The goal of this Pharmacogenetics Research Group is to identify common gene variants that contribute to interindividual differences in response to drugs used to reduce risk for cardiovascular disease (CVD). The Group comprises a multidisciplinary team of investigators with expertise in lipoprotein metabolism and blood pressure regulation; genomics and related computational methodology; clinical trials; human genetics and genetic epidemiology; transgenic mouse models, and database management and biostatistics. For the present study, the drugs chosen are atorvastatin, an HMG CoA reductase inhibitor that lowers plasma lipid levels, and ramipril, an ACE inhibitor that lowers blood pressure. Candidate genes are those with products in metabolic pathways that are potential targets of these drugs. DNA sequence variations in 50 genes will be determined in 24 Caucasians and 24 African-Americans, two ethnic groups with differing degrees of sequence diversity. Based on patterns of single nucleotide polymorphisms (SNPs), haplotypes will be constructed for each gene in both ethnic groups, and groups of SNP genotypes will be identified that are characteristic for the 2-4 most common haplotypes in each gene, present in at least 10 percent of the population. Haplotypes for genes related to atorvastatin effects (27 genes) will be determined in 600 individuals (300 from each ethnic group) who will receive 10 mg/day of this drug for 8 weeks. Haplotypes for genes related to ramipril effects (23 genes) will be determined in 600 individuals (300 from each ethnic group) who will receive 10 mg/day of this drug for 12 weeks. Detailed measurements of phenotypes related to lipoprotein and blood pressure regulation will be performed in the two respective cohorts, and associations will be sought with each of the respective candidate haplotypes. Functional effects of specific sequence variants will be tested in appropriate transgenic mouse models. Future studies will corroborate positive findings using samples from large ongoing clinical endpoint trials of atorvastatin and ACE inhibitor therapy. Data will be transmitted to the Pharmacogenetics Knowledge Base and other genomic databases. The findings will advance our fundamental understanding of the roles of specific genes and their variants in modulating biologic pathways of importance in the pathogenesis and management of CVD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL069757-01
Application #
6340506
Study Section
Special Emphasis Panel (ZRG1-PHRA (01))
Program Officer
Gerschenson, Mariana
Project Start
2001-09-27
Project End
2002-07-31
Budget Start
2001-09-27
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$2,538,048
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Lee, Seung-Been; Wheeler, Marsha M; Patterson, Karynne et al. (2018) Stargazer: a software tool for calling star alleles from next-generation sequencing data using CYP2D6 as a model. Genet Med :
Theusch, E; Kim, K; Stevens, K et al. (2017) Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner. Pharmacogenomics J 17:222-229
Feng, Q; Wei, W Q; Chung, C P et al. (2017) The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy. Pharmacogenomics J 17:204-208
Elbadawi-Sidhu, Mona; Baillie, Rebecca A; Zhu, Hongjie et al. (2017) Pharmacometabolomic signature links simvastatin therapy and insulin resistance. Metabolomics 13:
Gordon, Adam S; Fulton, Robert S; Qin, Xiang et al. (2016) PGRNseq: a targeted capture sequencing panel for pharmacogenetic research and implementation. Pharmacogenet Genomics :
Norby, Faye L; Eryd, Samuel Adamsson; Niemeijer, Maartje N et al. (2016) Association of Lipid-Related Genetic Variants with the Incidence of Atrial Fibrillation: The AFGen Consortium. PLoS One 11:e0151932
Hall, Kathryn T; Jablonski, Kathleen A; Chen, Ling et al. (2016) Catechol-O-methyltransferase association with hemoglobin A1c. Metabolism 65:961-967
Ehret, Georg B (see original citation for additional authors) (2016) The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 48:1171-1184
Mora, Samia; Caulfield, Michael P; Wohlgemuth, Jay et al. (2015) Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvasta Circulation 132:2220-9
Luzum, Jasmine A; Theusch, Elizabeth; Taylor, Kent D et al. (2015) Individual and Combined Associations of Genetic Variants in CYP3A4, CYP3A5, and SLCO1B1 With Simvastatin and Simvastatin Acid Plasma Concentrations. J Cardiovasc Pharmacol 66:80-5

Showing the most recent 10 out of 106 publications