Lipoprotein(a): Knowns, unknowns and uncertainties

Area of Science:

• Cardiovascular Medicine
• Clinical Chemistry
• Genetics

Background:

• Lipoprotein(a) [Lp(a)] is a significant causal risk factor for atherosclerotic cardiovascular diseases (ASCVD).
• Current immunoassays for Lp(a) may not be fully isoform-insensitive, leading to advocacy for LC-MS/MS methods for molar concentration assays.
• The precise role of Lp(a) molar concentration, apo(a) isoform size, and LPA gene variants in ASCVD risk remains debated.

Purpose of the Study:

• To review recent advancements in understanding lipoprotein(a).
• To discuss the clinical implications of high lipoprotein(a) and its association with ASCVD.
• To explore the potential of emerging lipoprotein(a)-lowering therapies.

Main Methods:

• Review of genome-wide association studies, epidemiological data, and clinical research on lipoprotein(a).
• Discussion of analytical methods for lipoprotein(a) measurement, including LC-MS/MS.
• Analysis of Mendelian randomization studies and ongoing clinical outcome trials.

Main Results:

• High lipoprotein(a) is established as a causal ASCVD risk factor, with risk potentially increasing linearly across its distribution.
• Lipoprotein(a)-raising SNPs do not appear to add predictive value for ASCVD beyond Lp(a) concentrations.
• Hyperlipoproteinemia(a) confounds familial hypercholesterolemia diagnosis but increases ASCVD risk in FH patients.

Conclusions:

• Further research is needed to clarify the independent contributions of Lp(a) concentration, isoform size, and genetic variants to ASCVD risk.
• Identification of hyperlipoproteinemia(a) during cascade testing can aid in identifying high-risk individuals.
• Ongoing trials, such as the pelacarsen outcome trial, are crucial for determining if significant Lp(a) reduction translates to reduced ASCVD events, especially considering its inverse association with type 2 diabetes risk.