Genetics and Pathophysiological Mechanisms of Lipoprotein(a)-Associated Cardiovascular Risk

Abstract

Elevated lipoprotein(a) is a genetically transmitted codominant trait that is an independent risk driver for cardiovascular disease. Lipoprotein(a) concentration is heavily influenced by genetic factors, including LPA kringle IV-2 domain size, single-nucleotide polymorphisms, and interleukin-1 genotypes. Apolipoprotein(a) is encoded by the LPA gene and contains 10 subtypes with a variable number of copies of kringle -2, resulting in >40 different apolipoprotein(a) isoform sizes. Genetic loci beyond LPA, such as APOE and APOH, have been shown to impact lipoprotein(a) levels. Lipoprotein(a) concentrations are generally 5% to 10% higher in women than men, and there is up to a 3-fold difference in median lipoprotein(a) concentrations between racial and ethnic populations. Nongenetic factors, including menopause, diet, and renal function, may also impact lipoprotein(a) concentration. Lipoprotein(a) levels are also influenced by inflammation since the LPA promoter contains an interleukin-6 response element; interleukin-6 released during the inflammatory response results in transient increases in plasma lipoprotein(a) levels. Screening can identify elevated lipoprotein(a) levels and facilitate intensive risk factor management. Several investigational, RNA-targeted agents have shown promising lipoprotein(a)-lowering effects in clinical studies, and large-scale lipoprotein(a) testing will be fundamental to identifying eligible patients should these agents become available. Lipoprotein(a) testing requires routine, nonfasting blood draws, making it convenient for patients. Herein, we discuss the genetic determinants of lipoprotein(a) levels, explore the pathophysiological mechanisms underlying the association between lipoprotein(a) and cardiovascular disease, and provide practical guidance for lipoprotein(a) testing.

Keywords: atherosclerotic cardiovascular disease; cardiovascular risk; coronary heart disease; genetics; lipoprotein(a); oxidized phospholipids; single nucleotide polymorphisms.

Figure 1. Structure of lipoprotein(a) vs LDL.

apoB indicates apolipoprotein B; CE, cholesterol ester; FC, free cholesterol; KIV, kringle IV; LDL, low‐density lipoprotein; Lp(a), lipoprotein(a); OxPL, oxidized phospholipid; PL, phospholipid; SS, disulfide bond; and TG, triglyceride.

Figure 2. Evolution and structure of apo(a), effect of kringle IV‐2 CNV on apolipoprotein(a) molecular weight, and relationship with plasma lipoprotein(a) levels.

apo(a) indicates apolipoprotein(a); CNV, copy number variation; K, kringle; kDa, kilodalton; KIV, kringle IV; KV, kringle 5; Lp(a), lipoprotein(a); and P, protease.

Figure 3. Genetic determinants of Lp(a) levels.

apo(a) indicates apolipoprotein(a); Lp(a), lipoprotein(a); and SNP, single‐nucleotide polymorphism.