Abstract

This is an application to continue work initiated in 1987 in the RFHS to address whether knowledge about genomic variability may provide information for the prediction of CAD beyond that provided by the quantitative intermediate risk factors that link the effects of genetic and environmental variation to variation in risk of disease. This competing continuation application proposes five Specific Aims that take advantage of three major developments over the past five years: expanded theory for linkage and association studies, a human transcript map of over 8,000 genes, and the establishment of the RFHS resource of 575 pedigrees for which DNA samples measures of intermediate biological risk factors (plasma levels of apolipoprotein (apo) Al, apo All, apo B, apo Cll, apo Clll apo E, total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, insulin, and glucose), body mass index smoking, and disease endpoints are available on the 3941 persons at no cost to this project.
Specific Aims 1 and 2 will identify genomic regions containing new CAD susceptibility genes, using 234 tandem repeat marker loci at a 10 centimorgan (cM) density and the variance component method of linkage in 274 multigeneration pedigrees, both globally and in particular contexts defined by gender, age, (body mass index) BMI, and smoking. For those regions that show linkage, confirmatory linkage analysis will be conducted in a second independent sample of 301 multigeneration pedigrees. In regions where linkage is replicated, fine structure linkage analyses will be conducted, using additional marker loci, located approximately every 1 cM.
Specific Aims 3 and 4 will identify functional DNA variations in the new candidate CAD susceptibility genes. Direct DNA sequencing and cladistic analyses will be used to estimate the average, context dependent, dominant, and epistatic effects associated with these functional DNA variations.
Specific Aim 5 will estimate the association between the risk of CAD and functional genotypes identified by the cladistic analyses carried out in Specific Aims 3 and 4 before and after considering the intermediate biological risk factors that link the effects of genetic and environmental variation to variation in risk of disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039107-12
Application #
2750327
Study Section
Special Emphasis Panel (ZRG4-HPD (02))
Project Start
1987-08-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Genetics
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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