Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology

Abstract

Human epidemiologic and genetic evidence using the Mendelian randomization approach in large-scale studies now strongly supports that elevated lipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular disease, that is, for myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis. The Mendelian randomization approach used to infer causality is generally not affected by confounding and reverse causation, the major problems of observational epidemiology. This approach is particularly valuable to study causality of Lp(a), as single genetic variants exist that explain 27-28% of all variation in plasma Lp(a). The most important genetic variant likely is the kringle IV type 2 (KIV-2) copy number variant, as the apo(a) product of this variant influences fibrinolysis and thereby thrombosis, as opposed to the Lp(a) particle per se. We speculate that the physiological role of KIV-2 in Lp(a) could be through wound healing during childbirth, infections, and injury, a role that, in addition, could lead to more blood clots promoting stenosis of arteries and the aortic valve, and myocardial infarction. Randomized placebo-controlled trials of Lp(a) reduction in individuals with very high concentrations to reduce cardiovascular disease are awaited. Recent genetic evidence documents elevated Lp(a) as a cause of myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis.

Keywords: apolipoproteins; atherosclerosis; cholesterol; dyslipidemias; inflammation; lipids; low density lipoprotein; plasminogen; vascular biology.

Fig. 1.

Summary of the strongest causal genetic evidence linking high Lp(a) concentrations with corresponding small apo(a) size due to low number of KIV-2 repeats to risk of disease.

Fig. 2.

Distribution of and correlation between plasma Lp(a) concentrations and KIV-2 number of repeats in the Danish general population.

Fig. 3.

Distribution of plasma Lp(a) concentrations as a function of LPA KIV-2 number of repeats and of LPA rs10455872 in the Copenhagen General Population Study. Green and red parts correspond to the bottom 80% and top 20% of the entire population distribution of plasma Lp(a) concentrations (see Fig. 3).

Fig. 4.

The four different statistical parts of a complete Mendelian randomization study design to examine causality from high plasma Lp(a) concentrations to high risk of cardiovascular disease. Potential limitations are shown with question marks.

Fig. 5.

Comparison of observational studies and Mendelian randomization studies to help understand causality from high plasma Lp(a) concentrations to high risk of cardiovascular disease.

Fig. 6.

Observational associations between high plasma Lp(a) concentrations and risk of cardiovascular disease in the Copenhagen City Heart Study and Copenhagen General Population Study combined (left panel) and in the Emerging Risk Factors Collaboration (right panel). Hazard ratios in the left panel were estimated by Cox proportional hazard regression models and were adjusted for age and sex and corrected for regression dilution bias. Right panel was adapted from (7).

Fig. 7.

Observational and causal genetic associations between high plasma Lp(a) concentrations and risk of cardiovascular disease in the Copenhagen City Heart Study and Copenhagen General Population Study combined. Hazard ratios for observational analyses of plasma Lp(a) concentrations were estimated by Cox proportional hazard regression models and were adjusted for age and sex. Causal risk ratios for analyses of genetically determined plasma Lp(a) concentrations were estimated by instrumental variable analyses and were adjusted for age and sex.

Fig. 8.

Observational associations between high plasma Lp(a) concentrations and risk of coronary, carotid, and femoral atherosclerotic stenosis in the Copenhagen Ischemic Heart Disease Study, Copenhagen Carotid Stroke Study, and Copenhagen City Heart Study, respectively. Odds ratios were estimated by logistic regression models and were adjusted for age and sex. CIHDS, Copenhagen Ischemic Heart Disease Study; CCSS, Copenhagen Carotid Stroke Study; CCHS, Copenhagen City Heart Study. Adapted from (111).

Fig. 9.

Observational associations between high plasma Lp(a) concentrations and risk of aortic valve stenosis in the Copenhagen City Heart Study and Copenhagen General Population Study combined. Hazard ratios were estimated by Cox proportional hazard regression models and were multivariable adjusted for age, sex, total cholesterol, HDL cholesterol, systolic blood pressure, smoking, and diabetes. Lp(a) in milligrams per deciliter is shown as median (interquartile range). Adapted from (11).

Fig. 10.

Observational associations between high plasma Lp(a) concentrations and risk of venous thromboembolism in the Copenhagen City Heart Study and Copenhagen General Population Study combined. Hazard ratios were estimated by Cox proportional hazard regression models and were adjusted for age and sex. Lp(a) in milligrams per deciliter is shown as median (interquartile range). HR, hazard ratio.

Fig. 11.

Speculations on physiological role and pathophysiology of high plasma Lp(a) concentrations, with corresponding small apo(a) size due to low number of KIV-2 repeats.

Fig. 12.

Observational and causal genetic associations between high Lp(a) cholesterol, high LDL cholesterol, and high remnant cholesterol with C-reactive protein concentrations. Observational changes were by linear regression and causal genetic estimates were by instrumental variable analyses. Adapted from (112, 254).