BackgroundHydrocodone and oxycodone are widely used for acute postoperative pain and are metabolized by CYP2D6 to more potent agonists. The clinical impact of CYP2D6 metabolizer status on hydrocodone and oxycodone analgesic response remains uncertain. This secondary analysis of A Depression and Opioid Pragmatic Trial in Pharmacogenetics (ADOPT PGx) evaluated associations between CYP2D6 phenotype and postoperative pain and opioid consumption among patients taking hydrocodone or oxycodone.MethodsThis analysis included participants from the ADOPT PGx Acute Pain Trial (NCT05966129). Among patients who consumed hydrocodone or oxycodone postoperatively, analyses were conducted separately by drug, comparing outcomes between poor (PM) vs. normal (NM) and intermediate (IM) vs. normal CYP2D6 metabolizers, with phenotypes predicted by genotype and concomitant CYP2D6 inhibitor use. A positive control analysis was performed among tramadol users. Outcomes were cumulative opioid use (morphine milligram equivalents) and composite Patient-Reported Outcomes Measurement Information System® pain intensity scores at 10 days post-surgery. Regression models adjusted for demographics, surgery type, trial site, and non-opioid analgesic use; P-values were corrected for multiple comparisons.ResultsThe cohort primarily underwent orthopedic procedures and concomitant non-opioid analgesic use was common across hydrocodone, oxycodone, and tramadol cohorts, with 88%–100% of patients receiving at least one non-opioid analgesic or nerve block. Among hydrocodone users, predicted CYP2D6 phenotype was not associated with postoperative hydrocodone consumption (PM vs. NM: mean ratio [MR] = 1.12, 95% CI 0.92–1.36, P = 0.262) or pain intensity (PM vs. NM: odds ratio [OR] = 1.13, 95% CI 0.66–1.92, P = 0.668). Among oxycodone users, CYP2D6 phenotype was not associated with postoperative oxycodone consumption (PM vs. NM: MR = 1.02, 95% CI 0.79–1.34, P = 0.880) or pain intensity (PM vs. NM: OR = 0.84, 95% CI 0.47–1.51, P = 0.568). Similarly, in the positive control tramadol cohort, CYP2D6 phenotype was not associated with tramadol consumption (PM vs. NM: MR = 1.02, 95% CI 0.79–1.32, P = 0.847) or pain intensity (PM vs. NM: OR = 1.43, 95% CI 0.66–3.00, P = 0.668).ConclusionPredicted CYP2D6 metabolizer status was not associated with postoperative pain control or opioid use in patients taking hydrocodone, oxycodone, or positive-control tramadol, suggesting that multimodal analgesic use may have weakened pharmacogenetic effects. These findings suggest that CYP2D6 phenotype associations with hydrocodone or oxycodone analgesic response, if present, are attenuated in multimodal postoperative pain management.

Importance:Oxycodone and hydrocodone are the most frequently prescribed opioids for postoperative joint arthroplasty pain, yet comparative effectiveness data remain limited. Objective:To compare postoperative pain outcomes and opioid consumption for hydrocodone vs oxycodone among patients undergoing elective joint arthroplasty. Design, Setting, and Participants:This cohort study was a preplanned secondary analysis of a randomized clinical trial conducted among cytochrome P450 2D6 (CYP2D6) normal metabolizers (NMs) who underwent elective joint arthroplasty in 5 US surgery clinical sites from March 2021 to September 2023 and received hydrocodone or oxycodone postoperatively. Follow-up concluded in March 2024. Data analysis was conducted from October 2024 to December 2025. Exposure:Postoperative analgesia with hydrocodone or oxycodone within a multimodal pain management approach (opioids and nonopioids). Main Outcomes and Measures:Coprimary outcomes were composite pain score at postoperative day 10 (sum of current, worst, and mean pain over 7 days; range 3-15) and cumulative morphine milligram equivalents (MMEs) over 10 days. Secondary outcomes included mobility scores at day 10 and Patient-Reported Outcomes Measurement Information System anxiety and depression scores at day 30. Multivariable regressions were adjusted for demographic and clinical covariates. Results:Among 663 participants (mean [SD] age, 66 [10.6] years; 384 [57.9%] female), 217 received oxycodone and 446 received hydrocodone. Hydrocodone was associated with significantly lower composite pain scores compared with oxycodone (mean [SD], 9.0 [2.0] vs 9.3 [2.2]; adjusted P = .001) and significantly lower cumulative MME (mean [SD], 93.5 [159.3] vs 154.5 [121.6]; adjusted P < .001). Secondary outcomes did not differ between groups (mobility score: mean [SD], 26.3 [10.4] vs 30.9 [14.7]; P = .29; anxiety score: mean [SD], 45.4 [8.3] vs 45.5 [8.7]; P = .31; depression score: mean [SD], 43.8 [7.8] vs 44.0 [7.9]; P = .97). Findings were consistent in sensitivity analyses, restricting to opioid and acetaminophen combinations, restricting to sites prescribing both opioids, and in subgroups of knee arthroplasty, but not consistent in hip arthroplasty. Conclusions and Relevance:In this cohort study of CYP2D6 NMs undergoing joint arthroplasty, within multimodal analgesia, hydrocodone provided comparable pain control to oxycodone with significantly lower opioid exposure, supporting its use as a viable and possibly preferable analgesic option.

Importance Apolipoprotein L1 locus ( APOL1 ) high-risk alleles are associated with incidence of chronic kidney disease (CKD) among people with African ancestry. Few studies have examined the effect of genetic return of results on blood pressure (BP) management and control. Objective To determine whether providing APOL1 high-risk genotype results to people with hypertension and their clinicians would reduce systolic BP (SBP) and improve CKD screening and diagnosis. Design, Setting, and Participants From July 1, 2020, to September 30, 2023, adults aged 18 to 70 years with hypertension and self-reported African ancestry were enrolled at 14 institutions and 54 clinical sites across the US. Eligible patients either (1) lacked diagnoses of diabetes and CKD or (2) had a diagnosis of CKD with or without diabetes. Interventions Participants were randomized to receive APOL1 genotype results immediately (intervention) or 6 months after enrollment (control). Clinical decision support encouraged appropriate CKD screening, diagnosis, and antihypertensive therapy. Main Outcomes and Measures The primary outcome was change in SBP in individuals with APOL1 high-risk allelles at 3 months, assessed in a modified intention-to-treat analysis. Prespecified per-protocol subgroup analyses included those with uncontrolled BP (baseline SBP ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg), uncontrolled BP while receiving antihypertensive therapy, and CKD at enrollment. Secondary outcomes included urine microalbumin screening and new CKD diagnoses. Results Of 6754 individuals recruited (mean [SD] age, 55.3 [10.3] years; 4310 women [63.8%]), 954 (14.1%; mean [SD] age, 54.9 [10.0] years; 600 women [62.9%]) had 2 APOL1 risk alleles. At 3 months, there was no difference in SBP between the intervention and control groups (between-group difference, −0.3 mm Hg [95% CI, −2.7 to 2.1 mm Hg]). Among 377 individuals with uncontrolled BP, the mean SBP change was −4.1 mm Hg (95% CI, −7.7 to −0.5 mm Hg) more in the intervention group than the control group ( P = .004). SBP improvement was also observed for the intervention in the subgroup of patients with uncontrolled BP receiving antihypertensive therapy (SPB difference, −4.3 mm Hg [95% CI −8.0 to −0.5 mm Hg]; P = .004), but not the CKD subgroup (SPB difference, 0.8 mm Hg [95% CI, −3.0 to 4.5 mm Hg]). Provision of APOL1 genotype led to increased urine microalbumin screening (between-group difference, 17.3% [95% CI, 9.6%-24.9%]; P < .001) and CKD diagnoses (between-group difference, 5.7% [95% CI, 2.2%-9.3%]; P = .002) at 6 months. Conclusions and Relevance Provision of APOL1 genotype high-risk results to participants and clinicians was not associated with SBP reduction overall. Among the subset of patients with uncontrolled BP, the intervention group had a significant SBP reduction. APOL1 disclosure also increased the rate of CKD screening and diagnosis. Effects of reporting APOL1 genotype merit further investigation among those with uncontrolled BP. Trial Registration ClinicalTrials.gov Identifier: NCT04191824

Importance:Apolipoprotein L1 locus (APOL1) high-risk alleles are associated with incidence of chronic kidney disease (CKD) among people with African ancestry. Few studies have examined the effect of genetic return of results on blood pressure (BP) management and control. Objective:To determine whether providing APOL1 high-risk genotype results to people with hypertension and their clinicians would reduce systolic BP (SBP) and improve CKD screening and diagnosis. Design, Setting, and Participants:From July 1, 2020, to September 30, 2023, adults aged 18 to 70 years with hypertension and self-reported African ancestry were enrolled at 14 institutions and 54 clinical sites across the US. Eligible patients either (1) lacked diagnoses of diabetes and CKD or (2) had a diagnosis of CKD with or without diabetes. Interventions:Participants were randomized to receive APOL1 genotype results immediately (intervention) or 6 months after enrollment (control). Clinical decision support encouraged appropriate CKD screening, diagnosis, and antihypertensive therapy. Main Outcomes and Measures:The primary outcome was change in SBP in individuals with APOL1 high-risk allelles at 3 months, assessed in a modified intention-to-treat analysis. Prespecified per-protocol subgroup analyses included those with uncontrolled BP (baseline SBP ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg), uncontrolled BP while receiving antihypertensive therapy, and CKD at enrollment. Secondary outcomes included urine microalbumin screening and new CKD diagnoses. Results:Of 6754 individuals recruited (mean [SD] age, 55.3 [10.3] years; 4310 women [63.8%]), 954 (14.1%; mean [SD] age, 54.9 [10.0] years; 600 women [62.9%]) had 2 APOL1 risk alleles. At 3 months, there was no difference in SBP between the intervention and control groups (between-group difference, -0.3 mm Hg [95% CI, -2.7 to 2.1 mm Hg]). Among 377 individuals with uncontrolled BP, the mean SBP change was -4.1 mm Hg (95% CI, -7.7 to -0.5 mm Hg) more in the intervention group than the control group (P = .004). SBP improvement was also observed for the intervention in the subgroup of patients with uncontrolled BP receiving antihypertensive therapy (SPB difference, -4.3 mm Hg [95% CI -8.0 to -0.5 mm Hg]; P = .004), but not the CKD subgroup (SPB difference, 0.8 mm Hg [95% CI, -3.0 to 4.5 mm Hg]). Provision of APOL1 genotype led to increased urine microalbumin screening (between-group difference, 17.3% [95% CI, 9.6%-24.9%]; P < .001) and CKD diagnoses (between-group difference, 5.7% [95% CI, 2.2%-9.3%]; P = .002) at 6 months. Conclusions and Relevance:Provision of APOL1 genotype high-risk results to participants and clinicians was not associated with SBP reduction overall. Among the subset of patients with uncontrolled BP, the intervention group had a significant SBP reduction. APOL1 disclosure also increased the rate of CKD screening and diagnosis. Effects of reporting APOL1 genotype merit further investigation among those with uncontrolled BP. Trial Registration:ClinicalTrials.gov Identifier: NCT04191824.

Background:Opioid use disorder (OUD) is heritable, yet most genome-wide association studies (GWAS) have focused on European populations, leaving the genetic architecture of OUD in non- European populations underexplored. Methods:We conducted GWAS of OUD across three ancestries using electronic health records and genomic data from 52,357 All of Us Research Program participants (8,912 cases; 43,445 matched opioid-exposed controls; 48.5% female). Participants were stratified into European (EUR), African (AFR), and Admixed American (AMR) ancestry groups for logistic regression GWAS, with independent replication in the Million Veteran Program. We then applied the deep- learning model AlphaGenome to predict the tissue-specific transcriptomic and splicing consequences of top risk variants across 13 reward-pathway brain regions. Results:We identified and replicated a novel DDX6 risk locus, alongside established OPRM1 and FURIN signals. AlphaGenome predicted the DDX6 regulatory allele downregulates the stress-resistance gene FOXR1 in the nucleus accumbens, while the protective OPRM1 variant (rs1799971) upregulates OPRM1 expression across reward networks. Other signals of interest included IL6R and SHISA9 (EUR); GHR (AFR); and ASTN2 (AMR). Conclusions:This study identifies DDX6 as a novel OUD risk locus, replicates associations with OPRM1 and FURIN , and highlights biologically plausible ancestry-specific signals in AFR and AMR populations. We also replicated top variants in an independent population. Finally, integrating GWAS with deep-learning annotations provides specific, localized biological hypotheses to guide future experimental validation and targeted therapeutics.

Importance:The effectiveness of pharmacogenetics to guide prescribing of selective serotonin reuptake inhibitors (SSRIs) for depression remains unclear, despite the well-established association between SSRI pharmacokinetics and genetic variation. Objective:To determine whether pharmacogenetic-guided prescribing of SSRIs improves treatment response in patients with depression. Design, Setting, and Participants:The ADOPT PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) Depression pragmatic randomized clinical trial was conducted from August 10, 2021, through April 27, 2024, at primary care, psychiatry, or family medicine clinics at enrolling sites throughout the US. Patients were aged 8 years or older and had experienced depression for 3 months or longer. Intervention:Patients were randomized to genotype-guided SSRI prescribing (intervention group) or usual care (control group). Actionable drug metabolism phenotypes were defined as those for which pharmacogenetic clinical guidelines recommend alternative medication selection or dose adjustment. Main Outcomes and Measures:The primary outcome was change in Patient-Reported Outcomes Measurement Information System (PROMIS) depression T scores at 3 months among patients with the actionable phenotype. Secondary end points included adverse effect severity of SSRIs at 3 months and depression remission (measured with PROMIS depression scores and Patient Health Questionnaire-8 [PHQ-8] scores) at 6 months. Results:This study of 1460 patients included 1239 adults (84.9%) (mean [SD] age, 40.6 [16.7] years) and 221 children (15.1%) (mean [SD] age, 14.6 [1.8] years). Most patients were female (1096 [75.1%]). A total of 692 patients (47.4%) had an actionable phenotype; 351 (50.7%) were assigned to the intervention, and 341 (49.3%) were assigned to usual care. At baseline, 463 of the 692 patients (66.9%) reported having depressive symptoms for more than 2 years, 603 (87.1%) were receiving pharmacologic treatment, and 354 (51.2%) were receiving nonpharmacologic treatment. At 3 months, no significant differences were observed between the intervention and usual care groups in change in PROMIS depression T scores (mean [SD] change, -4.3 [8.4] vs -4.0 [8.1]; P = .68), medication adverse effect burden (mean [SD] change, 8.2 [4.3] vs 7.8 [4.5]; P = .37), or Patient Health Questionnaire-8 score change (mean [SD] change, -3.3 [5.2] vs -2.7 [4.8]; P  = .13). However, at 6 months, the PROMIS depression T-score remission rate (score ≤16) was higher in the intervention group compared with the usual care group (153 of 317 patients [48.3%] vs 122 of 310 patients [39.4%]; P = .02). Conclusions and Relevance:In this randomized clinical trial, genotype-guided prescribing of SSRIs did not improve control of depression symptoms at 3 months compared with usual care but was associated with higher depression remission rates at 6 months. These findings suggest a possible longer-term clinical benefit and indicate that future studies should focus on the durability and long-term impact of genotype-guided prescribing in the management of depressive symptoms. Trial Registration:ClinicalTrials.gov Identifiers: NCT04445792 (Master Protocol Research Program platform trial) and NCT05966155 (ADOPT PGx Depression trial).

QuestionDoes pharmacogenetic-guided prescribing of selective serotonin reuptake inhibitors (SSRIs) improve treatment response in patients with depression?FindingsIn this randomized clinical trial of 1460 adults and children, analyses were conducted among those with an actionable drug metabolism phenotype. In this group, genotype-guided management using validated, publicly available guidelines for SSRI prescribing did not improve depression symptom scores at 3 months compared with usual care, but remission rates between 3 and 6 months were higher.MeaningThe higher remission rates observed at 6 months in this trial suggest a potential longer-term benefit that warrants further study. This randomized clinical trial investigates whether pharmacogenetic-guided prescribing of selective serotonin reuptake inhibitors (SSRIs) improves treatment response in patients with depression. ImportanceThe effectiveness of pharmacogenetics to guide prescribing of selective serotonin reuptake inhibitors (SSRIs) for depression remains unclear, despite the well-established association between SSRI pharmacokinetics and genetic variation.ObjectiveTo determine whether pharmacogenetic-guided prescribing of SSRIs improves treatment response in patients with depression.Design, Setting, and ParticipantsThe ADOPT PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) Depression pragmatic randomized clinical trial was conducted from August 10, 2021, through April 27, 2024, at primary care, psychiatry, or family medicine clinics at enrolling sites throughout the US. Patients were aged 8 years or older and had experienced depression for 3 months or longer.InterventionPatients were randomized to genotype-guided SSRI prescribing (intervention group) or usual care (control group). Actionable drug metabolism phenotypes were defined as those for which pharmacogenetic clinical guidelines recommend alternative medication selection or dose adjustment.Main Outcomes and MeasuresThe primary outcome was change in Patient-Reported Outcomes Measurement Information System (PROMIS) depression T scores at 3 months among patients with the actionable phenotype. Secondary end points included adverse effect severity of SSRIs at 3 months and depression remission (measured with PROMIS depression scores and Patient Health Questionnaire-8 [PHQ-8] scores) at 6 months.ResultsThis study of 1460 patients included 1239 adults (84.9%) (mean [SD] age, 40.6 [16.7] years) and 221 children (15.1%) (mean [SD] age, 14.6 [1.8] years). Most patients were female (1096 [75.1%]). A total of 692 patients (47.4%) had an actionable phenotype; 351 (50.7%) were assigned to the intervention, and 341 (49.3%) were assigned to usual care. At baseline, 463 of the 692 patients (66.9%) reported having depressive symptoms for more than 2 years, 603 (87.1%) were receiving pharmacologic treatment, and 354 (51.2%) were receiving nonpharmacologic treatment. At 3 months, no significant differences were observed between the intervention and usual care groups in change in PROMIS depression T scores (mean [SD] change, -4.3 [8.4] vs -4.0 [8.1]; P = .68), medication adverse effect burden (mean [SD] change, 8.2 [4.3] vs 7.8 [4.5]; P = .37), or Patient Health Questionnaire-8 score change (mean [SD] change, -3.3 [5.2] vs -2.7 [4.8]; P = .13). However, at 6 months, the PROMIS depression T-score remission rate (score <= 16) was higher in the intervention group compared with the usual care group (153 of 317 patients [48.3%] vs 122 of 310 patients [39.4%]; P = .02).Conclusions and RelevanceIn this randomized clinical trial, genotype-guided prescribing of SSRIs did not improve control of depression symptoms at 3 months compared with usual care but was associated with higher depression remission rates at 6 months. These findings suggest a possible longer-term clinical benefit and indicate that future studies should focus on the durability and long-term impact of genotype-guided prescribing in the management of depressive symptoms.Trial RegistrationClinicalTrials.gov Identifiers: NCT04445792 (Master Protocol Research Program platform trial) and NCT05966155 (ADOPT PGx Depression trial)

Tramadol is frequently co-prescribed with oxycodone or hydrocodone after surgery under the assumption that its dual mechanism of action provides an opioid-sparing benefit. However, evidence supporting this practice is limited and inconsistent. We conducted a secondary analysis of the multicenter IGNITE ADOPT-PGx pragmatic trial of patients undergoing elective surgery who were prescribed oxycodone alone (n = 317) versus tramadol + oxycodone (n = 96), or hydrocodone alone (n = 563) versus tramadol + hydrocodone (n = 42). Co-primary outcomes of this study were cumulative morphine milligram equivalents (MME) consumed during the 10 days following surgery and composite pain scores at day 10 defined as the sum of current pain and average and worst pain in the past 7 days (score ranges from 3 to 15). Inverse probability of treatment weighting (IPTW) was used to adjust for demographic characteristics, comorbidities, and concomitant analgesics. Sensitivity analyses restricted to CYP2D6 normal metabolizers and sites prescribing both monotherapy and combination therapy and subgroup analysis including total knee arthroplasty patients were conducted. Compared to oxycodone alone, the combination of oxycodone and tramadol was associated with higher MME (adjusted mean 205.2 vs 122.5; P < 0.0001) and lower mobility, without meaningful differences in pain scores (adjusted mean 9.6 vs 9.4; P = 0.41). Similar findings were observed for hydrocodone-only vs hydrocodone + tramadol groups. Results were consistent in sensitivity and subgroup analyses. Co-administration of tramadol with oxycodone or hydrocodone was associated with substantially higher total MME and reduced mobility without any demonstrable improvement in pain control.

Will clinical translational pharmacology (CTP) seize the opportunity to become a leadership discipline driving the next era of patient-centered therapeutics? This white paper, based on input and discussion from the ASCPT Summit on the Future of Clinical Translational Pharmacology, issues a bold call to action for CTP to define itself as a discipline that embraces its multidisciplinary breadth, demanding a radical shift that visibly inhabits the full scope of its multitudinous identity. We propose a five-priority roadmap-Foundational Principles, Workforce and Leadership, Innovation and Technology, Health Equity and Global Health, and Public Visibility and Scientific Trust-to transform CTP into an engine of therapeutic advancement and optimization. The future of medicine depends on CTP's ability to lead, adapt, influence, and unify across silos, ensuring that scientific breakthroughs translate into real-world benefit for every patient, everywhere. The next decade demands urgency, unity, and unapologetic ambition to move beyond incremental change.

Importance:Individuals with genetic variation that results in absent (poor metabolizers) or reduced (intermediate metabolizers) cytochrome P450 2D6 (CYP2D6) enzyme activity have lower concentrations of highly potent active metabolites of tramadol, hydrocodone, and codeine and are thus at increased risk for inadequate pain control. Objective:To determine the effect of CYP2D6-guided opioid prescribing on postoperative pain and opioid use. Design, Setting, and Participants:This open-label randomized clinical trial enrolled participants from surgery clinics at 8 US health systems. Individuals undergoing a planned surgery anticipated to cause postoperative pain for at least 7 to 10 days were enrolled from March 2021 to September 2023, with follow-up concluded in March 2024. Intervention:Participants in the CYP2D6-guided arm underwent CYP2D6 genotyping before surgery, with recommendations to avoid tramadol, hydrocodone, and codeine for postoperative pain in CYP2D6 poor and intermediate metabolizers, as defined by genotype and use of CYP2D6 inhibitors. Participants in the control arm had usual pain management. Main Outcomes and Measures:The primary outcome was the 10-day Silverman integrated analgesic assessment (SIA) score, a rank-based composite measure of average pain intensity on a 10-point scale, with higher scores indicating greater pain and opioid use (in morphine milligram equivalents [MMEs]). Secondary end points included individual components of the primary outcome and concordance between metabolizer phenotype and prescribed opioid 10 days after surgery. The primary analysis compared outcomes between poor and intermediate metabolizers in the CYP2D6-guided arm vs the control study arm. The analytical population comprised the subset of intent-to-treat participants with an actionable phenotype who completed surgery. Results:Of 1602 participants enrolled, 351 (mean [SD] age, 62 [13] years; 237 [68%] female) had a CYP2D6 poor or intermediate metabolizer phenotype, proceeded to surgery, and were randomized to the CYP2D6-guided (n = 176) or control (n = 175) study arm. The most common procedures in the actionable population were total knee (177 [50%]) and total hip (97 [28%]) arthroplasties. Concordance between postsurgical opioid treatment and CYP2D6 phenotype was 64% (n = 112) in the CYP2D6-guided arm and 27% (n = 47) in the control arm (difference, 37 [95% CI, 27-46] percentage points; P < .001). At 10 days, the mean (SD) SIA score was 1.4 (95.9) in the CYP2D6-guided arm and -1.4 (93.1) in the control arm (difference, 2.8 [95% CI, -18.3 to 23.8]; P = .80). Mean (SD) numeric pain intensity rating (5.2 [2.2] and 5.1 [2.3]), overall opioid use (13.7 [14.9] and 13.2 [14.7] MME/d), and other secondary end points did not differ between the CYP2D6-guided arm and the control arm. Conclusions and Relevance:In this randomized clinical trial of CYP2D6-guided postoperative opioid prescribing, there were significant prescribing changes in CYP2D6 poor and intermediate metabolizers but no differences in pain control compared with usual care. The data do not support a role for CYP2D6-guided opioid therapy in the contemporary postoperative setting of multimodal pain management. Trial Registration:ClinicalTrials.gov Identifier: NCT05966129.

Pharmacogenetic variation is common and an established driver of response for many drugs. There has been tremendous progress in pharmacogenetics knowledge over the last 30 years and in clinical implementation of that knowledge over the last 15 years. But there have also been many examples where translation has stalled because of the lack of available data sets for discovery or validation research. The recent availability of data from very large cohorts with linked genetic, electronic health record, and other data promises new opportunities to advance pharmacogenetics research. This review presents the stages from pharmacogenetics discovery to widespread clinical adoption using prominent gene-drug pairs that have been implemented into clinical practice as examples. We discuss the opportunities that the All of Us Research Program and other large biorepositories with genomic and linked electronic health record data present in advancing and accelerating the translation of pharmacogenetics into clinical practice.

AbstractGenetics plays an important role in the response to some drugs. Clinical pharmacogenetic testing can be used to guide pharmacotherapy selection or dosing to optimize outcomes. Growing evidence over the past decade has led to the identification of numerous pharmacogenetic associations, which have been integrated across multiple clinical areas, including cardiology, primary care, pain management, surgery, and oncology. Increased access to pharmacogenetic testing via national laboratories and pharmacogenetic testing companies has facilitated uptake and heightened public interest. While clinical adoption of pharmacogenetics has increased, challenges remain, including a lack of clinician confidence in navigating the logistics of testing and applying pharmacogenetics results in patient care; limited reimbursement for testing in some cases; the need for extensive outcomes and economic data; and limited inclusion of testing in clinical guidelines. Future opportunities include the broader use of multigene panels, enhanced clinician training, the integration of pharmacogenetic data within electronic health records, and increased documentation of outcomes data from real-world implementation to support insurance coverage.

Re-triage is the emergent inter-hospital transfer of severely injured patients from non/low-level to high-level trauma centers. The aim was to apply user-centered design to develop a robust, acceptable, and feasible solution to improve the re-triage process. The mixed methods, observational, cross-sectional study applied the 5 phases of a user-centered design approach, including Phase 1: Understanding the design needs, through site visit observations and virtual focus groups; Phase 2: Ideation of potential solutions through a second round of virtual focus groups; Phase 3: Rank Ordering solutions to identify the most robust, acceptable, and potentially feasible solutions; Phase 4: Prototyping by creating low-fidelity prototypes for the highest-ranked solutions; and Phase 5: Validation of the robustness of the prototypes through virtual focus groups. All virtual sessions were recorded, transcribed, and inductively coded to generate themes of robustness, acceptability, and feasibility of the re-triage solution. Thematic analysis was anchored on the Desirability, Viability, and Feasibility Design Thinking Methodology. A total of 19 sessions were conducted across all 5 phases with 49 participants from 12 trauma centers across Illinois. Participants included front-line users and leadership. The key design requirement was resource transparency between centers. The ideation phase produced 70 solutions. A systemwide bed-tracker was ranked the highest by participants. Protoyping and validation resulted in a centralized, systemwide, bed-tracker with hourly updated bed availability being the final solution to improve the re-triage of trauma patients from non-trauma/low-level and high-level trauma centers. A 5 phase user-centered design approach resulted in a single solution consisting in a centralized bed-tracker of available beds at high-level trauma centers to improve re-triage.

African Americans (AAs) are underrepresented in pharmacogenomics which has led to a significant gap in knowledge. AAs are admixed and can inherit specific loci from either their African or European ancestor, known as local ancestry (LA). A previous study in AAs identified single nucleotide polymorphisms (SNPs) located in the CYP2C cluster that are associated with warfarin dose. However, LA was not considered in this study. An IWPC cohort (N=340) was used to determine the LA-adjusted association with warfarin dose. Ancestry-specific GWAS's were conducted with TRACTOR and ancestry tracts were meta-analyzed using METAL. We replicated top associations in the independent ACCOuNT cohort of AAs (N=309) and validated associations in a warfarin pharmacokinetic study in AAs. To elucidate functional roles of top associations, we performed short-read RNA-sequencing from AA hepatocytes carrying each genotype for expression of CYP2C9 and CYP2C19. We identified 6 novel genome-wide significant SNPs (P<5E-8) in the CYP2C locus (lead SNP, rs7906871 (P=3.14E-8)). These associations were replicated (P≤2.76E-5) and validated with a pharmacokinetic association for S-Warfarin concentration in plasma (P=0.048). rs7906871 explains 6.0% of the variability in warfarin dose in AAs. Multivariate regression including rs7906871, previously associated SNPs, clinical and demographic factors explain 37% of dose variability, greater than previously reported studies in AAs. RNA-seq data in AA hepatocytes identified a significant alternate exon inclusion event between exons 6 and 7 in CYP2C19 for carriers of rs7906871. In conclusion, we have found and replicated a novel CYP2C variant associated with warfarin dose requirement and potential functional consequences to CYP2C19.

Importance:Cytochrome P450 2D6 (CYP2D6) bioactivates hydrocodone, tramadol, codeine, and oxycodone to active metabolites that primarily provide analgesic activity. Reduced CYP2D6 activity may be associated with poor pain control. Objective:To evaluate associations of impaired CYP2D6 activity based on genotype or CYP2D6 inhibitors, alone and together, with analgesic activity of CYP2D6-metabolized opioids among patients with pain. Design, Setting, and Participants:This retrospective national, community-based cohort study used electronic health records and genetics data from the All of Us Research Program. Participants included adults prescribed at least 1 CYP2D6-metabolized opioid for more than 7 days between January 1, 2014, and December 31, 2022, with whole-genome sequencing data available. Analysis groups were defined by CYP2D6 phenotype, which was determined based on CYP2D6 genotype or CYP2D6 inhibitor-mediated phenoconversion. Statistical analysis was performed from July 1, 2023, to January 15, 2025. Exposures:CYP2D6-metabolized opioids, with or without concomitant CYP2D6 inhibitor exposure, based on prescription records and overlap with opioids. Main Outcomes and Measures:The primary outcome was occurrence of any pain-related emergency department (ED) visits during opioid treatment, up to 60 days after opioid initiation. The association between ED visits and CYP2D6 phenotype was assessed using inverse probability treatment weighting-adjusted logistic regression. Additional analyses were conducted by drug and isolating CYP2D6 genotype and inhibitors. Results:Among 31 669 patients (mean [SD] age, 51.2 [15.4] years; 66.5% women) prescribed CYP2D6-metabolized opioids, 15 960 had reduced CYP2D6 activity, and 15 709 had normal or high CYP2D6 activity based on genotype and inhibitors. A higher percentage of patients with reduced CYP2D6 activity (hereafter referred to as phenotypic intermediate metabolizers [pIMs] or phenotypic poor metabolizers [pPMs]) had experienced pain-related ED visits compared with patients with normal or high CYP2D6 activity (phenotypic normal metabolizers [pNMs] and phenotypic ultrarapid metabolizers [pUMs]) (2.1% vs 1.8%; inverse probability-weighted odds ratio, 1.19; 95% CI, 1.06-1.33). There were no significant differences in ED visits among CYP2D6 genotypic IMs or PMs vs NMs or UMs when testing all 4 drugs together. Among genotypic NMs, ED visits were more frequent among the individuals prescribed CYP2D6 inhibitors (inverse probability-weighted odds ratio, 1.49; 95% CI, 1.32-1.68). In analyses by medication, drug interactions were important for all 4 medications, while genotype associations were significant only for hydrocodone, tramadol, and codeine. Conclusions and Relevance:In this cohort study, reduced CYP2D6 activity was associated with increased ED visits among individuals treated with CYP2D6-metabolized opioids. This finding suggests that incorporating data on CYP2D6 genotype and accounting for drug interactions in opioid prescribing may improve pain management and reduce ED visits.

Tacrolimus is an immunosuppressive agent with difficult dosing due to a narrow therapeutic index and large interpatient pharmacokinetic variability, for which CYP3A5 variation plays a role. Tacrolimus/CYP3A5 pharmacogenetic guidelines exclude liver transplant patients with a donor/recipient CYP3A5 mismatch. We sought to determine the influence of donor vs. recipient CYP3A5 genotype early post-transplant and evaluate tacrolimus dosing strategies in liver transplant recipients with various recipient/donor CYP3A5 genotype combinations. This was a single-center, retrospective analysis of 58 prospectively enrolled adult liver transplant patients prescribed tacrolimus post-transplant, with donor and recipient CYP3A5 genotype data, which were categorized as recipient expresser (RE) or nonexpresser (RN) and donor expresser (DE) or nonexpresser (DN). Patients were stratified as REDE, REDN, RNDN, or RNDE with comparisons across groups. Prediction error (PE) based on predicted versus actual therapeutic dose was calculated for eight published dosing methods. Donor/recipient genotype was mismatched in 41% of liver transplant recipients. Weight-adjusted total daily dose for first therapeutic tacrolimus concentration was significantly different across CYP3A5 combinations, with recipient expressors requiring the highest doses (REDE 0.15 mg/kg/day, REDN 0.19 mg/kg/day, RNDE 0.12 mg/kg/day, RNDN 0.09 mg/kg/day, p = 0.006). Of the eight dosing methods analyzed, two performed with < 2% PE overall, and ≤ 20% PE for all four genotype combinations: one included recipient genotype only; the other included donor and recipient genotype. Collectively, our findings suggest recipient CYP3A5 genotype may be more important than donor genotype in the immediate post-liver transplant period for predicting optimal tacrolimus dosing to achieve therapeutic trough concentrations.

INTRODUCTION:Fentanyl overdose is a public health crisis in the United States, as fentanyl was implicated in nearly 70% of drug overdose deaths in 2023. To provide insight into genetic factors that may influence risk of fentanyl overdose, we conducted a scoping review of associations between cytochrome P450 3A4 (CYP3A4) and 3A5 (CYP3A5) genetic variants and relevant phenotypes. AREAS COVERED:We searched databases through August 2025 for peer-reviewed studies of human subjects or postmortem samples, and integrated evidence from 64 genetic association studies that analyzed single nucleotide polymorphisms in CYP3A4 or CYP3A5. We considered a diverse range of phenotypes relevant to fentanyl overdose, including opioid overdose, fentanyl pharmacokinetics and pharmacodynamics, opioid use (disorder), and pharmacotherapy response. EXPERT OPINION AND COMMENTARY:Evidence from 64 studies suggested that the no-function CYP3A5 * 3 (rs776746) allele contributes to increased fentanyl overdose risk, with strongest support coming from studies of fentanyl pharmacokinetics in clinical settings. There was less robust evidence for the role of CYP3A4 variants (e.g. rs2242480). Future research should prioritize prospective genotyping of at-risk populations, development of models that integrate pharmacogenetics with psychiatric genetics, and large-scale harmonization of relevant datasets.

Tramadol, the 41st most prescribed drug in the United States in 2021 is a prodrug activated by CYP2D6, which is highly polymorphic. Previous studies showed enzyme-inhibitor affinity varied between different CYP2D6 allelic variants with dextromethorphan and atomoxetine metabolism. However, no study has compared tramadol metabolism in different CYP2D6 alleles with different CYP2D6 inhibitors. We hypothesize that the inhibitory effects of CYP2D6 inhibitors on CYP2D6-mediated tramadol metabolism are inhibitor- and CYP2D6-allele-specific. We performed comparative analyses of CYP2D6*1, CYP2D6*2, CYP2D6*10, and CYP2D6*17 using recombinant enzymes to metabolize tramadol to O-desmethyltramadol, measured via UPLC-MS/MS. The Michaelis constant (Km) and maximum velocity (Vmax) for each CYP2D6 allele, and IC50 values for different inhibitors were determined by nonlinear regression analysis. Intrinsic clearance was calculated as Vmax/Km. The intrinsic clearance of tramadol was almost double for CYP2D6*2 (180%) but was much lower for CYP2D6*10 and *17 (20% and 10%, respectively) compared to CYP2D6*1. The inhibitor potencies (defined by Ki) for the various inhibitors for the CYP2D6*1 allele were quinidine > terbinafine > paroxetine ≈ duloxetine >>bupropion. CYP2D6*2 showed the next greatest inhibition, with Ki ratios compared to CYP2D6*1 ranging from 0.96 to 3.87. For each inhibitor tested, CYP2D6*10 and CYP2D6*17 were more resistant to inhibition than CYP2D6*1 or CYP2D6*2, with most Ki ratios in the 3-9 range. Three common CYP2D6 allelic variants showed different metabolic capacities toward tramadol and genotype-dependent inhibition compared to CYP2D6*1. Further studies are warranted to understand the clinical consequences of inhibitor and CYP2D6 genotype-dependent drug-drug interactions on tramadol bioactivation.