The overall goal of the proposed research is to identify specific genes that mediate the pathogenesis of arterial lesions. The proposed research is part of a multicenter study to examine arterial lesions in 3000 young persons (15-34 years), and to identify risk factors that are associated with extent and nature of atherosclerotic lesions. This proposal is in response to recommendations of the review committee for phase I of the multicenter study to include genetic analyses (using restriction fragment length polymorphisms, RFLPs) that will detect associations between specific genes and atherogenesis. The long- term objectives of the multi-center study are: (1) to define more precisely the developmental processes by which arterial lesions characteristic of late childhood (fatty streaks) progress to form advanced lesions (fibrous plaques) associated with atherosclerosis in adulthood, and (2) to relate selected risk factors (serum cholesterol) and lipoprotein concentrations, cigarette smoking, blood pressure, diabetes, and obesity) to characteristics of atherosclerotic lesions in young persons.
The aims of this proposed research relate to the second objective of the multi-center study and include: (1) determination of genotypes for each subject with respect to RFLPs in apolipoprotein and the LDL receptor genes (Southern blot analyses of DNA from liver samples sent from each collection center), (2) typing of subjects for apo E isoform genotypes using oligonucleotide probes, and (3) examination of the effects of RFLP genotypes on extent and characteristics of arterial lesions in young people. Detection of an associated RFLP not only provides evidence for genetic mediation of the pathogenesis of arterial lesions, but identifies which gene(s) is responsible for the underlying molecular processes of atherosclerosis. To maximize the probability of detecting RFLPs associated with pathogenesis of arterial lesions, specific RFLPS have been selected from published reports from other studies of human subjects. Most of these RFLPs have previously been associated with heart disease or altered levels of serum lipids and lipoproteins. This proposal presents a unique and important extension to genetic studies of heart disease, and will be the first direct examination of the effects of specific genes on the early stages of atherosclerotic lesions in young persons.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039913-04
Application #
3356881
Study Section
Special Emphasis Panel (SRC (FH))
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1991-07-05
Budget End
1992-06-30
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Southwest Foundation for Biomedical Research
Department
Type
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78245
McMahan, C Alex; Gidding, Samuel S; Malcom, Gray T et al. (2007) Comparison of coronary heart disease risk factors in autopsied young adults from the PDAY Study with living young adults from the CARDIA study. Cardiovasc Pathol 16:151-8
Zieske, Arthur W; McMahan, C Alex; McGill Jr, Henry C et al. (2005) Smoking is associated with advanced coronary atherosclerosis in youth. Atherosclerosis 180:87-92
Zieske, Arthur W; Tracy, Russell P; McMahan, C Alex et al. (2005) Elevated serum C-reactive protein levels and advanced atherosclerosis in youth. Arterioscler Thromb Vasc Biol 25:1237-43
Scheer, W Douglas; Boudreau, Donald A; Hixson, James E et al. (2005) ACE insert/delete polymorphism and atherosclerosis. Atherosclerosis 178:241-7
McGill Jr, Henry C; McMahan, C Alex; Herderick, Edward E et al. (2002) Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation 105:2712-8
McGill Jr, H C; McMahan, C A; Zieske, A W et al. (2001) Effects of nonlipid risk factors on atherosclerosis in youth with a favorable lipoprotein profile. Circulation 103:1546-50
Cole, S A; Hixson, J E (1998) PCR methodology applied to genetic studies of lipoprotein metabolism and atherosclerosis. Methods Mol Biol 110:1-34
Hixson, J E; Powers, P K (1995) Detection and characterization of new mutations in the human angiotensinogen gene (AGT). Hum Genet 96:110-2
Powers, P K; Hixson, J E (1993) BanI and PvuII polymorphisms in intron 2 of selectin E (SELE). Hum Mol Genet 2:1082
Hixson, J E; Powers, P K; McMahan, C A (1993) The human apolipoprotein B 3' hypervariable region: detection of eight new alleles and comparisons of allele frequencies in blacks and whites. Hum Genet 91:475-9

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