Genetics
Structural model separates functional LPA gene variants from bystanders shaping Lp(a) and CAD risk, review (Prog Lipid Res 2026)
Original title: Structure-guided dissection of the genetic variations within human LPA locus and its role in the development of cardiovascular diseases
Structure-guided review building a model to distinguish functional genetic variants within the LPA locus from mere associates. Copy-number changes in kringle IV type 2 (KIV-2) repeats, together with single-nucleotide polymorphisms, regulate apo(a) size, expression and function, falling into Lp(a)-increasing, Lp(a)-lowering and null alleles with population-specific prevalence. Risk alleles rs10455872 and rs3798220 explain substantial variance in circulating Lp(a) and confer higher coronary artery disease risk, while splice-altering and nonsense alleles markedly lower Lp(a). Conventional lipid-lowering therapies barely affect Lp(a), whereas the antisense oligonucleotide pelacarsen and siRNA agents including olpasiran achieve robust reductions. The authors argue that integrating genetic and structural insight can separate causal from proxy LPA variants and guide efforts to neutralise Lp(a)'s cardiovascular hazard.
Original abstract
Lipoprotein (a) [Lp(a)] is a highly heterogeneous lipoprotein particle promoting panvascular disease. Structurally, it consists of an LDL-like core covalently bound to apolipoprotein (a) [apo(a)]. Molecular determinants linking various genetic variants of apo(a) constituent of Lp(a) to vascular pathology remain incompletely defined. We have built a model allowing dissection which variations in LPA gene are functional, and which are mere associates of these functional variations. Copy number changes in kringle IV type 2 (KIV-2), together with a spectrum of single nucleotide polymorphisms (SNPs), regulate apo(a) size, expression, and function. These variants can be broadly categorized into Lp(a)-increasing, Lp(a)-lowering, and null alleles, with distinct prevalence across populations. Notably, risk alleles such as rs10455872 and rs3798220 account for substantial variance in circulating Lp(a) and confer elevated susceptibility to coronary artery disease, whereas splice-altering and nonsense alleles markedly reduce Lp(a) concentrations. The therapeutic implications of modifying circulating Lp(a) levels are profound. While conventional lipid-lowering therapies exert little influence on Lp(a), antisense oligonucleotides (pelacarsen) and small interfering RNA agents (olpasiran, SLN360) achieve robust Lp(a) reductions. Integrating genetic insights with structural modeling provides a framework to disentangle functional from proxy associations within LPA and neutralize the cardiovascular hazard conferred by elevated levels of Lp(a).
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.