The large-scale genomics study has helped to disentangle the attributes of Lp(a) that drive cardiovascular risk.
Continued progress in lowering the worldwide toll from heart disease may hinge on deeper insights into a stealthy blood fat called lipoprotein(a), or Lp(a). While there is a link between higher levels of Lp(a) and cardiovascular risk, the complexity of this lipid has made it hard to pin down the nature of the risk.
Unlike its molecular cousin and well-known heart disease culprit LDL cholesterol, Lp(a) particles vary greatly in size depending on the genes you inherit. To date, it has been unclear if the danger posed by high Lp(a) is due to the size of the particles you inherit, the concentration of particles in the blood, or a mix of both factors. Resolving this question is vital to determining the best way to measure Lp(a), calculate risk, and identify patients in need of therapy.
The largest-ever genomics study of Lp(a) has provided substantial evidence that the cardiovascular risk from high Lp(a) can be explained by its concentration in the blood. The study was led by scientists at Amgen’s deCODE Genetics subsidiary along with colleagues from the National University Hospital in Iceland. They reached their conclusions based on whole genome data from about 150,000 Icelanders participating in deCODE’s research, including 18,000 with coronary artery disease (CAD) and 9,000 with type 2 diabetes. The results were published in the Journal of the American College of Cardiology (JACC), along with an editorial that discussed the significance of the findings.
“This study from our little island may well turn out to be an important contribution to global health,” said Kári Stefánsson, CEO of deCODE and a senior author on the paper. “We have very effective LDL-lowering drugs, but heart disease remains the biggest killer worldwide. Understanding Lp(a) is key to addressing residual risk.”
“The findings are of particular importance because, if replicated in other studies with more diverse populations, they could help eliminate one of the hurdles of using Lp(a) as a therapeutic target for residual cardiovascular risk in patients with high Lp(a) levels,” said the editorial’s author, Benoit Arsenault, an associate professor in the Department of Medicine at the Université Laval in Quebec, Canada.
Up to double the risk for heart disease observed
Lp(a) consists of an LDL cholesterol-like particle with a second protein, called apolipoprotein(a), or apo(a), coiled around it (see illustration). There are many different gene variants for apo(a) that make longer or shorter versions of the protein.
The deCODE team directly measured Lp(a) blood concentrations in approximately 12,000 study participants, and then used these data to impute the blood levels of the remaining participants. That was possible because Lp(a) levels are driven almost solely by the genes you inherit, and deCODE has developed statistical methods that leverage genealogical data to track genes that travel together among blood relatives.
A particle of LDL cholesterol on the left and a particle of Lp(a) on the right. Lp(a) consists of an LDL cholesterol-like particle with a second protein, called apolipoprotein(a), or apo(a), coiled around it. The apo(a) protein can be longer or shorter, depending on the genes you inherit.
Previous studies have suggested that the size of Lp(a) particles helps to determine risk, and that smaller particles are associated with higher risk. In assessing the role of particle size in risk, the deCODE team looked at a fairly common variant of the LPA gene, G4925A, which leads to smaller Lp(a) particles but lower concentrations of this lipid. Despite having smaller particles, individuals who carry the G4925A variant are at no higher risk for heart disease than non-carriers, contributing to the evidence that the number of Lp(a) particles in the blood, not their size, drives risk.
Across the entire population that took part in the study, the median blood concentration of Lp(a) was 14 nanomoles (nM) per liter. Every 50 nM increase in Lp(a) level was associated with a 16 percent increase in the risk for coronary artery disease (CAD). About 7 percent of the study participants had Lp(a) levels over 150 nM, which was predicted to increase CAD risk by 50 percent. About 1 percent of participants had an Lp(a) level above 250 nM, which was predicted to double the risk of CAD.
The study also demonstrated that increased Lp(a) levels correspond with risk for peripheral artery disease, aortic valve stenosis, heart failure, and reduced lifespan. In addition, the study replicated the observation that very low levels of Lp(a)—below 3.5 nM—are associated with increased risk of type 2 diabetes.
Global testing for Lp(a) needed
Stefánsson noted that the impact of elevated Lp(a) levels on heart disease risk “is independent of other risk factors and is 95 percent genetically determined, so you can't reduce it by improving your lifestyle or diet. The clear message is therefore that we need to test for Lp(a) globally to identify those at significantly elevated risk, and speed the development of new therapies aimed at silencing the apo(a) gene. The good news is that our colleagues at Amgen as well as other pharmaceutical companies are already taking such therapies into clinical trials."
“We know that Lp(a) is an independent risk factor for cardiovascular disease, and Amgen is proud of the work we have done and continue to do in pursuing this therapeutic target,” said Dave Reese, Amgen’s executive vice president for Research and Development. “This new study from deCODE will help steer and inform research into the clinical development of molecules targeting Lp(a). It’s a great example of the potential we are just beginning to uncover using genetic insights and validation to power drug development.”
An important next step in this research will be to validate the results in other populations and determine how the contribution of Lp(a) levels to heart disease might vary between populations of different ancestry.
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