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2 Comment:The progress achieved in this program since my last visit in 1986 does not appear to be especially notable. This may,well be due to the difficulty in obtaining enough large family groups. However, the frequent appearance of the very large and very small proteins in hyperlipidemia and associated heart disease implies a significant relationship, which may be useful in understanding the development of atherosclerosis.Further, if the correlation between heart disease and these proteins is confirmed when the subject population is larger, an evaluation for these proteins may serve as an easy method for dectecting risk. Whether they will be successful in obtaining enough family groups to consider the inheritability of this trait remains to be seen. Their slow progess till this date implies that they may not be able to. Thus, if Dr. Albers or Dr. Cheung submits a proposal for continuing this study in 1990, their degree of progress over the long period of this investigation should be considered. DHF 0

Memorandum To: Dr. J.F.Glenn and Staf.f From: D. H. Ford Re: Site visit with ~~~A~t~, Seattle,Washington, May 25, 1988. Grant No. 1372BR1 entitled "HDL subclasses." Goal: To determine if the subclasses of proteins which constitute the HDL apoprotein demonstrate.a significant relationship toward the risk of cardiovascular disease. Results: July 1st will represent the beginning of the 8th year of support for this program. During this period he and Mariane Cheung have found that if they separate the lipo- proteins by use of a high affinity column instead of by ultra- centrifugation, a number o~subpopulations of HDL proteins in the Apo I fraction become apparent. When the separation is done by centrifugation, the Apo II protein masks the rather large number of subclasses. Since making this observation Albers and Cheung have started anylizing family groups to determine if these extra large and somewhat smaller proteins in the Apo I HDL fraction relate in anyway to heart disease. In one hypo HDL family, one spouse demonstrated the additional protein peaks in the Apo I fraction. Both sons demonstrated the same condition. In a non-related male with normal values for HDL, the Apo I protein lacked the aberant size protein com- ponents. In a family in which one spuse had above normal levels of HDL protein, both sons demonstrated similar increases ok the the extra large HDL subpopulation components, while the spouse had a normal distribution. In another family wherein the proband had hyper HDL levels as well as hyperbetal.ipoproteinemia, a daughter demonstrated the presence of the larger and smaller proteins, while her son did not. In another family (proband and spouse both 40 years old), theoproband had both aberant HDL protein subpopulations, the spouse did not. Two daughters- (ages 9 and 14) had a normal distribution of the HDL protein (like the spouse), while two other daughters and a son possessed the aberrant proteins. When one examined the HDL proteins from this family using the commonly employed centrifugation method of separation, these aberrant proteins were not detected. As a result of the slowly accumulated data, DR Albers has concluded that the presence of the very large and very small HDL sub- classes is more indicative of a-risk to develop. coronary artery disease than the commonly used LDL/HDL ratio. So far, based on a small population, it would appear that even individuals with a low level of HDL Apo proteins may not be at too great a risk if they also lack the aberrant proteins. For future work Albers and Cheung plan to increase'the number of families to confirm their observations. If these early results are confirmed, they plan to evaluate the genetic code to locate the site of control of which proteins are present. If these very large and very small HDL Apo I proteins do prove to be indicative of coronary artery disease risk, it would not only provide a new method of eveluating risk, but also indicate that a high LDL/HDL ratio need not-indicate that a person is at high risk for a heart attack..