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Anitschkow Lecture: Genetics - from Ugly Duckling to Beautiful Swan - Professor Anne Tybjaerg-Hansen

Sunday 6 May 2018   (0 Comments)
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In another first for the EAS, Professor Anne Tybjaerg-Hansen (Copenhagen University Hospital, and the University of Copenhagen, Copenhagen, Denmark) is the first female recipient of the Anitschkow Award. According to EAS President Professor Tokgözoğlu: Professor Tybjaerg-Hansen is truly a pioneer in genetics, playing a key role in delineating the role of genetics in lipid metabolism, and importantly, cardiovascular risk. Her research has led to novel therapeutic approaches in the fields of cardiovascular disease, most recently in the development of agents targeting apolipoprotein CIII, which plays a key role in the regulation of triglycerides, a marker for triglyceride rich lipoproteins and their remnants.

So, why the title?

Well, in the beginning, genetic research has truly been the ugly duckling, with tedious, cumbersome methodologies limiting study. The advent of polymerase chain reaction technology changed this. Professor Tybjaerg-Hansen recognized the power of this, and in 1991-1994, was the driving force in efforts to link DNA from 9000 individuals in the Copenhagen City Heart Study to aid further research possibilities. This culminated four years later in a number of prestigious papers relating to several genetic variants linked with dyslipidaemia and cardiovascular disease, including APOB and LDLR mutations of relevance to familial hypercholesterolaemia,1 and LPL mutations and risk for elevated triglycerides and ischaemic heart disease.2

Inadvertently, Professor Tybjaerg-Hansen had incorporated Mendelian randomization in genetic research, a powerful approach using genetic epidemiology to unravel the determinants of cardiovascular disease.  The Human Genome project and related projects such as the International HapMap Project provided the opportunity to investigate associations between single-nucleotide polymorphisms (SNPs), lipid metabolism and risk for cardiovascular disease. As a consequence, research using the Copenhagen City Heart Study, together with the Copenhagen General Population Study databases provided insights into the association between nonfasting triglycerides and risk for myocardial disease,3 as well as changing thinking about the role of high-density lipoprotein cholesterol (HDL-C) from participant to bystander in cardiovascular disease,4,5 later borne out by a raft of disappointing clinical studies of interventions targeting HDL-C. Research also identified genetically elevated C-reactive protein with risk for ischaemic heart disease,6 as well as elevated lipoprotein(a) and risk for myocardial infarction.7

Rapid genetic sequencing has been instrumental in genome-wide association studies, which are not only instruments for Mendelian randomization studies, but also offer insights into potential drug targets, as well as the possibility of predicting the long-term effects and side effects of drugs. The association between loss of function variants in APOC3 and risk for ischaemic heart disease is one example of the role of genetic research in developing novel therapeutic approaches,8 as is gain in function ABCG5/8 variants and risk for gallstones,9 and NPC1L1 variants with risk of ischaemic heart disease and gallstone disease.10 Most recently, research by Professor Tybjaerg-Hansen’s group has been instrumental in showing that the observational association between liver fat content and non-alcoholic fatty liver disease and ischaemic heart disease is not causal but due to confounding,11 as well as identifying genetic variants in CYP7A1 associated with increased risk of LDL cholesterol and symptomatic gallstone disease.12 

This revolution in genetic research has – and continues to have – wide-ranging implications, not only for identification of novel therapeutic approaches, PCSK9 inhibitors as one example, but also in application to guideline development.

It has been a long journey but now genetic research has truly come of age, just like the transformation from ugly duckling to beautiful swan - Professor Tybjaerg-Hansen

References

1. Tybjaerg-Hansen A1, Steffensen R, Meinertz H, Schnohr P, Nordestgaard BG. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med 1998;338:1577-84.

2. Nordestgaard BG, Abildgaard S, Wittrup HH, Steffensen R, Jensen G, Tybjaerg-Hansen A. Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease. Circulation 1997;96:1737-1744.

3. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299-308.

4. Frikke-Schmidt R, Nordestgaard BG, Jensen GB, Tybjaerg-Hansen A. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population. J Clin Invest 2004;114:1343-1353.

5. Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P, Grande P, Tybjaerg-Hansen A. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 2008;299:2524-2532.

6. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008;359:1897-1908.

7. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;301:2331-2339.

8. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.

9. Stender S, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease. J Am Coll Cardiol 2014;63:2121-2128.

10. Lauridsen BK, Stender S, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A.  Genetic variation in the cholesterol transporter NPC1L1, ischaemic vascular disease, and gallstone disease. Eur Heart J 2015;36:1601-1608.


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