P310: Polygenic and rare variant contributions to the genetic architecture of familial hypercholesterolemia in a Mexican registry cohort

Introduction: Pharmacogenomics (PGx) is a rapidly developing field that utilizes an individual's genetic profile to establish a personalized medication treatment that best suits their genotype and variance in metabolism.PGx results can reactively or preemptively guide drug selection, dosing adjustment, and avoidance of certain medications and prevent adverse drug reactions (ADRs).A Pharmacogenomics Clinic (PGC) was established in January 2021 at Washington University School of Medicine (WUSM) to meet the expanding demands of PGx testing.The aims of this study were to examine the clinical utility and challenges of implementing PGx testing, determine the diagnostic yield, evaluate change of management, and propose guidelines for the selection of patients who will benefit from PGx testing.Methods: We conducted a retrospective chart review study of the first 100 patients evaluated at our PGC between January 2021 and November 2024.The study was approved by the WUSM Institutional Review Board.The majority of the patients in our cohort had PGx testing, which primarily comprised 25 pharmacogenes selected based on the availability of CPIC guidelines for their related variations.Patient data were extracted from electronic medical records, including demographic information, indications for testing, medication history, lack of insurance, and genetic results.Results: Two-thirds of the patients presented to the clinic were female and 94% of patients were referred from the outpatient setting.The mean age of patients was 26.2 years old (range: 1-79) and 90% identified as non-Hispanic White.The patients were mostly referred from genetics (48%), pediatrics (21%), and family medicine (19%).For patients who were referred to the PGC, the most frequent current diagnoses were anxiety (36%), depression (30%), migraine (20%), and constipation (20%).The most common currently used medications by patients were albuterol (27%), melatonin (23%), cetirizine (19%), and clonidine (17%), none of which have CPIC guidelines.Sertraline was the most often reported medication with ADRs (18%), followed by gabapentin, wellbutrin, guanfacine, and methylphenidate (16% each).Of the patients who presented to the PGC, 72% had never had prior PGx testing.The mean turnaround time for tests ordered by the PGx team was 27.6 days (range: 1 to 142 days).Analysis of PGx results revealed that all patients harbored at least one potentially actionable pharmacogenomic variant (mean: 5.6; range:1-9 per patient).The most frequently observed pharmacogenes with potentially actionable drug response phenotypes were: CYP2C19 (58%), UGT1A1 (57%), CYP2D6 (48%), and CYP2C9 (43%).Preliminary analysis, though incomplete, showed that PGx results led to patient management changes and improved medication selection outcomes.Conclusion: This study demonstrates the feasibility and clinical utility of PGx in a dedicated PGC.All patients in our cohort harbored at least one actionable variant in pharmacogenes including CYP2D6, CYP2C19, and CYP2C9 that are known to be involved in the metabolism of several mediation classes.Our findings suggest that PGx testing can inform medication management decisions and potentially improve patient outcomes.However, several challenges need to be addressed including long turnaround times for test results, high out-of-pocket costs, integrating PGx data into electronic health records, inclusion of underrepresented minorities, and lack of awareness of PGx testing availability.Further research is needed to establish comprehensive guidelines for patient selection and to fully evaluate the long-term impact of PGx-guided therapy on clinical outcomes and medication efficacy.