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

Scanu, and colleagues cloned and sequenced the LPA gene coding for apo(a) (4, 5), a protein with homology to plasminogen, which accounts for the difference between an Lp(a) particle and an LDL particle.These observations generated a huge scientific interest in Lp(a), leading to an exponential growth in the number of articles published, which then later declined again.Renewed interested in Lp(a) came in 2009 from Pia Kamstrup et al. ( 6) with genetic evidence from Mendelian randomization that high Lp(a) is causally associated with cardiovascular disease, from the Emerging Risk Factors Collaboration led by John Danesh that Lp(a) epidemiologically is continuously and independently associated with cardiovascular disease risk (7), and from Robert Clarke et al. (8) that of 2,100 candidate genes for cardiovascular disease, genetic variation in the LPA gene was the strongest genetic cardiovascular risk factor.Following the publication of these studies, high concentrations of Lp(a) have been considered to be a direct cause of cardiovascular disease, just like high LDL cholesterol concentrations.Genetic evidence largely free of confounding and fully free of reverse causation, two major problems of observational epidemiology, is what has cemented the understanding of causality of Lp(a) for cardiovascular disease.These novel and important findings led the European Atherosclerosis Society to publish a 2010 consensus panel statement recommending screening for elevated Lp(a) in individuals at intermediate, high, or very high cardiovascular risk, and suggested a desirable plasma concentration of less than 50 mg/dl (9).Of note, we naturally were fully aware that the risk of cardiovascular disease increases already at Lp(a) levels above 30 mg/dl, but to get the attention of the clinical community, we believed it was the best strategy to start focusing on individuals with the highest cardiovascular risk, that is, the 20% of individuals with concentrations above 50 mg/dl.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.-Nordestgaard,B. G., and A. Langsted.Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology.