Abstract

The overall goal of this proposal is to relate observations at the DNA level to the distribution of coronary heart disease (CHD) in the population at large. We propose to study measurements of the genes coding for the apolipoproteins and the low density lipoprotein (LDL) receptor, gene products (apolipoproteins), cholesterol (C), triglycerides (TG), high density lipoprotein cholesterol (HDL-C) and CHD endpoints from 2259 individuals in 300 three-generation pedigrees ascertained independently of their disease or risk factor status from the Rochester, MN, population. There are currently no data available to support the hypothesis that measures of DNA variation will improve the prediction of CHD endpoints beyond that provided by the quantitative measurements of the apolipoproteins (apos), C, TG, and HDL-C. We will obtain an estimate of the information about CHD that resides in the gene loci coding for the apos and the LDL receptor that is independent of information obtained from the quantitative measurements of the apos, C, TG, and HDL-C levels. Detection of such pleiotropic effects of DNA variations not expressed in the traditional lipid and lipoprotein risk factor phenotypes would support the argument for a molecular genetic approach to the epidemiology of CHD.
Five aims are proposed that present a logical progression of studies to link variation in DNA to the occurrence of CHD.
In Aim 1 we will characterize variation at the DNA level using restriction fragment length polymorphisms and at the protein level by isoelectric focusing.
Aim 2 defines the relationships in the population between the apolipoproteins (measured by polyclonal and monoclonal antibodies), C, TG, HDL-C phenotypes and estimates the effects of age, sex, smoking, drug use and obesity on these relationships.
Aim 3 estimates the fraction of the interindividual variation in the apos that is attributable to gene loci coding for these molecules.
Aim 4 estimates the fraction of interindividual variation in C, TG, and HDL-C that is attributable to gene loci coding for the apos and the LDL receptor. And, Aim 5 will determine whether genotypic variation for the gene loci coding for the apo and the LDL-receptor contributes to the prediction of CHD beyond that provided by the effects of these gene loci on the interindividual variation in the apos, C, TG, and HDL-C.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039107-02
Application #
3355699
Study Section
Epidemiology and Disease Control Subcommittee 3 (EDC)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Montasser, May E; Shimmin, Lawrence C; Hanis, Craig L et al. (2009) Gene by smoking interaction in hypertension: identification of a major quantitative trait locus on chromosome 15q for systolic blood pressure in Mexican-Americans. J Hypertens 27:491-501
Bressler, Jan; Fornage, Myriam; Hanis, Craig L et al. (2009) The INSIG2 rs7566605 genetic variant does not play a major role in obesity in a sample of 24,722 individuals from four cohorts. BMC Med Genet 10:56
Chung, Charles C; Shimmin, Lawrence; Natarajan, Sivamani et al. (2009) Glucocorticoid receptor gene variant in the 3' untranslated region is associated with multiple measures of blood pressure. J Clin Endocrinol Metab 94:268-76
Klos, Kathy; Shimmin, Lawrence; Ballantyne, Christie et al. (2008) APOE/C1/C4/C2 hepatic control region polymorphism influences plasma apoE and LDL cholesterol levels. Hum Mol Genet 17:2039-46
Leduc, Magalie S; Shimmin, Lawrence C; Klos, Kathy L E et al. (2008) Comprehensive evaluation of apolipoprotein H gene (APOH) variation identifies novel associations with measures of lipid metabolism in GENOA. J Lipid Res 49:2648-56
Frikke-Schmidt, Ruth; Sing, Charles F; Nordestgaard, Borge G et al. (2007) Subsets of SNPs define rare genotype classes that predict ischemic heart disease. Hum Genet 120:865-77
Stengard, J H; Frikke-Schmidt, R; Tybjaerg-Hansen, A et al. (2007) Variation in 5'promoter region of the APOE gene contributes to predicting ischemic heart disease (IHD) in the population at large: the Copenhagen City Heart Study. Ann Hum Genet 71:762-71
Hand, B D; McCole, S D; Brown, M D et al. (2006) NOS3 gene polymorphisms and exercise hemodynamics in postmenopausal women. Int J Sports Med 27:951-8
Rea, Thomas J; Brown, Christine M; Sing, Charles F (2006) Complex adaptive system models and the genetic analysis of plasma HDL-cholesterol concentration. Perspect Biol Med 49:490-503
Brown, C M; Rea, T J; Hamon, S C et al. (2006) The contribution of individual and pairwise combinations of SNPs in the APOA1 and APOC3 genes to interindividual HDL-C variability. J Mol Med 84:561-72

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