Structure, function, and genetics of lipoprotein (a)

Abstract

between apoB-100 of the LDL moiety and one of the kringle domains in apo(a) (4,5,(14)(15)(16). The assembly of Lp(a) is believed to occur at the hepatocyte cell membrane surface (17), but other scenarios have also been proposed [reviewed in (18, 19)].Lp(a) was originally described as a dichotomous (Lp+, Lp) genetic trait (20), but it soon became evident that it is quantitative rather than qualitative in nature (21-23). Lp(a) plasma concentrations are highly heritable (24-28). The major locus controlling the Lp(a) concentrations is the LPA gene (MIM 152200; ENSG00000198670) on the reverse strand of chromosome 6q27 (29-31), which encodes the apo(a) component of Lp(a) (25,26,(32)(33)(34). Close LPA orthologs are found in all apes and in Old World monkeys. INTRA-AND INTER-POPULATION DIFFERENCES INLp ( INTRODUCTION TO THE LIPOPROTEIN (a) TRAITHuman lipoprotein (a) [Lp(a)] is a macromolecular complex in plasma that was first described in 1963 by the Norwegian physician Kåre Berg (1). Ever since its discovery, this enigmatic particle has intrigued basic researchers and clinicians due to its unknown physiological function and its association with atherosclerotic diseases, in particular coronary heart disease (CHD) [reviewed in (2)]. Lp(a) is composed of one molecule of a LDL-particle containing apoB-100 and one molecule of a large highly polymorphic glycoprotein named apo(a) (3-6). A characteristic feature of apo(a) is the presence of loop-like structures called kringles (7,8). Kringle domains are triple loop structures stabilized by three internal disulfide bonds and are also present in other coagulation factors, such as plasminogen (PLG), prothrombin, urokinase, and tissue-type PLG activators (9-12). In contrast to PLG, the linker domain between kringles is glycosylated in apo(a). The apo(a) is synthesized by the liver (13). The two components of Lp(a) are covalently linked together by a disulfide bond

LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk

“…Genetic studies of polymorphisms affecting Lp(a) levels can be used to substantiate the causality. The serum Lp(a) concentrations were found to be a large extent genetically determined via by guest, on May 10, 2018 www.jlr.org Downloaded from variations in the LPA gene which encodes apolipoprotein(a) (13). Among the variants, the LPA kringle IV type 2 (KIV-2) repeat polymorphism is particularly important, which is defined by a 5.5 kb repeat that exists in multiple copy numbers from 1 to more than 40 copies (13).…”

“…As the size of apolipoprotein(a) inversely correlates with its hepatic production rate, small Lp(a) isoforms are associated with higher Lp(a) concentrations, while large Lp(a) isoforms with lower concentrations (13). Single nucleotide polymorphisms (SNP) at the LPA locus like rs10455872 and rs3798220 were also associated with an increased level of Lp(a) (13,14).…”

“…As the size of apolipoprotein(a) inversely correlates with its hepatic production rate, small Lp(a) isoforms are associated with higher Lp(a) concentrations, while large Lp(a) isoforms with lower concentrations (13). Single nucleotide polymorphisms (SNP) at the LPA locus like rs10455872 and rs3798220 were also associated with an increased level of Lp(a) (13,14). Several studies using Mendelian randomization approaches have demonstrated that LPA variants were associated with the risk of coronary heart disease (CHD) and myocardial infarction (14)(15)(16)(17), which supports a causal role of Lp(a) in ischemic cardiovascular disease.…”

“…Therefore, the KIV-2 repeat polymorphism determines the number of kringle structures in apolipoprotein(a), which affect the size of the protein (13). As the size of apolipoprotein(a) inversely correlates with its hepatic production rate, small Lp(a) isoforms are associated with higher Lp(a) concentrations, while large Lp(a) isoforms with lower concentrations (13).…”

High baseline lipoprotein(A) Level as a risk factor for coronary artery calcification progression: Sub-analysis of a prospective multicenter trial

“…Apolipoprotein B is covalently linked to apolipoprotein(a) by a single disulfide bond [1]. Circulating concentrations of Lp(a) vary widely across individuals and ethnic subgroups, mediated in large part by genetic variations at the LPA gene locus [2]. A meta-analysis of 126,634 participants in 36 prospective studies found that Lp(a) was an independent risk factor for coronary heart disease and stroke [3].…”