Beyond Cholesterol: Landmark deCODE Study Elucidates Role of Lipoprotein(a) as Major Risk Factor for Heart Disease

Highly diverse, understudied and not routinely screened for, Lp(a) -- an alipoprotein(a) bound to an LDL cholesterol particle -- may be the next most important serum risk factor after LDL itself

Results provide population-based evidence in support of standardized testing for Lp(a) and for the acceleration of novel therapies targeting alipoprotein(a) for those at higher risk

News provided by

deCODE genetics

Dec 09, 2019, 16:00 ET

REYKJAVIK, Iceland, Dec. 9, 2019 /PRNewswire/ -- Scientists at deCODE genetics and colleagues from the National University Hospital in Iceland today present the largest-scale study to date of the role and public health impact of Lipoprotein(a) as a risk factor for cardiovascular disease. The study appears today in the online edition of the Journal of the American College of Cardiology.

Lipoprotein(a), abbreviated as Lp(a), is an alipoprotein(a), abbreviated as apo(a), bound to an LDL cholesterol particle and has been known as a risk factor since the 1970s. But the high variability of the apo(a) gene that controls its production, the diverse isoforms of Lp(a) that result, the difficulty of assaying them, and conflicting reports of how they impart risk left it largely neglected alongside the clearer success story of LDL, the statins and PCSK9 inhibitors. The deCODE team turned its unique population-scale capabilities and data to address the complexity of Lp(a) and discovered a simple answer: it is the molar concentration of Lp(a) that directly correlates with increased risk of heart disease, whatever the variety of apo(a) alleles and independently of traditionally measured or treated HDL or LDL cholesterol.

"This study from our little island may well turn out to be an important contribution to global public health," said Kari Stefansson, 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 and understanding Lp(a) is key to addressing the residual risk."

"What we show today, by analyzing an unprecedented amount of both clinical and genetic data from across the Icelandic population, is that by measuring Lp(a) in the blood we can identify a quarter of the population that is from an additional 25% to double the average risk of heart disease. This risk is independent of other risk factors and is 95% 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 are already taking such therapies into clinical trials," Dr Stefansson added.

"We know that Lp(a) is a causal, independent risk factor for cardiovascular risk, and Amgen is proud of the work we have done and continue to do investing in pursuing this therapeutic target," said David M Reese, MD, executive vice president of Research and Development at Amgen. "This new study from deCODE will help steer and inform research into the clinical development of molecules targeting Lp(a), and is a great example of the potential we are just beginning to uncover using genetic insights and validation to power drug development. We believe we are still in the early years of large-scale human genetic research, and most of the major discoveries in this field still lie in the future. That's why we are continuing to grow our investment in genetics by increasing the scope and diversity of the data that deCODE can access and analyze for research purposes."

The study utilized whole genome data from some 150,000 Icelanders participating in deCODE's genetics research, including 18,000 with coronary artery disease (CAD) and other cardiovascular phenotypes, and 9,000 with type-2 diabetes. By directly measuring molar concentration of Lp(a) from 12,000 participants and comparing them with the sequence of participants' apo(a) genes, the research team was able to establish how different variants in apo(a) and the resulting Lp(a) isoforms affect the risk of coronary artery disease. Imputing these results through the entire dataset and correlating the results with disease status enabled the testing of multiple previous findings related to Lp(a) and the discovery that it is overall molar concentration of Lp(a) rather than specific isoforms or isoform size itself that correlates with CAD risk. The study also demonstrated that Lp(a) levels correlate with risk for peripheral artery disease, aortic valve stenosis, heart failure and lifespan. An important next step in this research is to validate the results in other populations, to understand how the contribution of Lp(a) levels to heart and other diseases may vary between populations of different continental ancestry.

Based in Reykjavik, Iceland, deCODE is a global leader in analyzing and understanding the human genome. Using its unique expertise and population resources, deCODE has discovered genetic risk factors for dozens of common diseases. The purpose of understanding the genetics of disease is to use that information to create new means of diagnosing, treating and preventing disease. deCODE is a wholly-owned subsidiary of Amgen (NASDAQ:AMGN).