OBJECTIVES/GOALS: Supported by the State of Alabama, the Alabama Genomic Health Initiative (AGHI) is aimed at preventing and treating common conditions with a genetic basis. This joint UAB Medicine-HudsonAlpha Institute for Biotechnology effort provides genomic testing, interpretation, and counseling free of charge to residents in each of Alabama’s 67 counties. METHODS/STUDY POPULATION: Launched in 2017, as a state-wide population cohort, AGHI (1.0) enrolled 6,331 Alabamians and returned individual risk of disease(s) related to the ACMG SF v2.0 medically actionable genes. In 2021, the cohort was expanded to include a primary care cohort. AGHI (2.0) has enrolled 750 primary care patients, returning individual risk of disease(s) related to the ACMG SF v3.1 gene list and pre-emptive pharmacogenetics (PGx) to guide medication therapy. Genotyping is done on the Illumina Global Diversity Array with Sanger sequencing to confirm likely pathogenic / pathogenic variants in medically actionable genes and CYP2D6 copy number variants using Taqman assays, resulting in a CLIA-grade report. Disease risk results are returned by genetic counselors and Pharmacogenetics results are returned by Pharmacists. RESULTS/ANTICIPATED RESULTS: We have engaged a statewide community (>7000 participants), returning 94 disease risk genetic reports and 500 PGx reports. Disease risk reports include increased predisposition to cancers (n=38), cardiac diseases (n=33), metabolic (n=12), other (n=11). 100% of participants harbor an actionable PGx variant, 70% are on medication with PGx guidance, 48% harbor PGx variants and are taking medications affected. In 10% of participants, pharmacists sent an active alert to the provider to consider/ recommend alternative medication. Most commonly impacted medications included antidepressants, NSAIDS, proton-pump inhibitors and tramadol. To enable the EMR integration of genomic information, we have developed an automated transfer of reports into the EMR with Genetics Reports and PGx reports viewable in Cerner. DISCUSSION/SIGNIFICANCE: We share our experience on pre-emptive implementation of genetic risk and pharmacogenetic actionability at a population and clinic level. Both patients and providers are actively engaged, providing feedback to refine the return of results. Real time alerts with guidance at the time of prescription are needed to ensure future actionability and value.

Oral anticoagulants (OACs) are commonly used to reduce the risk of venous thromboembolism and the risk of stroke in patients with atrial fibrillation. Endorsed by the American Heart Association, American College of Cardiology, and the European Society of Cardiology, direct oral anticoagulants (DOACs) have displaced warfarin as the OAC of choice for both conditions, due to improved safety profiles, fewer drug-drug and drug-diet interactions, and lack of monitoring requirements. Despite their widespread use and improved safety over warfarin, DOAC-related bleeding remains a major concern for patients. DOACs have stable pharmacokinetics and pharmacodynamics; however, variability in DOAC response is common and may be attributed to numerous factors, including patient-specific factors, concomitant medications, comorbid conditions, and genetics. Although DOAC randomized controlled trials included patients of varying ages and levels of kidney function, they failed to include patients of diverse ancestries. Additionally, current evidence to support DOAC pharmacogenetic associations have primarily been derived from European and Asian individuals. Given differences in genotype frequencies and disease burden among patients of different biogeographic groups, future research must engage diverse populations to assess and quantify the impact of predictors on DOAC response. Current under-representation of patients from diverse racial groups does not allow for proper generalization of the influence of clinical and genetic factors in relation to DOAC variability. Herein, we discuss factors affecting DOAC response, such as age, sex, weight, kidney function, drug interactions, and pharmacogenetics, while offering a new perspective on the need for further research including frequently excluded groups.

The Alabama Genomic Health Initiative (AGHI) is a state-supported, IRB-approved research study, that began in 2017 to explore the utility and impact of population-based screening for rare Mendelian disorders, and has helped to serve as a model and platform for other participant-facing programs. Over the last year a new model has been developed that is focused on health care providers, with a primary goal to bring and apply genomic knowledge in a primary care setting.