Biomarker Information

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Lipoprotein(a)

Molar Levels Decrease with Reduction of PCSK9

kringle

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein that is found only in humans. It is essentially identical to LDL, except that an apolipoprotein(a) moiety is disulfi delinked to LDL apolipoprotein B-100. The amino acid sequence of apo(a) is highly homologous to that of plasminogen, the zymogen of the fibrinolytic enzyme, plasmin. Like plasminogen, apo(a) contains domains that are intramolecularly cross-linked to produce a structure called a kringle (structurally reminiscent of the bow-like Danish pastry). Plasminogen contains five kringle domains (K-I to K-V), in addition to its protease domain. Apo(a), on the other hand, contains 10 K-IV – homologous domains, and one of these, K-IV2, is repeated a variable number of times. Thus, human apo(a) genes code for apo(a) isoforms of varying size (mass). In addition to increased in risk of CVD associated with a molar increase in Lp(a) 1, an approximate 2-fold increased risk is associated with smaller isoforms (≤ 22 K-IV2) 2

Immunoassays for Lp(a) measure the amount of apo(a). This is complicated because as described above, the apo(a) isoforms from different genetic cohorts have different numbers of kringle repeats. Thus, every human has few to many of these repeated kringles. Most immunoassays measure the total mass of all of the kringles. Hence, people with isoforms containing many kringles have higher measured levels of Lp(a) by these assays compared to people with isoforms containing fewer of them. Dr. Santica Marcovina at Northwest Lipid Labs has developed an ELISA assay that is considered the gold standard for Lp(a) assays. It does not recognize the kringles, but instead, is specific for a site on the protein that is unique (present only once), and therefore gives results that are proportional to the molar Lp(a) concentration. 3

The method used at Pacific Biomarkers has been developed by Denka Seikin and gives mass values for the different Lp(a) variants that are essentially identical to the ones obtained from Marcovina’s method. 4

As suggested above, Lp(a) has been considered an emerging risk factor for CHD and stroke. A prepublication report very recently added some edifi cation to the mechanism of this effect. Thus, oxidized phospholipids are covalently associated with K-V10 kringle of the apo(a) portion of Lp(a) 5 , and in concordance with the oxidized-LDL hypothesis of atherogenesis, these oxidized moieties render this complex atherogenic. 6

It has recently been shown that circulating Lp(a) (size independent) levels decrease with removal of other apo B-containing lipoproteins in correspondence with reduction of circulating Proprotein Convertase Subtilisn Kexin 9 (PSCK9). Thus, administration of the AMG145 monoclonal antibody against PSCK9 during the LAPLACE-TMI 57 trial produced a decrease in Lp(a) that was at least as great was noted for all apo B-containing lipoproteins (LDL, IDL, VLDL and RLP). 7 The latter appears to be at odds with another study where the level of PCSK9 in women changed in relationship with the changes in estrogen level during the menstrual cycle. During periods of higher circulating estrogen, PSCK9 levels fell in parallel with decreases in LDL and VLDL. However, Lp(a) did not decrease. 8 This difference could be because the decrease in PSCK9 was small in the estrogen study, or perhaps because the assay used was not one that produces size-independent Lp(a) results. It will be very interesting to see if the several other biologics and drugs targeting PCKS9 that are in development will affect levels of the atherogenic Lp(a).

References

1. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009; 302:412-423.

2. Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, Marcovina S, Danesh J. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol. 2010; 55:2160-2167.

3. Marcovina SM, Albers JJ, Gabel B, Koschinsky ML, Gaur VP. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem 1995; 41:246-255.

4. Marcovina SM, Albers JJ, Scanu AM, Kennedy H, Giaculli F, Berg K, Couderc R, Dati F, Rifai N, Sakurabayashi I, Tate JR, Steinmetz A. Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem. 2000; 46:1956-1967.

5. Leibundgut G, Scipione C, Yin H, Schneider M, Boffa MB, Green S, Yang X, Dennis EA, Witztum JL, Koschinsky ML, Tsimikas S. Determinants of Binding of Oxidized Phospholipids on Apolipoprotein (a) and Lipoprotein (a). J Lipid Res. 2013 Jul 4. [Epub ahead of print]

6. Taleb A, Witztum JL, Tsimikas S. Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. Biomark Med. 2011; 5:673-694.

7. Desai NR, Kohli P, Giugliano RP, O’Donoghue M, Somaratne R, Zhou J, Hoffman E, Huang F, Rogers WJ, Wasserman SM, Scott R, Sabatine MS. AMG 145, A Monoclonal Antibody Against PCSK9, Significantly Reduces Lipoprotein (a) in Hypercholesterolemic Patients Receiving Statin Therapy: An Analysis From the LAPLACE-TIMI 57 Trial. Circulation. 2013 Jul 24. [Epub ahead of print].

8. Persson L, Henriksson P, Westerlund E, Hovatta O, Angelin B, Rudling M. Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women. Arterioscler Thromb Vasc Biol. 2012; 32:810-814.

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