During this study, I became interested in an unusual lipoprotein called lipoprotein (a) which was quite prevalent in the subjects under study. Although it was not considered very important at that time, I developed methods to estimate the amount circulating in plasma. Through collaboration with Dr. David Hewitt and Dr. J.A. Little, we were able to show that the amount of this lipoprotein in plasma was determined by inheritance.
In 1972, as a young biochemistry faculty member at the University of Toronto, I started a research program in a large internationally funded study to determine whether lowering blood cholesterol would reduce the development of coronary heart disease in North American men. The targeted study was designed to address a very fundamental clinical question about heart disease and cholesterol. However, the individuals responsible for the project had considerable foresight to realize that the project should encompass clinical, epidemiological and basic science questions and should try to promote interaction of clinical and basic research scientists.
Fats are transported in blood as lipoproteins, an aggregate of fat and proteins (apolipoproteins). At that time, researchers were just beginning to understand the role of the proteins. I decided that there was a strong possibility that individuals with mutant or abnormal proteins with defective functions would be found in the extensive population surveys if the proteins had important functions. I established techniques for identifying and measuring biological functions of the apolipoproteins. As a result of these studies, and in collaboration with Dr. J.A. Little, I identified two new metabolic deficiencies which result in massive accumulation of blood fats. Although these deficiencies are rare in the population, they are important in identifying the role of proteins in the breakdown of blood fats and they assist in designing the most appropriate therapeutic regimes for abnormal elevations of blood fats.
During this study, I became interested in an unusual lipoprotein called lipoprotein (a) which was quite prevalent in the subjects under study. Although it was not considered very important at that time, I developed methods to estimate the amount circulating in plasma. Through collaboration with Dr. David Hewitt and Dr. J.A. Little, we were able to show that the amount of this lipoprotein in plasma was determined by inheritance. I continued these studies after moving to Dalhousie and was able to isolate the apolipoprotein responsible for the unique characteristics and develop methods for estimating the amount of this apolipoprotein. There are different forms of this apolipoprotein which are inherited and which determine the amount of the lipoprotein. We are currently exploring the possibility of commercializing this test. Lipoprotein (a) has now been shown by several groups to be closely associated with an increased risk of coronary heart disease and it is currently a very dynamic area of research. Lipoprotein (a) represents one form of genetic predisposition to premature coronary heart disease. Most therapeutic approaches for lowering cholesterol do not affect this lipoprotein. However, we can identify the person at risk and intervene to lower other common risk factors for coronary heart disease. I believe lipoprotein(a) represents the first of several genetic links to premature coronary heart disease which are common in the population. It is important to explore the association of genetic factors with environmental factors, such as diet or smoking, because we know that environmental factors are a major cause in coronary heart disease. If we can identify genetic factors which combine with environmental factors to increase risk, we should be able to be very selective in improving intervention in those individuals most at risk.
This research has covered 19 years and has involved clinicians, epidemiologists and basic scientists. The work has been funded by the National Heart Lung and Blood Institute (USA), the Medical Research Council of Canada and the Heart and Stroke Foundation of Canada. As a result of the international study, there is now a massive campaign to reduce cholesterol concentrations in the North American population through dietary intervention. The public is now much more conscious of ways to reduce fat and cholesterol intake than 20 years ago. New highly effective drugs have been developed to combat elevated cholesterol. Finally, I believe my work on lipoprotein (a) has helped to show that there may be important interactions between genetic and environmental factors.
Dr. Breckenridge is now at Dalhousie University.