{Davignon photo} Jean Davignon

Professor, Department of Medicine
Professor, Department of Nutrition
Université de Montréal

Division of Experimental Medicine, Department of Medicine
Faculty of Medicine, McGill University

Emeritus Physician, Hôtel-Dieu Hospital, Montréal

Director, Hyperlipidemia and Atherosclerosis Research Group
Institut de Recherches Cliniques de Montréal (IRCM)
110 avenue des Pins Ouest
Montréal, Québec
H2W 1R7

Phone... +1 (514) 987-5626
FAX... +1 (514) 987-5700
email... DavignJ@IRCM.UMontreal.CA
web... http://www.ircm.umontreal.ca/ext/ircm/labo/chercheu/davig-an.htm

Dr. Jean Davignon obtained his doctorate honoris causa from the Université Paul Sabatier of Toulouse, and his medical degree summa cum laude from the University of Montréal. Then in 9 years of post-graduate studies he trained in internal medicine, vascular medicine, and clinical research, at the Hôtel-Dieu Hospital of Montréal, McGill University, Mayo Clinic, and Rockefeller University. Upon his return to Montréal, he set up a research laboratory on hyperlipidemia and atherosclerosis linked with a Nutrition, Metabolism and Atherosclerosis Clinic at the IRCM.

His research group of nearly 40 people works on the characterization of hereditary hyperlipidemias, the atherogenic potential of plasma lipoprotein fractions, gene-gene and gene-environment interactions in the causation of disease, the pathogenesis of dyslipoproteinemia and atherosclerosis, the role of gamma-LpE and reverse cholesterol transport, the pharmacology of lipid-lowering agents, and nutritional aspects of cardiovascular diseases. This has resulted in 302 scientific publications, 248 abstracts, 42 book chapters and three books.

He was a recipient of the John and Mary Markle Scholar in Academic Medicine Award, the Bristol Senior Research Award of the Canadian Lipoprotein Conference, the Frederick Newton Gisborne Starr Award of the Canadian Medical Association, and the Grande médaille d'or du centenaire de l'Institut Pasteur de Lille. In 1995 he was inducted in the Academy of Sciences of the Royal Society of Canada and in 1996 was elected Officer of the Order of Canada.

Dr. Davignon is one of the founders of the Canadian Atherosclerosis Society, of the Canadian Association for Familial Hypercholesterolemia, and a founding member of the Canadian Institute of Academic Medicine. A participant in many national and international committees, Dr. Davignon was elected President of the Xth International Symposium on Atherosclerosis held in Montréal in October 1994, which attracted more than 3000 delegates.

Apolipoprotein E and atherosclerosis

Major advances have been made in recent years in understanding the role of apolipoprotein E (apoE) in the onset and development of atherosclerosis. The discovery in the mouse that disruption of the apoE gene by homologous recombination causes atherosclerosis has given a major impetus to the field. Several lines of evidence from animal experiments suggest that apoE plays an antiatherogenic role. These include:

  1. apoE knockout (KO) mice, but not knockouts of apolipoprotein A-I or the LDL receptor, have severe spontaneous atherosclerosis
  2. lipoproteins of apoE KO mice are more oxidized and more susceptible to oxidation
  3. enhanced atherosclerosis occurs when C57BL/6 mice are reconstituted with apoE-null macrophages
  4. rat apoE gene expression in transgenic mice lowers plasma lipoprotein levels
  5. human apoE gene specific expression in the arterial wall inhibits diet-induced atherosclerosis in mice
  6. chronic intravenous administration of apoE in the WHHL rabbit prevents atherosclerosis.

Caution should be excised, however, in extrapolating findings from mouse models to other species. In humans, the situation is somewhat different because apoE is polymorphic (3 alleles, 6 phenotypes) and different alleles have varying impacts on the fate and atherogenic potential of plasma lipoproteins. Discovery of type III dyslipoproteinemia and its atherosclerotic complications, occurring in association with the E2/2 phenotype or in the absence of apoE, was the first observation in humans that established a link between apoE and atherosclerosis. This led to a better understanding of the effect of apoE alleles on lipoprotein clearance. The situation is further confounded, in humans, by a multitude of environmental and genetic factors which can alter the beneficial or deleterious effect of an allele. These factors explain the inconsistency of the relationship between apoE genotype and coronary artery disease (CAD) risk in different populations. Furthermore, the apoE gene is pleiotropic (has multiple functions) and is both a level gene (influences level of a parameter) and a variability gene (influences variation around the mean). Finally, apoE gene mutations (or polymorphic variations other than the common polymorphism) may also be a source of confusion.

Generally speaking, the epsilon4 allele is proatherogenic and the epsilon2 allele is anti-atherogenic unless a second factor intervenes to interact with the epsilon2 allele to promote higher levels of atherogenic plasma remnant lipoproteins. In population studies, the epsilon4 allele is associated with higher LDL-C concentrations, although variation at the LDL receptor gene or the apolipoprotein B gene may alter this effect. The epsilon4 allele occurs with a higher frequency in populations at increased CAD risk, which is in part ascribed to an LDL effect, though some evidence indicates an independent mechanism as well. An effect on CAD risk may take place in the absence of a major effect on LDL-C, or is still present when one corrects for LDL-C. In the apoE KO mice, expression of human apoE3 improves atherosclerosis without changing plasma cholesterol or triglyceride levels. ApoE has an antioxidant effect, but apoE4 is less effective than apoE2. ApoE contributes to efflux of cholesterol from macrophages, but apoE4 is less effective than apoE2. ApoE plays a putative role in reverse cholesterol transport, being the major constituent of gammaLpE, a lipoprotein particle which is a potent initial acceptor of cell-derived cholesterol; there is less gammaLpE in the presence of the epsilon4 allele than with the other alleles. The epsilon2 allele, in contrast to the epsilon4 allele has, overall, a potentially protective effect on atherosclerosis, by virtue of being associated with lower levels of LDL cholesterol in the general population. ApoE2 has better antioxidant properties and clears cholesterol from macrophages more effectively than apoE4. The caveat is that in the wrong environment its presence is associated with atherogenic remnant lipoproteins, as occurs in type III dyslipoproteinemia, but as could occur as well when a single epsilon2 allele is present. With the new knowledge acquired on the importance of apoE in health and disease, it becomes important to ask the question whether assessment of apoE polymorphism should be made more accessible to clinical practitioners.

Click here {PDF icon} to download a MedLine search report of Dr. Davignon's recent publications (140 KB)

Version 2.0(5), revised May 10, 1998