THE IMPORTANCE OF LPA GENE POLYMORPHISM IN THE EARLY DEVELOPMENT OF ATHEROSCLEROSIS

Abstract

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like particle in which apolipoprotein B-100 is covalently linked to apolipoprotein(a) [apo(a)], a plasminogen-related glycoprotein encoded by the LPA gene. Plasma Lp(a) concentration is among the most strongly heritable quantitative traits in human biology: variation at the LPA locus explains the large majority of its interindividual variance, and adult-equivalent levels are established in early childhood and remain largely stable thereafter. The kringle IV type 2 (KIV-2) copy number variation, which determines apo(a) isoform size, together with single-nucleotide variants such as rs10455872 and rs3798220 and a growing catalogue of loss-of-function alleles, governs lifelong exposure to Lp(a). Genome-wide association studies and Mendelian randomization analyses have established Lp(a) as a causal, independent risk factor for coronary heart disease, ischemic stroke, peripheral arterial disease and calcific aortic valve stenosis. Because the genetic determinants of Lp(a) operate from birth, high-risk LPA genotypes are particularly relevant to premature atherosclerosis, arterial ischemic stroke in children and young adults, and to the amplified risk observed in familial hypercholesterolemia. In this review, we summarize the structure and genetic architecture of the LPA locus, the mechanisms through which Lp(a) promotes early atherogenesis, including arterial retention, oxidized phospholipid-driven inflammation and impaired fibrinolysis, and the epidemiological evidence linking LPA variation to early-onset disease. We also discuss measurement and screening strategies, the implications of recent outcome data for nucleic acid-based Lp(a)-lowering therapies, and the open questions that must be addressed before genotype-guided prevention can be implemented from youth.