ESC Geoffrey Rose Lecture in Population Sciences
Pathogenesis, diagnosis and treatment of CVD: Genetic insights
29 Aug 2025
The presenter of this year’s ESC Geoffrey Rose Lecture in Population Sciences is Professor Anne Tybjaerg-Hansen (Rigshospitalet, Copenhagen University Hospital - Copenhagen, Denmark), whose research on the genetics of cardiovascular disease (CVD) in large prospective studies of the general population (The Copenhagen City Heart Study and The Copenhagen General Population Study) has led to several important breakthroughs, including understanding the relationship between different lipoproteins and atherosclerotic CVD.
What are the key themes of your lecture?
We have seen tremendous progress in the field of genetics, driven primarily by technological evolution. This started with the introduction of the polymerase chain reaction in the late 1980s, followed by the first human genome published in 2001. The HapMap project, launched in 2002, generated data on single nucleotide polymorphisms every 5 kb across the genome in some 300 samples. At around the same time, genome-wide association studies provided us with the instruments to examine causality of biomarkers using Mendelian randomisation, to identify potential drug targets and repurpose known drug targets, to predict long-term effects and potential side-effects, and so on.
This progress generated important results in my main area of interest, lipids. Early on, we were able to identify a causal association between familial defective apolipoprotein B-100 and familial hypercholesterolaemia.1,2,3 Genetic studies suggested that neither high-density lipoprotein-cholesterol nor C-reactive protein were causally linked to CVD but were disease markers;4,5 while lipoprotein(a) was found to be genetically determined and causally associated with cardiovascular risk.6 Genetic studies also helped to describe loss-of-function mutations in apolipoprotein C3 (APOC3), characterised by low triglyceride levels, low levels of remnant cholesterol and low CVD risk, which led to ApoC3 being recognised as a potential drug target.7 Furthermore, using genetics, we were able to describe the risks and benefits of modulating Niemann-Pick C1-like protein 18 (ezetimibe’s target) and cholesteryl ester transfer protein.9
My focus then shifted towards the duality between CVD risk and gallstone disease and fatty liver disease.10–12 More recently, I have focussed on transthyretin cardiac amyloidosis. Our studies in the general population showed that increased transthyretin stability compared to wildtype was associated with higher plasma transthyretin, lower risk of cerebrovascular events and longer life expectancy.13 In contrast, lower transthyretin stability was associated with lower plasma transthyretin and increased risk of heart failure, CV and total mortality, indicating a potential pathway for earlier detection.14–15
What are the most important current opportunities and challenges?
The challenges and opportunities are somehow the same. Wide access to open-source data, particularly the enormously useful UK Biobank, gives any researcher the opportunity to conduct genetic studies. The challenge is to do this wisely. It is important that investigators using these resources pose research questions that are of biological and/or clinical relevance.
What lies ahead?
There are a lot of ongoing trials in the lipid field – for example, modulating lipoprotein(a), angiopoietin-like protein 3 and ApoC3 – and their results will be very important for our future understanding of managing CVD risk.
In addition to identifying new treatments, it is important that we better incorporate genetics within the treatment paradigm and develop a more clinically relevant approach to the use of polygenic risk scores, affording them equal importance with other recognised risk factors. Finally, there has to be greater integration of genetics into the education curriculum if we are to raise awareness among healthcare professionals about their contribution to CVD.
References
- Tybjaerg-Hansen A, et al. Atherosclerosis. 1990;80:235–242.
- Tybjaerg-Hansen A & Humphries SE. Atherosclerosis. 1992;96:91–107.
- Tybjaerg-Hansen A, et al. N Engl J Med. 1998;338:1577–1584.
- Frikke-Schmidt R, et al. JAMA. 2008;299:2524–2532.
- Zacho J, et al. N Engl J Med. 2008;359:1897–1908.
- Kamstrup P, et al. JAMA. 2009;301:2331–2339.
- Jørgensen AB, et al. N Engl J Med. 2014;371:32–41.
- Lauridsen BK, et al. Eur Heart J. 2015;36:1601–1608.
- Nordestgaard LT, et al. JAMA Cardiol. 2022;7:55–64.
- Lauridsen BK, et al. Eur Heart J. 2018;39:385–93.
- Qayyum F, et al. Eur Heart J. 2018;39:2106–2116.
- Ghouse J, et al. Nat Genet. 2024;56:827–837.
- Hornstrup LS, et al. Arterioscler Thromb Vasc Biol. 2013;33:1441–1447.
- Greve AM, et al. JAMA Cardiol. 2021;6:258–266.
- Christoffersen M, et al. JAMA Cardiol. 2025;10:155–163.
