Abstract
PURPOSE OF REVIEW: Our understanding of the genetic regulation of lipoprotein(a) [Lp(a)] is hindered by the complex structure of the LPA gene, limited non-European datasets and its elusive cellular receptor(s). This review summarizes recent efforts and advances providing new insights on its genetic architecture, variability across ancestries and regulators beyond the LPA gene. RECENT FINDINGS: Impressive advances in DNA sequencing and bioinformatics now resolve LPA variants and kringle IV-type 2 copy number at scale. This provides new reference datasets and enables tools that unlock hidden variation also from already available sequencing datasets. In parallel, genetic studies broaden our understanding of the regulation of Lp(a) across ancestries and improve genetic risk scores. Finally, while recent studies implicate new mechanisms for Lp(a) uptake, upcoming genome-wide gene knockout screens allow comprehensive, agnostic scans for regulators and receptors. Puzzlingly, this still converges on the LDL receptor, whose exact role in Lp(a) uptake remains enigmatic. SUMMARY: Technological advances establish a foundation for more accurate genetic risk assessment across ancestries. These advances are enhancing our understanding of Lp(a) regulation and build a framework for future integrative genetic studies, which may shed new light on the evolution of the Lp(a) trait, adding important context for its physiological and clinical relevance.