Featured Reagent – Lp(a)

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Featured Reagent – Lp(a)

Featured Reagent | Lipoprotein(a)

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Current Challenges

The biggest challenge that exists surrounding Lp(a) measurement is the heterogeneity of the apo(a) isoforms, resulting in the underestimation or overestimation of Lp(a) concentrations. In immunoassays, the variable numbers of repeated KIV-2 units in Lp(a) act as multiple epitopes. This is where standardisation across calibrators is vital. If the calibrants do have the same range of isoforms as test samples, those with higher numbers of the KIV-2 repeat, will represent with an overestimation in Lp(a) concentrations and those with smaller numbers of the KIV-2 repeat, will represent with an underestimation. The smaller isoforms are strongly associated with higher Lp(a) concentrations. Lack of standardisation of the calibrant would result in an underestimation of Lp(a) associated CVD risk. It is important to note that an Lp(a) immunoassay employing isoform insensitive antibodies does not exist 6.

Physiological Significance

Lipoprotein (a) [Lp(a)] is described as “the most complex and polymorphic of the lipoprotein particles”. Composed of a low-density lipoprotein (LDL) particle, an apolipoprotein(a) [apo(a)] particle which is covalently bonded to the apoB-100 via a disulphide bridge 1. Lp(a) is believed to have a chemical weight between 1.05 to 1.21 g/ml 2. Lp(a) behaves very differently to other apoB particles; LDL-C / sdLDL-C 3.

Apo(a) is the main component that distinguishes LDL from Lp(a) (Fig 2). Apo(a) is a large glycoprotein belonging to the plasminogen gene superfamily 1, 2. Comprised of five cysteine-rich domains called kringles, which are encoded by the LPA gene, located on the long (q) arm of chromosome 6 at positions 26 and 27 (6q26-27), and the plasminogen (PLG) gene, also located on the long (q) arm of chromosome 6 at position 26 (6q26) 2, 4, 5.

The PLG gene is believed to encode 5 kringles (types 1 to V) as well as an active protease domain. Conversely, kringles IV and V and an inactive protease domain are present in apo(a) 2. Apo(a) is described as polymorphic as the kringle type IV undergoes duplication, coding for 10 kringle IV types (K1 through K10).

The gold standard Lp(a) method is the Northwest Lipid Metabolism and Diabetes Research Laboratory (NLMDRKL) method which employs an isoform insensitive antibody and is meticulously calibrated with well characterised material, however, this test is not commercially available 6.

All kringles, except for K2, are present as single copies. K2 is present in multiple copies, ranging from 2 to >40, within the apo(a) proteins of distinct sizes (Fig 2). The number of K2 repeats determines the size of the apo(a) isoform, thus heterogeneously affecting the size of the apo(a) protein and the plasma levels of Lp(a). An inverse correlation between the size of the apo(a) isoform and plasma concentrations of Lp(a) has been identified 2.

Did you know?

Lp(a) should be measured utilising a method where the effect of the apo(a) isoform size has been minimised using calibrators that are certified against the WHO/IFCC reference material 5.

Benefits of Lp(a)

WHO/IFCC reference material – The Randox Lp(a) assay is calibrated in nmol/l and traceable to the WHO/IFCC reference material (IFCC SRM 2B) and provides an acceptable bias compared with the Northwest Lipid Metabolism Diabetes Research Laboratory (NLMDRKL) gold standard method.

Dedicated calibrator & control available – Five point calibrator with accuracy-based assigned target values (in nmol/l) is available, accurately reflecting the heterogeneity of the apo(a) isoforms. Dedicated Lp(a) control is available offering a complete testing package.

Excellent correlation – A correlation coefficient of r=0.995 was displayed when the Randox method was compared against other commercially available methods.

Precision Excellent precision – The Randox Lp(a) assay displayed a within run precision of <2.54%.

Liquid ready-to-use – The Randox Lp(a) assay is available in a liquid ready-to-use format for convenience and ease-of-use.

Applications available – Instrument-specific settings can be provided for a wide range of clinical chemistry analysers.

Clinical Significance

Lp(a) has been identified as a potent risk factor for calcific aortic valve stenosis. Understanding a patients Lp(a) levels could aid in informing the selection of the interval for valve surveillance as patients with elevated Lp(a) levels are likely to require earlier intervention 6.

Lp(a) measurement could be of value in those with a family history of premature CVD (<60 years), especially when a causative mutation for familial hypercholesterolemia (FH) hasn’t been identified.

In patients with heterozygous FH (HeFH), Lp(a) levels are higher compared to their non-affected siblings. Lp(a) has been identified as a strong risk factor of coronary heart disease (CHD) in patients with HeFH, independent of age, sex, smoking status, and LDL-C levels 6.

Lp(a) measurements aids in the re-classifying of those deemed at an intermediate CVD risk. Patients who over 10 years have >15% risk of a CV event should be receiving treatment, such as statin therapy irrespective of Lp(a) levels. The uptake of statin therapy in the UK as a primary prevention method for those deemed at an intermediate risk of CVD is poor 5. In the ‘Statin initiations and QRISK2 scoring in UK general practice: a THIN database study’ concluded that most patients deemed at a high risk of CVD were not initiated on statin therapy 7. Only 14% of patients with a 10-year CVD risk (10 – 19.9% risk) were initiated on statin therapy with one in six statin initiations were to low-risk patients 6, 8.

Fig 3: Lp(a) Infographic 7

  • WHO/IFCC Reference Material
  • HEART UK

The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), through its Working Group on Lp(a) and together with research institutions and several diagnostic companies recommends that laboratories use assays which do not suffer from apo(a) size-related bias. The IFCC SRM 2B was accepted by the WHO Expert Committee on Biological Standardisation as the First WHO/IFCC International Reference Reagent for Lp(a) to ensure conformity by diagnostic companies to the European Union’s Directive on In vitro Diagnostic Medical Devices for the metrological traceability of calibrator materials 9.

References

[1] Marcovina SM, Albers JJ. Lipoprotein (a) measurements for clinical application. Journal of Lipid Research 2019; 57(): 526-537.

[2] Nordestgaard BG, Chapman MJ, Ginsberg HN. Lipoprotein (a): EAS Recommendations for Screening, Desirable Levels and Management, 1st ed. Dorset: Sherborne Gibbs Limited; 2012.

[3] AMGEN Science. 10 Things to Know About Lipoprotein(a). https://www.amgenscience.com/features/10-things-to-know-about-lipoproteina/ (accessed 17 December 2019).

[4] Bermudez V, Rojas J, Salazar J, Bello L, Anez R, et al. Variations of Lipoprotein(a) Levels in the Metabolic Syndrome: A Report from the Maracaibo City Metabolic Syndrome Prevalence Study. Journal of Diabetes Research 2013; 2013(416451): 1-12. https://www.hindawi.com/journals/jdr/2013/416451/ (accessed 29 November 2019).

[5] Genetics Home Referencing. PLG gene. https://ghr.nlm.nih.gov/gene/PLG (accessed 29 November 2019).

[6] Cegla J, Dermot R, Neely G, France M, Ferns G, et al. HEART UK consensus statement on Lipoprotein(a): A call to action. Atherosclerosis 2019; 291(): 62-70.

[7] McGill University Health Centre. What is high lipoprotein(a), and should I be concerned?. https://medicalxpress.com/news/2017-02-high-lipoproteina.html (accessed 17 December 2019)

[8] Finnikin S, Ryan R, Marshall T. Statin initiations and QRISK2 scoring in UK general practice: a THIN database study. British Journal of General Practice 2017; 67(665): 881-887. https://bjgp.org/content/67/665/e881.long (accessed 3 December 2019).

[9] Dati F, Tate JR, Marcovina SM, Steinmetz A, et al. First WHO/IFCC International Reference Reagent for Lipoprotein(a) for Immunoassay–Lp(a) SRM 2B. Clinical Chemistry and Laboratory Medicine 2004; 42(6): 670-676.

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