This is a revised application by Dr. Bhatnagar, an MD, MPH in the early stages of establishing a research career in clinical epidemiology, with a focus on pharmacogenetic predictors of antihypertensive drug response. She has completed an MPH degree from the Harvard School of Public Health (1999), continued post-doctoral training in clinical epidemiology at the University of California San Diego (UCSD) (2000 to2002), and has now established a primary care hypertensive patient cohort (N=1,502) from the VA San Diego Healthcare System (2003-2005). She has several first authored primary research publications and, since the last submission, has written three first-authored research manuscripts directly related to this proposal (one recently published and two in review). She will be developing a comprehensive medical genomic database. Patients on monotherapy for hypertension- ie. angiotensin converting enzyme inhibitor, beta adrenergic receptor blocker or thiazide diuretic-will be genotyped at specific candidate genetic loci and the association between drug response (blood pressure response) and genoype will be measured (ANOVA).Logistic regression analyses will be used to control for other predictors of drug response. Haplotype analyses will focus on teasing out the contribution of multiple polymorphisms on a gene, as well as uncover the contribution of a gene region to drug response. A sample size of about 200 patients per monotherapy group will be adequate to detect moderate effect sizes (moderate differences in response rates) between patients with and without common polymoprhisms (minor allele frequency over 15%). Only common polymorphisms in this patient population will be studied because the investigator is interested in the clinical applications of genotype testing to patient care. The training portion will focus on: 1) didactic coursework in medical genomics;2) lab training in DNA quantification and processing;and 3) training in bioinformatics and database development, and the use of software programs for genomic analyses. Dr. Bhatnagar will be working in a rich environment under successful senior UCSD investigators: 1) Mentor - Dr. Daniel T. O'Connor (Chief of Hypertension, investigator in pharmacogenomics and hypertension pathophysiology);2) Co-mentor - Dr. Sanjay K. Nigam (Professor, investigator in renal drug handling);and 3) Biostatistical consultant - Dr. Nicholas J. Schork (Professor, expertise in statistical genomics).
