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.
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.
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