jan;42(1):e48-e60. Epub 2021 Oct 14. PMID: 34647487; PMCID: PMC9989949.
2. Ciffone N, et.al. Lipoprotein(a): An important piece of the ASCVD risk factor puzzle across diverse populations. Am Heart J Plus. 2023 Nov 24;38:100350. PMID: 38510747; PMCID: PMC10945898.