Precision Medicine for Gulf War Veterans: Integrating Pharmacogenetic Testing into Clinical Practice

About This Grant

Significance to VA: Adverse drug reactions (ADRs), the harmful unintended reactions resulting from the use of medications, can result in hospital visits, or even death. Polypharmacy is a known risk factor for ADRs. This is especially true for Gulf War Veterans (GWV); one fifth (21.2%) of GWV experience central nervous system (CNS)-active polypharmacy and 39.6% of these GWV experience an ADR. This is likely because ~30% of GWV meet criteria for Gulf War Illness (GWI). Two enzymes, CYP2D6 and CYP2C19, metabolize many of the drugs used to treat GWI, contribute to ADRs. Precision medicine, a medical approach that considers individual differences in genes, environment, and lifestyle, can improve treatment outcomes. This approach uses pharmacogenetic (PGx) testing, a method that examines how one's DNA affects the response to medications. To reduce risk of harm in GWV, prescribers could optimize pharmacologic treatment via precision medicine. This application is highly relevant to VA and Health Systems Research (HSR) priorities including: 1) The Commander John Scott Hannon Veterans Mental Health Care Improvement Act that requires the VA to implement precision mental health care; 2) suicide prevention; 3) quality and safety of health care; and 4) the Promise to Address Comprehensive Toxics (PACT) Act. This study will improve our understanding of the risk factors of ADRs among GWV, a result that will promote gene-informed prescribing which will in turn save lives, improve a patient's function and quality of life, and reduce hospitalizations. Innovation and Impact: Currently, there is growing evidence supporting the use of PGx testing for clinically relevant outcomes. This CDA-2 will provide observational evidence of the potential benefit of PGx testing to prevent ADRs in a high risk, high priority cohort within the VHA. It will also uncover barriers and facilitators of enhanced implementation of the VHA's PGx testing program; and help to clarify the pathway for the promotion of PGx testing in GWV by the creation [and pilot testing] of a clinical workflow that will identify [GWV with CNS-active polypharmacy] who may benefit from PGx testing, thus improving medication safety and selection. Specific Aims: Aim 1: Show that CNS-active polypharmacy (>3 medications) and other pharmacotherapy regimen characteristics are associated with ADRs among GWV who are connected to VHA clinical care from the Cooperative Studies Program (CSP) 2006/Million Veteran Program (MVP) 029 dataset, “Genomics of Gulf War Illness.” Aim 2: Demonstrate that genetic variants of CYP2D6/CYP2C19 moderate the relationship between CNS-active polypharmacy and ADRs, underscoring the potential to improve care with PGx testing. Aim 3: Partner with the National Pharmacogenomics Program (NPP) to design [and pilot test] a clinical workflow aimed at integrating PGx testing into clinical practice for [GWV with CNS-active polypharmacy.] Methodology: In Aim 1, we will conduct multivariable logistic regressions from GWV participants in CSP 2006/MVP 029 to examine the associations between CNS-active polypharmacy, other patient and pharmacotherapy regimen characteristics, and ADRs. In Aim 2, using the CSP 2006/MVP 029 dataset, we will perform moderation modeling to explore the impact that PGx tested pharmacogenes could have on ADRs among GWV with CNS-active polypharmacy who were newly exposed to a CNS-active medication. In Aim 3a, we will conduct semi-structured interviews of healthcare providers who evaluate and manage Veterans with documented [CNS-active] polypharmacy, including GWV, and who can order PGx tests to identify opportunities to improve the clinical impact of PGx testing. In Aim 3b, informed by combined results from prior Aims, we will use the NPP process of clinical workflow development to develop and refine a clinical workflow for [GWV with CNS-active polypharmacy; and in Aim 3c, we will pilot test the clinical workflow.] Path to Translation/Implementation: We will submit research proposals to further study the impact of PGx testing has in [both GWV and in all Veterans] and; support NPP's efforts to promote PGx testing in clinic.