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Lipoprotein (a)

Genes included: LPA

Number of variants called: 43

Lipoprotein(a) (Lp(a)) is a Low Density Lipoprotein (LDL) particle that, in addition to apolipoprotein B, contains a protein known as apolipoprotein(a) (commonly called little a). High levels of Lp(a) have been shown in multiple case-control and prospective studies to be associated with elevated risk of cardiovascular disease (CVD).
Genetic variation is known to account for up to 95 percent of lipoprotein(a) level variation in the population. Lp(a) concentrations are not substantially influenced by environmental factors, such as diet and physical activity so genetic analysis is well positioned to identify high concentrations.
Lp(a) levels should be expressed in molar units – nmol/L. For comparison, the Lp(a) concentrations have been converted to mass units – mg/L using the following equation: Lp(a), mg/L= (2.18/Lp(a), nmol/dL–3.83)*10 (Langsted et al 2019)

The Emerging Risk Factors Collaboration published a meta-analysis of 39 long-term prospective studies, that comprised a total of 126,634 individuals (1.3 million person-years of follow-up). The risk ratio for CVD, adjusted for age and sex, was 1·16 (95% CI, 1·11-1·22) per 3·5-fold higher usual Lp(a) levels (ie, per 1 SD), and 1·13 (95% CI, 1·09-1·18) after further adjustment for traditional risk factors.(Erqou et al 2009)
Furthermore genetically verified Familial Hypercholesterolemia subjects with high Lp(a) levels, but with otherwise similar risk profile, have twice the prevalence (30% vs 14%) of CHD (Bogsrud et al 2019)

This Target includes a panel of 43 known genetic variants in the LPA gene. This panel has been shown to be a comparable risk predictor of CVD to measured Lp(a) concentrations in an observational study of approximately 500,000 adults ages 40 to 69 (Trinder et al 2020).
Following Heart UK Consensus Statement, this template categorises an individual’s cardiovascular risk conferred by the Lp(a) serum concentration as follows:

  • MINOR – 32-90 nmol/L
  • MODERATE – 90-200 nmol/L
  • HIGH – 200-400 nmol/L
  • VERY HIGH – >400 nmol/L

These cut-offs expressed in molar units are derived from population percentiles of Lp(a) measured in nmol/L and mg/dL from 13,900 participants (Nov. 2015 to June 2017) in the on-going Copenhagen General Population Study (Kamstrup et al 2009)

Heart UK recommend that in individuals with risk levels of Moderate, High and Very High (Lp(a) levels >90?nmol/L) management should include, reducing overall atherosclerotic risk and controlling dyslipidemia with a desirable non-HDL-cholesterol level of <100mg/dL (2.5mmol/L). (Cegla et al 2019) In individuals with Lp(a) levels >150 nmol/L whose LDL-C remains 125 mg/dL (3.3 mmol/L) despite maximal lipid-lowering therapy consideration of lipoprotein apheresis as per the HEART UK Lipoprotein apheresis statement (Thomson et al 2008) and testing of 1st degree relatives may be useful.

For future consideration an antisense agent APO(a)-LRx has shown great promise in lowering Lp(a) levels and is currently under trial to demonstrate clinical utility. (Tsimikas et al 2020)