This competitive renewal proposal will determine the contribution of polymorphic variation in nine candidate genes involved in lipid metabolism [APO(a), APOD, hepatic lipase (HL), cholesteryl ester transfer protein (CETP), LDL receptor related protein (LRP), 3- hydroxy-3 methyl glutryl-coenzyme A (HMG COA), VLDL-receptor, Lecithin cholesterol acyletransferase (LCAT) and paraoxonase (PON)] in determining quantitative lipoprotein-lipid levels in Hispanics and non-Hispanic Whites of the San Luis Valley, Colorado. The proposal will also determine the molecular basis of the functional mutation in the lipoprotein lipase (LPL) gene which is associated with plasma triglyceride and HDL cholesterol variations. The objectives will be achieved by fulfilling the following specific aims: 1) by PCR, DNA sequencing and SSCP analyses, all coding exons and putative regulatory elements in the LPL gene of individuals who are homozygous for the HindIII restriction site to detect nucleotide changes in the coding region which affect directly triglycerides and HDL- cholesterol levels will be screened, in vitro mutagenesis and expression studies will be conducted to confirm which of the putative functional mutations is the actual functional mutation; 2) genetic variations in genes coding for CETP, HL, LRP, APOD, HMG COA, VLDL-receptor, LCAT and PON will be identified by PCR or standard Southern blotting techniques, and the impact of individual polymorphisms and the joint impact of polymorphisms at different loci (genotype-genotype interaction) in determining quantitative lipoprotein-lipid levels in Hispanics and NHWs will be estimated; and 3) the distribution of APO(a) kringle 4 and pentanucleotide polymorphisms will be determined by SDS-agarose gel electrophoresis and PCR, respectively, and LP(a) levels will be quantified by enzyme-linked immunosorbent assay, and the correlation between APO(a) polymorphisms and LP(a) levels will be investigated. The investigators state that the answers to these questions will contribute to our understanding of the role of genes in determining quantitative risk factors, and ultimately to our understanding of genetic determinants of coronary heart disease risk in the general population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044672-06
Application #
2685356
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1991-05-01
Project End
2001-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Public Health
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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