Lipoprotein(a)-dependent cardiovascular risk in different populations: are thresholds the same?

Lipoprotein(a) [Lp(a)] is a genetically determined, independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Large prospective cohort studies together with Mendelian Randomization studies have established its role in cardiovascular risk which has led to the introduction of screening and the development of Lp(a)-lowering therapies. However, interpretation of Lp(a) results in clinical practice remains a challenge, particularly across populations with significantly different baseline levels.

Lp(a) levels vary according to ancestry. People of African ancestry having the highest median Lp(a) levels, followed by people from South Asia, East Asia and Europe, respectively. However, despite these differences, current Lp(a) risk thresholds are derived from populations of predominantly European ancestry and broadly applied across underrepresented population groups.Available evidence from multi-ancestry cohort studies have shown that while proportional risk for ASCVD may be similar across ancestries, the absolute risk associated with specific thresholds may differ. The application of a universal threshold may lead to over-classification of risk in some populations, resulting in unnecessary edicalization and strain on healthcare systems. Conversely, some populations may be under-classified by a universal threshold potentially resulting in avoidable ASCVD events.

This commentary explores the epidemiological, biological and methodological factors underlying variability in Lp(a) levels and their association with ASCVD across populations. We discuss the advantages and limitations of applying ancestry-specific Lp(a) risk thresholds. Lp(a) measurements in clinical practice should be interpreted in within a broader clinical and population context rather than in isolation.