PROJECT SUMMARY/ABSTRACT This administrative supplement application responds to PA-20-272: “Administrative Supplements to Existing NIH Grants and Cooperative Agreements.” The parent grant is “Leveraging genetic and electronic health record data to identify novel targets and drugs for treating alcohol use disorder” (R01 AA030041-01). The parent grant aims to leverage advances in genomics and access to electronic health record (EHR) data to: 1) elucidate biological networks linked to alcohol consumption and problematic alcohol use (Aims 1 and 3); and 2) identify promising drugs for repurposing to treat alcohol use disorder (AUD) (Aim 2). Here, we propose to conduct analyses of complementary EHR data from Kaiser Permanente Northern California to increase the rigor of Aim 2c of the parent grant: Estimate the effect of exposure to drugs from Aim 2b on changes in alcohol consumption using national data from the Veterans Affairs (VA) EHR. Specifically, we are evaluating the effect of the brain penetrant L-type calcium channel blockers, nifedipine and felodipine, in the VA data in the parent R01 and here we are proposing to also evaluate whether they have treatment effects in the Kaiser EHR data as a validation in the supplement. Our Aim 1 analyses have shown that L-type calcium channels are genetically supported targets with theoretical and preclinical support for repurposing for treating AUD. The inclusion of data from Kaiser Permanente EHR will substantially enhance the parent project by enabling us to evaluate the replicability of R01 findings, their generalizability to a population outside the VA and examine sex-specific effects and dosage specific effects of the medication. We will employ an active-comparator (non-brain-penetrant L-type calcium channel blockers), new-user design, with propensity score matching. We will conduct follow-up analyses stratified by sex and by dosage level. Of note, a critical characteristic of the Kaiser Permanente population is that it is much more balanced on sex distribution than the VA population, which is ~10% female, making analyses of sex-specific medication effects more feasible and therefore overcoming a known limitation of the parent grant. This proposal is within the scope of the aims from the original parent grant. We believe it is consistent with the following NIAAA criteria for administrative supplements: “Addition of patients, populations… due to… a need for statistically significant data…” and “Increased cost of equipment and related services, e.g., data analysis…” Of note, the Kaiser Permanente team includes Dr. Stacy Sterling (Co-Director) and Ms. Vanessa Palzes, lead Statistical Analyst, from the Center for Addiction and Mental Health Research within the Kaiser Division of Research. This team has worked closely with Dr. Lorenzo Leggio (Collaborator on the R01), recently publishing in Neuropsychopharmacology a propensity-score analysis of the effect of spironolactone on alcohol consumption. In summary, the proposed additional analyses are highly feasible and will significantly strengthen findings from the parent R01.

PROJECT NARRATIVE This proposal seeks to organize genes that have been linked to alcohol-related phenotypes into biological modules to elucidate novel pathways implicated in alcohol use and alcohol use disorder. The proposal will then explore drug-protein interactions with these implicated targets to identify promising drugs for repurposing to treat alcohol use disorder. Finally, the study will leverage access to the entire Veterans Affairs electronic health records to explore if the impact of exposure to any of these drugs leads to improvements in alcohol use disorder and thus justifies follow-up testing in clinical trials for potential repurposing.