# Pharmacogenetics to improve drug therapy

> **NIH NIH R35** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $340,000

## Abstract

ABSTRACT
The proposed research program will focus on two pharmacogenetic challenges that hold great potential for
improving patient therapy. 1) The first challenge is to define the clinical importance of known pharmacogenetic
associations, as related to drug toxicity and therapeutic failure—common outcomes of any therapy. The
genetic contribution to variability in pharmacokinetics and pharmacodynamics, and thus potentially to
differences in drug response, is well recognized. However, despite intensive research, little of this work has
translated to clinical practice. A critical barrier is that the effect of genotype on meaningful patient outcomes in
clinical practice is not known. Ideally, large randomized controlled trials would define the effect of genotype on
clinical outcomes, and a few such studies are underway. However, given the expense of such trials, the many
genotypes, drugs, and outcomes of interest, as well as the difficulties extrapolating from precise clinical trials to
imprecise clinical practice, this approach is limited. Consequently, the path forward to translate science into
practice is unclear. Accordingly, we propose a novel, cost effective approach: to use a de-identified electronic
medical record (EHR) linked to a DNA biobank with >200,000 patients (BioVU) to define the clinical importance
of variation in genes affecting drug metabolism or response. The long-term goal of this area of work is to
develop and implement methods to define the importance of genetic variation on the outcomes of drug therapy
in real world clinical practice. 2) The second challenge is to use genetics to predict unexpected toxicities and
benefits of drugs. Over time, most drugs newly introduced to the market are found to have additional
therapeutic indications and also unexpected toxicities. A critical barrier is that traditional post-marketing
approaches to define these effects often require decades of study. During this time patients would accrue
unwanted currently unknown adverse effects and forgo potential off-target benefits. Genetic approaches can
provide information to speed this process. The mechanism of action of some drugs (e.g., ezetimibe that inhibits
Nieman-Pick C1-like 1 (NPC1L1)) are mimicked by variations in genes (NPC1L1). By studying individuals who
carry these variants and determining their outcomes in large EHR databases using a technique called
phenome-wide association studies (PheWAS) followed by fine-phenotyping we can infer potential outcomes
when patients are exposed to the drug. The long-term goal of this area of work is to develop and implement
methods to use genetic information to discover unexpected benefits and risks of drugs. The two
pharmacogenetic challenge areas that will be the foundation of the research program have high public health
impact, not only in translating basic science to improved patient care for the drugs studied, but also in providing
new approaches for testing the clinical importance of a range of dr...

## Key facts

- **NIH application ID:** 10368071
- **Project number:** 5R35GM131770-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Charles M. Stein
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $340,000
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368071

## Citation

> US National Institutes of Health, RePORTER application 10368071, Pharmacogenetics to improve drug therapy (5R35GM131770-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368071. Licensed CC0.

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