Lipoprotein(a): a historical perspective

Br J Cardiol 2022;29(suppl 1):S3–S6doi:10.5837/bjc.2022.s01 Leave a comment
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This sponsored supplement was initiated and funded by Novartis Pharmaceuticals UK Ltd. Editorial control was retained by the authors and editors, however, Novartis reviewed the supplement for technical accuracy and compliance with relevant regulatory requirements.

Job code: 196574
Date of preparation: March 2022

Nearly 60 years after it was first described by the Norwegian physician and geneticist Kare Berg in 1963, lipoprotein(a) (Lp[a]) has finally become accepted as an inherited, causal cardiovascular disease risk factor, and a potential target for new therapeutic interventions. Why has it taken so long? A major reason has been the technical challenge of Lp(a) measurement, which has long confounded attempts to prove a causal role for Lp(a) in long-term prospective atherosclerotic cardiovascular disease (ASCVD) outcome studies. Due to its unique macromolecular structure, with a highly variable number of kringle IV type 2 domains in the covalently bound apolipoprotein(a) moiety, serum concentrations spanning a range of 1000-fold between individuals, and instability on long-term storage, it is extraordinarily difficult to quantify Lp(a) reliably. Only with more recent advances in understanding of the genetic determinants of Lp(a) concentrations, the advent of genome-wide association studies, and large-scale epidemiological investigations using the Mendelian-randomisation approach, has conclusive evidence finally been assembled to show that elevated Lp(a) concentrations are causally associated with increased risk of ASCVD.


Lipoprotein(a) or Lp(a) is a highly atherogenic, prothrombogenic, low-density lipoprotein (LDL)-like lipoprotein particle containing one copy of apolipoprotein(a) (Apo[a]) linked by a disulphide bridge to a single apolipoprotein B (ApoB). Unlike other ApoB-containing lipoproteins, Lp(a) concentrations appear independent of the LDL-receptor pathway and are largely unaffected by conventional lipid-lowering therapy (figure 1). High circulating concentrations of Lp(a) particles, measured by immunoassay, have been identified as an independent risk factor in cardiovascular disease, with a causal link to atherosclerosis, myocardial infarction, strokes, aortic valve disease and cardiac failure.1 Indeed, Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD), however, the journey leading to achievement of this status has been anything but straightforward.

BJC supplement 2022 Paper 1 - Figure 1. Lipoprotein(a) (Lp[a]) is a cholesterol-rich lipoprotein that resembles low-density lipoprotein (LDL), but which contains a second major protein component, apolipoprotein(a) (Apo[a]), covalently bound to apolipoprotein B (ApoB) in close proximity to the high-affinity ligand-binding domain for the LDL-receptor, enhancing pathogenicity by reducing recognition of the particle by hepatic LDL-receptors and increasing affinity to alternative receptors in extrahepatic sites, including the arterial wall
Figure 1. Lipoprotein(a) (Lp[a]) is a cholesterol-rich lipoprotein that resembles low-density lipoprotein (LDL), but which contains a second major protein component, apolipoprotein(a) (Apo[a]), covalently bound to apolipoprotein B (ApoB) in close proximity to the high-affinity ligand-binding domain for the LDL-receptor, enhancing pathogenicity by reducing recognition of the particle by hepatic LDL-receptors and increasing affinity to alternative receptors in extrahepatic sites, including the arterial wall

Discovery of Lp(a)

Lp(a) was first discovered by Kare Berg in experimental studies investigating antigenic variants in human beta-lipoprotein, a fraction easily isolated by chemical precipitation and now known to be composed of ApoB-containing lipoproteins, predominantly LDL.2 In rabbits immunised with beta-lipoprotein isolated from the sera of healthy human donors, he generated antisera, which identified positive and negative reactors to a novel antigen found on beta-lipoprotein in one-third of donors. He classified these as Lp(a)+ and Lp(a)–, with an apparent autosomal co-dominant mode of inheritance among related family members in his preliminary genetic studies.

Lp(a) was subsequently shown to be identical to the atypical “pre-beta-1-lipoprotein” sometimes detected in whole serum by qualitative electrophoretic methods, and to “sinking pre-beta-lipoprotein” (SBPL) also detected by electrophoresis in beta-lipoprotein fractions isolated by ultracentrifugation, and present in approximately one-fifth of normolipidaemic individuals, again with a dominant pattern of inheritance.3 With the advent of quantitative immunoassay methods it became apparent that Lp(a) was, in fact, detectable in 90% of healthy individuals, with lower concentrations in patients with mixed hyperlipidaemia and higher in those with isolated hypercholesterolaemia or familial hypercholesterolaemia.4 Measured serum concentrations were not correlated with age, sex or serum ApoB concentrations, and, unlike LDL-cholesterol, appeared unaffected by dietary changes or available lipid-lowering therapies. When the newly developed quantitative immunoassay method was compared with older qualitative techniques, electrophoretic detection of SPBL was found to be a highly specific marker for extremely elevated Lp(a), being present in all of those with measured Lp(a) greater than the 90th centile, but not consistently detectable in those with lower concentrations.4

Lp(a) and CVD – origins of a long-running controversy

Early case–control studies, based on older qualitative methods, found a somewhat higher prevalence of CHD in individuals who showed atypical lipoprotein electrophoresis patterns (with an extra pre-beta band or SBPL) and who were, therefore, considered “Lp(a)-positive”. However, the results of these studies were questioned on the basis that the electrophoretic methods were lacking in specificity and, therefore, potentially unreliable. However, when the first quantitative immunochemical assays became available, once again case–control studies confirmed the association of Lp(a) with CHD, as seen in the earlier studies, and an apparently stronger association was seen with premature CHD.5,6 Many confirmatory reports followed, including a large cross-sectional study in which Lp(a) concentrations were compared in young (<46 years) male survivors of myocardial infarction (MI) and in age-matched controls recruited from participants of the Prospective Cardiovascular Münster (PROCAM) study,7 and a notable family study, in which Lp(a) excess, defined as a concentration greater than 38 mg/dL using a commercial ELISA (enzyme-linked immunosorbent assay) assay, was found to be the most common inherited lipoprotein abnormality in the families of probands with premature coronary artery disease.8 Although these studies added weight to the case for Lp(a) as a CHD risk factor, a higher standard of evidence was required to prove causality, and the results of large prospective studies were awaited. After positive results were reported in the first small prospective study in Swedish men, two much larger prospective studies, the Helsinki Heart Study and the Physicians Health Study found no evidence of an association between Lp(a) concentration and risk of future MI.9 As all three studies had used the same commercial immunoassay to measure Lp(a) on deep-frozen stored samples, suggestions that the choice of assay and storage conditions may have affected the quality of measurements were dismissed as a reason for the unexpected results, and the alternative hypothesis of reverse causality – increased Lp(a) as the consequence, not the cause of MI – gained ground. The publication of negative results in these high-profile, influential studies was a major setback for Lp(a) research that was felt for the next 15 years.9 The controversy has persisted, despite evidence from subsequent prospective studies that used a variety of blood storage techniques and assay methods, including some with the earlier electrophoretic measures, as summarised in a large meta-analyses of 27 prospective studies, which concluded that there was, after all, clear association between Lp(a) and risk of CHD.10 Careful laboratory investigation demonstrated the inherent bias common to many commercial assays and, finally, provided an explanation for the failure to find a consistent association between immunologically measured Lp(a) and cardiovascular disease outcomes in the earlier prospective studies. The widely used commercial Lp(a) method that was used in the Helsinki Heart Study and Physicians’ Health Study was markedly affected by Apo(a) size and may have underestimated, or even obscured, the true relationship between Lp(a) concentration and CHD. A re-analysis of samples from the 1993 Physicians Health Study was undertaken with an improved immunoassay method, designed to give accurate results independent of isoform size, and found a positive association.11 But by that time the damage had already been done, and studies based on genetic markers of Lp(a) status would be required to banish the doubts that conventional biomarker studies had failed to dispel.12

Genetics of Lp(a)

Genetics of Lp(a)

The modern Apo(a) protein, which forms Lp(a) when bound covalently to ApoB, is the product of the LPA gene on the long arm of chromosome 6 (6q27), which evolved from the nearby plasminogen (PLG) gene by repeated duplications, deletions and single-base substitutions following an initial duplication event approximately 40 million years ago.13 Lp(a) has no known physiological function and most mammals, other than higher primates and new world monkeys, lack Apo(a), the only apparent disadvantage being to deprive modern researchers of suitable animal models to study it more easily. Astoundingly, the common hedgehog produces an Apo(a)-like protein, composed of highly repeated copies of a PLG kringle three-like domain, which like human Apo(a) can form covalently linked lipoprotein Lp(a)-like particles, an example of convergent evolution that suggests there may be some beneficial role of this particle, perhaps conferring a survival advantage by directing cholesterol to sites of wound repair.14

The discovery of a genetic size polymorphism of Apo(a) caused by a variable number of KIV-2 repeats (copy number variants or CNV) in the LPA gene provided the basis for understanding Lp(a) as a quantitative genetic trait, and established the LPA gene itself as the major locus that determines plasma Lp(a) concentrations. Overall, 70–90% of the inter-individual variation in Lp(a) concentrations is genetic.13 The number of KIV-2 repeats determine isoform size and correlate inversely with serum Lp(a) concentrations, largely due to size-dependent variation in the secretion rate of Apo(a), thereby, accounting for 30% to 70% of the variation in Lp(a) concentrations, depending on the population. Although the association between short KIV-2 CNV alleles, high Lp(a) concentrations and CHD is strong in the majority of populations studied so far (dominated by white Europeans and North Americans and East Asians), it appears much weaker in Asian Indian and African populations.13 Other genetic variations in the LPA gene, including common single nucleotide polymorphisms (SNPs) and “null alleles” account for most of the remaining variation, however, common variants of other genes, such as APOE and APOH, also have an influence. The most important non-genetic or secondary causes of elevated Lp(a) are chronic kidney disease and nephrotic syndrome, which can cause marked increase in Lp(a), as can clinically overt hypothyroidism, while a smaller increase may be seen in women post-menopausally.12 These secondary causes account for elevated Lp(a) concentration in a small number of cases and do not obscure the influence of genetics on Lp(a) variation. On an individual basis, plasma Lp(a) concentrations reflect the co-dominant expression of two inherited LPA alleles, conferring Apo(a) isoforms, which often differ in their contribution depending on the number of KIV-2 repeats, modulated by effect of LPA gene SNPs and other genetic and hormonal influences. The plasma concentrations of Lp(a) are associated with the sum of KIV-2 repeats of both Apo(a) alleles, and are highest when short isoforms of fewer than 22 KIV-2 repeats are present. As “null alleles” are frequent in many populations, co-dominantly expressed short isoforms often appear to have a dominant pattern of inheritance.13 The fact that plasma often contains a mixed population of Lp(a) particles of differing size and composition presents a difficult challenge to the development of suitable assay methods, but in clinical practice, accurate measurement of particle numbers (expressed in nmol/L) undoubtedly provides the best means to make an integrated assessment of all the genetic and non-genetic factors at play in an individual patient. 

With the advent of large genome-wide association studies, the LPA gene was consistently found to be the strongest genetic risk locus for CHD,15 findings confirmed by a large candidate gene study. The understanding of Lp(a) as a quantitative genetic trait, largely determined by the KIV-2 CNV in the LPA gene, together with the availability of improved, less isoform sensitive assay methods, finally provided a means of countering the hypothesis of reverse causality to account for the conflicting findings in the earlier biomarker studies. If high Lp(a) concentrations are causally associated with CHD, a variant in the LPA gene that affects Lp(a) concentrations must also be associated with a commensurate effect on CHD risk. Several large studies based on this approach, known as Mendelian randomisation, have provided compelling evidence against reverse causality in the case of Lp(a).12,16 The final proof required to confirm a causal relationship beyond doubt will be found in the cardiovascular outcomes trials with specific therapies to lower Lp(a) concentrations, which are currently underway.


Despite nearly 60 years of research and compelling evidence for Lp(a) as a vitally important, but unmeasured, inherited risk factor for cardiovascular disease, many barriers remain for its translation into routine clinical practice in the UK. Lp(a) is rarely used outside of the secondary care lipid clinic and few cardiologists or other vascular specialists consider Lp(a). Most clinicians are unaware of Lp(a), which is infrequently measured in patients with cardiovascular disease or atherosclerosis. Lp(a) is a co-dominant trait associated with familial hypercholesterolaemia and premature CHD, but rarely used in cascade testing and not mentioned in National Institute for Health and Care Excellence (NICE) lipid guidelines CG71 or CG181. The purpose in producing this supplement is to inform healthcare providers of developments in our understanding of Lp(a) and the mechanisms underlying its contribution to atherosclerotic cardiovascular disease. It is anticipated that this will ultimately lead to improved identification, management, and outcomes for patients at high genetic risk of atherosclerotic cardiovascular disease and calcific aortic valve disease.

Key messages

  • The field of lipoprotein(a) (Lp[a]) research has been hampered for decades by methodological problems, finally overcome with the help of genetics
  • Lp(a) is now accepted as a causative risk factor for coronary heart disease (CHD), stroke, peripheral artery disease (PAD), atherosclerosis and heart failure
  • Lp(a) is a quantitative genetic trait with autosomal co-dominant inheritance, the most important inherited cardiovascular disease (CVD) risk factor in most populations studied so far
  • Secondary causes account for elevated concentrations of Lp(a) in some cases – which should always be sought and managed appropriately

Conflicts of interest

RDGN has received honoraria for participation in advisory boards for Novartis.



R Dermot G Neely
Specialist Adviser on Lipids

Academic Health Science Network North East and North Cumbria (AHSN), Room 2.13, Biomedical Research Building, The Campus for Ageing and Vitality, Nun’s Moor Road, Newcastle, NE4 5PL

([email protected])

Articles in this supplement

Lipoprotein(a): mechanisms of pathogenicity
Lipoprotein(a): marker and target in calcific aortic valve disease
How to measure lipoprotein(a) and in whom
Current management of the patient with high lipoprotein(a)


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