Genetics
Kronenberg traces how genetic studies, absent good animal models, first proved Lp(a) causal in the early 1990s (Curr Atheroscler Rep 2024)
Original title: Lipoprotein(a): from Causality to Treatment
This review by a leading Lp(a) genetics researcher explains why Lp(a) is considered a causal cardiovascular risk factor and how elevated concentrations should be managed now and in the future. The author notes that no optimal, widely available animal model exists to study Lp(a) causality directly, a major historical obstacle for the field, one overcome by genetic studies applying what would later be called Mendelian randomisation as early as the 1990s. Genetic variants in the LPA gene, apolipoprotein(a) isoform size, kringle IV repeat number and sum, and later single nucleotide polymorphisms, are strongly associated with lifelong Lp(a) exposure and cardiovascular outcomes, providing the evidentiary basis for developing the specific Lp(a)-lowering drugs now in clinical testing. The review frames Lp(a) as one of the most important genetically determined cardiovascular risk factors, with specific Lp(a)-lowering therapies offering a potential tool to address it if ongoing outcome trials prove positive.
Original abstract
Purpose Of Review: This paper reviews the evidence why lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disease and how high Lp(a) concentrations should be managed now and with an outlook to the future.
Review Findings: No optimal and widely available animal models exist to study the causality of the association between Lp(a) and cardiovascular disease. This has been a major handicap for the entire field. However, genetic studies turned the page. Already in the early 1990s, the principle of Mendelian randomization studies was applied for the first time ever (even if they were not named so at that time). Genetic variants of the LPA gene such as the apolipoprotein(a) isoform size, the number and sum of kringle IV repeats and later single nucleotide polymorphisms are strongly associated with life-long exposure to high Lp(a) concentrations as well as cardiovascular outcomes. This evidence provided a basis for the development of specific Lp(a)-lowering drugs that are currently in clinical testing phase. Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease. With the specific Lp(a)-lowering therapies, we might get tools to fight this common risk factor in case the outcome trials will be positive.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.