Low Lipoprotein(a) Levels and Risk of Disease

Quick Takes

  • Lipoprotein(a), one of the important remaining atherogenic lipoprotein particles, will soon be treatable by apolipoprotein(a) antisense nucleotides.
  • It is reassuring that there is no evidence that markedly low lipoprotein(a) mass (e.g., <5 mg/dl), and LPA genotype will have no impact on risk for cancer and infectious diseases.
  • However, other untoward possibilities include the development of diabetes, which is more prevalent at very low levels of lipoprotein(a) when the LPA gene is associated with a high number of apolipoprotein(a) KIV-2 repeats.

Study Questions:

Do low levels of lipoprotein(a) [Lp(a)] and corresponding LPA genotypes associate with major disease groups including cancers and infectious disease?


The study included 109,440 individuals from the Copenhagen General Population Study from 2003–2014, in which plasma Lp(a) mass and related genetic variables were available; LPA kringle-IV type 2 (KIV-2) number of repeats, and LPA rs10455872/rs3798220 heterozygotes and homozygotes were combined and classified as carriers or noncarriers. Observational analysis for plasma Lp(a) was adjusted for age, sex, smoking, body mass index, hypertension, menopausal status, and hormone replacement therapy.


Mean age was 60 years, about 50% were women, 70% had hypertension, and 25% of those in the fourth quartile were on statins versus 12% in the first quartile. Lp(a) mass was about 8-fold greater in those with the lowest quartile of KIV-2 repeats and 7.5-fold greater in those who were carriers. Hazard ratio for the risk of any cancer was 1.06 (95% confidence interval [CI], 0.97–1.15) for the first versus fourth quartile of Lp(a) mass, 1.02 (95% CI, 0.97–1.07) for the fourth versus first quartile of KIV-2 number of repeats, and 1.01 (95% CI, 0.96–1.07) for rs10455872 noncarriers versus carriers. The corresponding hazard ratios for the risk of hospitalization for infection were 1.05 (95% CI, 0.99–1.10), 1.02 (0.98–1.07), and 0.97 (0.93–1.03), respectively.


In a large, contemporary, general population cohort, apart from the well-established association with cardiovascular disease, low levels of Lp(a) and corresponding LPA genotypes did not concordantly associate with any major disease groups including cancers and infections.


In the predominantly white Dutch population with Lp(a) levels between 30 and 76 mg/dl, there is a 1.6-fold increased risk for incident myocardial infarction (MI) compared to Lp(a) <5 mg/dl and rises to 2.6-fold at above 117 mg/dl, which is >95th percentile. The low levels of Lp(a) defined as <5 mg/dl (lower 20% of population) are associated with decreased risk of MI, aortic stenosis, and ischemic stroke, but have been shown to have a higher prevalence of diabetes. Lp(a) mass and the LPA gene associated with smaller apolipoprotein(a) (low number of kringle-IV repeats) are risk factors for atherosclerotic cardiovascular disease impacting both plaque and thrombosis, and are associated with a lower risk of diabetes.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension

Keywords: Apolipoproteins, Atherosclerosis, Communicable Diseases, Diabetes Mellitus, Type 2, Dyslipidemias, Genotype, Heterozygote, Homozygote, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Lipoprotein(a), Myocardial Infarction, Neoplasms, Plaque, Atherosclerotic, Plasma, Primary Prevention, Risk Factors, Stroke, Thrombosis

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