The benefits of modern drug therapies can be maximized by avoiding some medications in patients who are genetically susceptible to adverse reactions or by selecting other medications for patients who are genetically likely to benefit. Pharmacogenetic studies have usually relied on candidate-gene approaches;yet clinical applications with demonstrated health benefits remain few or far off. Recently, genome-wide association studies (GWAS) have discovered a large number of common genetic loci associated with complex disorders. GWAS methods to identify novel variants and pathways that affect drug response can complement the candidate-gene approaches. The setting is the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, formed to facilitate GWAS meta-analyses among multiple large population-based prospective cohort studies, including Age, Gene/ Environment Susceptibility Study, Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study, and the Rotterdam Study. Health ABC Study, the Multi-Ethnic Study of Atherosclerosis, the Coronary Artery Risk Development in Young Adults, and the Jackson Heart Study have joined the effort. The CHARGE data- sharing model has accelerated the discovery of novel genetic loci for complex diseases. With genome-wide data on more than 57,000 participants (22.4% African Americans), the proposed project will use GWAS methods to identify genetic loci that modify the effects of selected drugs on a variety of outcomes with a focus on unintended adverse drug effects. In this revised application, the primary aim involves the outcome of myocardial repolarization as assessed by the ECG QTc interval;and the four primary exposures of interest are: (1) use of high-torsades-risk QT-prolonging drugs (selected antiarrhythmics, antihistamines, antibiotics, and antidepressants);(2) sulfonylurea anti-diabetic agents;(3) thiazide diuretics, and (4) tri-cyclic and tetra- cyclic anti-depressants. In addition to this primary effort related to QTc, we plan to evaluate other potential drug-gene interactions such as the use of diuretics with serum potassium levels, the use of anti-depressants and diuretics with the ECG QRS interval, the use of beta-blockers and calcium antagonists and the PR interval, the use of aspirin with cardiovascular events ("aspirin failure" among aspirin users), and use of non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics with renal function. Public-health relevance: This broad-based discovery effort is likely to illuminate novel biologic mechanisms, affect how some drugs are prescribed, and identify novel targets for new therapies.

Public Health Relevance

By leveraging the dense genotyping, deep phenotyping and diverse expertise, the PWG will accelerate the discovery of drug-gene interactions that may affect a variety of unintended therapeutic effects. The proposed project is likely to identify new variants and new pathways that affect drug response and drug safety.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL103612-02
Application #
8318660
Study Section
Special Emphasis Panel (ZRG1-PSE-D (02))
Program Officer
Jaquish, Cashell E
Project Start
2011-08-10
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$1,341,853
Indirect Cost
$94,122
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Psaty, Bruce M; Weiss, Noel S (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol: a fresh interpretation of old evidence. JAMA 311:461-2
Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A et al. (2014) Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nat Commun 5:5068
Avery, Christy L; Der, Jane S; Whitsel, Eric A et al. (2014) Comparison of study designs used to detect and characterize pharmacogenomic interactions in nonexperimental studies: a simulation study. Pharmacogenet Genomics 24:146-55
Bis, Joshua C; White, Charles C; Franceschini, Nora et al. (2014) Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. Circ Cardiovasc Genet 7:359-64
Avery, C L; Sitlani, C M; Arking, D E et al. (2014) Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval. Pharmacogenomics J 14:6-13
Rosenberg, Michael A; Kaplan, Robert C; Siscovick, David S et al. (2014) Genetic variants related to height and risk of atrial fibrillation: the cardiovascular health study. Am J Epidemiol 180:215-22
Ng, Maggie C Y; Shriner, Daniel; Chen, Brian H et al. (2014) Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. PLoS Genet 10:e1004517
Bis, Joshua C; DeStefano, Anita; Liu, Xiaoming et al. (2014) Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. PLoS One 9:e99798
Tang, Wenbo; Kowgier, Matthew; Loth, Daan W et al. (2014) Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. PLoS One 9:e100776
Floyd, James S; Psaty, Bruce M (2014) The potential risks of expedited approval of drugs for acute bacterial infections. JAMA Intern Med 174:1436-7

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