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PubMed2025

A Complete Picture of the CYP2D6 Heterogeneity in Northeastern Italian Genetic Isolates.

The CYP2D6 gene is a highly polymorphic pharmacogene involved in the metabolism of 25% of commonly used drugs. We aim to assess the feasibility of extracting relevant pharmacogenomic information from Whole Genome Sequencing (WGS) data and to highlight any difference in CYP2D6 allele frequencies between the northeastern Italian and European populations. To achieve this aim, WGS was performed on two cohorts: 664 individuals from six different isolated communities (FIC) and 123 outbred Italian individuals (FOP). In silico CYP2D6 genotyping was performed and allele frequencies from the FIC cohort were compared to those of FOP and European individuals from 1000 Genomes. Interestingly, 18 alleles identified in FIC were absent in the control cohorts. In particular, 13 individuals carried the extremely rare CYP2D6*28x2 allele, whose activity is unknown. Moreover, we identified a carrier of the CYP2D6*34x2 allele, which has never been described before. The population structure and genetic differentiation of the cohorts were investigated, revealing that the genetic isolates differ only slightly from the outbred and the European populations, but still offer new insight into CYP2D6 heterogeneity. The findings described here will be relevant to tailoring the treatments in the northeastern Italian population.

Cytochrome P-450 CYP2D6↗

PubMed2026

Genetic Influence of CYP2D6 on Risperidone Metabolism: Pharmacokinetic and Pharmacodynamic Study in a Healthy South Indian Population.

OBJECTIVE: The CYP2D6*10 allele, which is prevalent in the Indian population, is of particular clinical significance. This study aims to investigate the effect of the CYP2D6*10 allele on the pharmacokinetics of risperidone and its metabolites following single-dose administration in healthy South Indian volunteers. METHODS: The study was conducted with twenty healthy volunteers who were administered a single 2 mg dose of risperidone. CYP2D6 genotyping was performed using the PCR-RFLP method. Plasma levels of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OHRIS) were quantified using a UPLC-DAD system. RESULTS: Significant differences in pharmacokinetic parameters were observed across the CYP2D6*10 genotypes. For intermediate metabolizers, the Cmax, AUC0-t, and T1/2 were approximately 1.2 times higher, and the metabolic ratio was double compared to normal metabolizers. Notably, the Cmax of the active moiety was significantly higher in intermediate metabolizers compared to normal metabolizers (p < 0.05). These findings indicate that CYP2D6 polymorphisms are associated with altered pharmacokinetic profiles of risperidone, with a reduced metabolic activation in individuals carrying the *10 allele. CONCLUSION: The results suggest that CYP2D6 genotyping could help inform personalized dosing strategies for risperidone, though further randomized controlled trials are required to confirm these findings.

Humans↗

PubMed2019

CYP2D6 genotype and adverse events to risperidone in children and adolescents.

BACKGROUND: There are few and conflicting data on the role of cytochrome P450 2D6 (CYP2D6) polymorphisms in relation to risperidone adverse events (AEs) in children. This study assessed the association between CYP2D6 metabolizer status and risk for risperidone AEs in children. METHODS: Children ≤18 years with at least 4 weeks of risperidone exposure were identified using BioVU, a de-identified DNA biobank linked to electronic health record data. The primary outcome of this study was AEs. After DNA sequencing, individuals were classified as CYP2D6 poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. RESULTS: For analysis, the 257 individuals were grouped as poor/intermediate metabolizers (n = 33, 13%) and normal/ultrarapid metabolizers (n = 224, 87%). AEs were more common in poor/intermediate vs. normal/ultrarapid metabolizers (15/33, 46% vs. 61/224, 27%, P = 0.04). In multivariate analysis adjusting for age, sex, race, and initial dose, poor/intermediate metabolizers had increased AE risk (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.1, P = 0.03). CONCLUSION: Children with CYP2D6 poor or intermediate metabolizer phenotypes are at greater risk for risperidone AEs. Pre-prescription genotyping could identify this high-risk subset for an alternate therapy, risperidone dose reduction, and/or increased monitoring for AEs.

Adolescent↗

PubMed2026

A de novo algorithm for allele reconstruction from Oxford nanopore amplicon reads, with application to CYP2D6.

MOTIVATION: The Oxford Nanopore Technologies' sequencing platform offers a path towards bedside genomics, producing long reads that can completely cover a gene of interest, and detect any known or novel variant the gene contains. However, the analysis of these long reads to identify actionable genotypes remains challenging and typically requires customization depending on the target gene. RESULTS: Here, we describe a generic algorithm to accurately reconstruct allele sequences derived from long-reads of amplicon-based data. Rather than calling variants directly from these long-reads, our method takes a "sequence-first" approach, performing an unbiased reconstruction of the underlying amplicon sequences to generate high-confidence reconstructed allele sequences. This is done without user input of the target gene, allowing for any source amplicon to be reconstructed. These high-confidence reconstructed allele sequences are then compared to the genomic reference sequence of the gene to infer the specific diplotype present in the sample. This approach is agnostic towards the number of genes and alleles present and readily detects novel variants. We demonstrate our approach using three independent data sets for CYP2D6, a diverse and complex gene with over 175 known alleles of clinical significance. We show how our approach can accurately recover validated CYP2D6 diplotypes from 20 Coriell samples covering 14 distinct alleles, using different amplicons, flow cell versions, and depths. This includes inferring occurrences of allele duplication events from relative abundances of each allele, a critical factor for ascribing functional effects to a diplotype. Further, we demonstrate our approach's utility for other genomic regions, including HLA. AVAILABILITY: Custom code is available at the following GitHub repository, along with instructions for use and test data: https://github.com/scottdbrown/allele-reconstruction-long-read-amplicon-data. A snapshot of the code at the time of publication is available on Zenodo.org; doi 10.5281/zenodo.19716004. Raw .fastq sequence data for our three sequencing runs is available at the SRA under Bioproject PRJNA1357883 (https://www.ncbi.nlm.nih.gov/bioproject/1357883).

Alleles↗

PubMed2024

Associations between (pharmaco-)genetic markers and postoperative pain after inguinal hernia repair - a prospective study protocol.

BACKGROUND: Postoperative pain is a common complication following surgery, with severity and duration varying between patients. Chronic postoperative pain after inguinal hernia surgery has an incidence rate of approximately 10%. Risk factors for acute and chronic pain following hernia surgery include age, sex, psychosocial factors, and demographic background. Additionally, genetic polymorphisms in enzymes involved in pain mechanisms, as well as the metabolism of analgesics might influence pain perception, pain development, and response to pain medications. Key enzymes include the catechol-o-methyltransferase (COMT), the µ-opioid receptor 1 (OPRM1), and the cytochrome P450 2D6 (CYP2D6). CYP2D6 plays a crucial role in metabolizing analgesics such as tramadol, codeine, and oxycodone. It is also suspected to be involved in the synthesis of catecholamines and endogenous morphines suggesting a potential role in pathophysiology of pain. We hypothesize that the CYP2D6 activity influences the development of postoperative pain after hernia surgery. METHODS: This study is a prospective, observational, multicenter association study investigating adult patients scheduled for inguinal hernia surgery using a robotic-assisted (rTAPP) approach. Patients are enrolled during the preoperative surgical consultation. A buccal swab is collected for genetic testing at this time. Pain at the site of the hernia is assessed using the validated EuraHSQoL score preoperatively and at 2, 4, and 6 weeks postoperatively. Additionally, information on co-medication and details of the surgery will be collected. The planned number of participants is 350 patients. The primary objective is to analyze the association between different genotype-predicted CYP2D6 phenotypes and patient-reported pain intensity 6 weeks after surgery. Secondary objectives include the association between further genetic variants, such as the COMT rs4680 and OPRM1 rs1799971 genotype, and pain severity. Additionally, the potential of pharmacogenetic panel testing to optimize analgesic therapy in hernia surgery patients will be explored. DISCUSSION: The findings of this study are expected to provide valuable insights into identifying patients at higher risk for postoperative pain before surgery. This knowledge could pave the way for tailored interventions during and after surgery for these specific patients. TRIAL REGISTRATION: Deutsches Register Klinischer Studien https://www.drks.de/DRKS00034796 Registered on August 07, 2024.

Genetic Association Studies↗

PubMed2022

Insights on the pathogenesis of type 2 diabetes as revealed by signature genomic classifiers in an African American population in the Washington, DC area.

AIMS: African Americans (AA) in the United States have a high risk of type 2 diabetes mellitus (T2DM) and suffer from disparities in the prevalence, mortality, and comorbidities of the disease compared to other Americans. The present study aimed to shed light on the molecular mechanisms of disease pathogenesis of T2DM among AA in the Washington, DC region. METHODS: We performed TaqMan Low Density Arrays (TLDA) on 24 genes of interest that belong to three categories: metabolic disease and disorders, cancer-related genes, and neurobehavioural disorders genes. The 18 genes, viz. ARNT, CYP2D6, IL6, INSR, RRAD, SLC2A2 (metabolic disease and disorders), APC, BCL2, CSNK1D, MYC, SOD2, TP53 (Cancer-related), APBA1, APBB2, APOC1, APOE, GSK3B, and NAE1 (neurobehavioural disorders), were differentially expressed in T2DM participants compared to controls. RESULTS: Our results suggest that factors including gender, smoking habits, and the severity or lack of control of T2DM (as indicated by HbA1c levels) were significantly associated with differential gene expression. APBA1 was significantly (p-value <0.05) downregulated in all diabetes participants. Upregulation of APOE and CYP2D6 genes and downregulation of the INSR gene were observed in the majority of diabetes patients. CONCLUSIONS: Tobacco smoking and gender were significantly associated with case-control differences in expression of the APBA1 and APOE genes (connected with Alzheimer's disease) and the INSR and CYP2D6 (associated with metabolic disorders). The results highlight the need for more effective management of T2DM and for tobacco smoking cessation interventions in this community, and further research on the associations of T2DM with other disease processes, including cancer and neurobehavioral pathways.

Humans↗

PubMed2026

Unraveling the Mystery of Pain: A Unique Clinical Encounter and Case Report.

BACKGROUND: The Clinical Pharmacogenetics Implementation Consortium published an updated guideline for opioids and CYP2D6, OPRM1, and COMT in December 2020. These guidelines include recommendations to avoid key opioids in patients who are ultrarapid or poor metabolizers of CYP2D6 to avoid toxicity and optimize efficacy. CASE REPORT: An older woman encountered a letter to the editor in a family magazine regarding genomically based responses to opioids. She reached out for more information and assistance, attesting to continued lack of analgesia to opioids prescribed during occasions of severe pain over the course of many years. A pharmacogenomic analysis proved to be the key to solving her mystery. CONCLUSION: Pharmacogenomic results may provide life-altering information transforming a patient's perspective on health care. Personalized medicine may be a key component in providing objective evidence for opioid treatment efficacy. There is a critical need for both provider and patient education to increase awareness of pharmacogenomics and how it can be applied to effective pharmacotherapy. Research is needed to explore appropriate, effective educational methods.

Humans↗

PubMed2026

Role of OPRM1 A118G polymorphism in tramadol analgesia following third molar surgery: a pharmacogenomic study.

BACKGROUND: The OPRM1 A118G (rs1799971) polymorphism has been implicated in interindividual variability in opioid analgesic response, but its influence on tramadol efficacy remains uncertain. This study evaluated the association between OPRM1 A118G and postoperative analgesic response to tramadol following mandibular third molar surgery. METHODS: In this prospective pharmacogenomic study, 53 adults undergoing impacted mandibular third molar extraction were enrolled. Genomic DNA was analyzed for OPRM1 A118G (rs1799971) using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). All procedures were performed under 2% lignocaine with adrenaline. Tramadol (50 mg) was administered after the onset of postoperative pain. Pain intensity was assessed using the Visual Analogue Scale (VAS) and Short-Form McGill Pain Questionnaire at 2, 4, and 6 hours. The primary outcome was summed pain intensity difference (SPID, 2-6 hours). RESULTS: Genotype frequencies were in Hardy-Weinberg equilibrium. No significant association was observed between OPRM1 genotype and SPID, VAS reduction, Pain Rating Index change, or responder status during the 6-hour observation period (all p > 0.05). CONCLUSION: OPRM1 A118G was not significantly associated with early tramadol analgesic response following third molar surgery. Larger studies incorporating both OPRM1 and CYP2D6 genotyping are needed to clarify the genetic determinants of tramadol analgesia as CYP2D6 gene is required for tramadol metabolism.

OPRM1↗

PubMed2026

Prevalence of pharmacogenomically implicated prescriptions in multi-ethnic populations in Singapore.

AIM: To assess the potential impact of implementing pre-emptive pharmacogenomic (PGx) testing in Singapore, focusing on prevalence and genetic actionability of PGx prescriptions. METHODS: Electronic Health Records from 2014 to 2021 were obtained from the National University Hospital (NUH), a tertiary medical centre serving approximately 6% of Singapore's population, which were filtered for pharmacogenomically implicated medicines (CPIC Level A or A/B), defined as PGx medications. Coupling this with published data of whole-genome sequencing of 9051 Singaporeans, we estimated the proportion of patients whose prescriptions might have been modified based on pre-emptive PGx at population level. RESULTS: From 2014 to 2021, a total of 1 157 359 unique patients were seen at NUH, with 38.1% to 43.0% of patients with prescriptions receiving at least one PGx medication annually, exhibiting minimal variance over year of prescription, sex or race/ethnicity. The most frequently prescribed PGx medications were omeprazole, statins and tramadol, while the most implicated pharmacogenes were CYP2C19, CYP2D6 and SLCO1B1. The age-dependent increase in PGx medication exposure varied significantly by sex, with males prescribed these medications earlier in life than females. Similarly, Indians and Malays were more likely to be prescribed these medicines at a younger age than Chinese. Based on frequency of PGx variants in Singaporeans, we estimate that 18.4% of patients could have their prescriptions modified from pre-emptive PGx testing. DISCUSSION: Pharmacogenomically implicated medication prescriptions are common in Singapore and are particularly prevalent in elderly populations. Strategic investments in infrastructure and policy development will be pivotal to the successful integration of pre-emptive PGx into clinical practice.

Asian genomes↗

PubMed2026

Leveraging the genetics of psychiatric disorders to prioritize potential drug targets and compounds.

Genetics can inform biologically relevant drug development and repurposing, which may improve patient care. Here, we leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds. We used the genome-wide association studies of four psychiatric disorders [attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] and genes encoding drug targets. We conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We conducted multiple molecular trait analyses using large-scale transcriptomic and proteomic datasets sampled from brain and blood tissue. This included the novel use of the UK Biobank proteomic data for a proteome-wide association study of psychiatric disorders. With the accumulated evidence, we prioritize potential drug targets and compounds for each disorder. We reveal candidate drug targets associated with a single or multiple disorders that implicate glutamate signaling. Drug prioritization indicated genetic support for psychotropic medications, including several top-ranked antipsychotics for schizophrenia. We also observed genetic support for commonly used psychotropics for psychiatric treatment (e.g., clozapine, duloxetine, and lithium). Revealed opportunities for drug repurposing included cholinergic drugs for ADHD, estrogen modulators for depression, and matrix metalloproteinases for ADHD and depression. Our findings indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression of CYP2D6, a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission. Our extensive analyses highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders, providing novel opportunities for improving patient outcomes. Depicted is the series of analyses conducted to generate a list of prioritized drug targets and compounds. First pairings of genome-wide association study (GWAS) traits with drugs are generated using enrichment analyses. Next, a series of molecular trait analyses is conducted to generate and rank a list of potential drug targets for each GWAS trait. Finally, enrichment and molecular trait results are combined to generate a ranked list of prioritized drugs for each GWAS trait based on supporting genetic evidence. ADHD = Attention deficit hyperactivity disorder, BIP = Bipolar disorder, DEP = Depression, SCZ = Schizophrenia, DBP = Diastolic blood pressure, T2D = Type 2 diabetes, RNA = ribonucleic acid, XWAS = both transcriptome and proteome-wide association studies, MR = Mendelian randomization, coloc = colocalization.

Humans↗

PubMed2026

Beyond enrichment: pharmacogenetic heterogeneity in treatment-resistant depression.

OBJECTIVES: Genetic variation has been proposed as a potential contributor to antidepressant nonresponse, but its role in treatment-resistant depression (TRD) remains unclear. This study used pharmacogenetics (PGx) to characterize genetic variation in TRD and determine whether actionable PGx variation and drug-gene interaction (DGI) mismatch were associated with antidepressant nonresponse and TRD burden. METHODS: This observational study included 158 individuals with TRD recruited from outpatient clinics in Western Australia. Genotype and genotype-predicted phenotypes for CYP2B6, CYP2C19, and CYP2D6 were derived from commercial PGx testing and compared with ethnicity-matched reference populations from ClinPGx. Antidepressant-specific DGIs were classified as actionable or nonactionable according to Clinical Pharmacogenetics Implementation Consortium guidelines, and unsupervised clustering was used to identify clusters based on these actionability profiles. Analyses were performed to determine if actionable PGx variation, cluster membership, or PGx mismatch was associated with TRD burden (number of failed antidepressant trials). RESULTS: PGx variation in the TRD cohort was consistent with population expectations, with no evidence of enrichment for actionable PGx variants. Clustering identified six clusters with distinct and gene-specific patterns of PGx variation independent of demographic and clinical characteristics. However, neither PGx mismatch nor cluster membership were associated with TRD burden. CONCLUSION: These findings suggest that actionable PGx phenotypes are neither enriched in TRD nor associated with greater TRD severity. Rather, the results indicate that TRD does not represent a single, unified PGx-predicted 'poor pharmacological responder' phenotype but instead reflects a biologically heterogeneous collection of distinct PGx profiles.

antidepressants↗

PubMed2026

Safety and Tolerability of Single and Multiple Daily Oral Doses of Dried Kratom Leaf Powder in a Randomized Trial in Healthy Volunteers.

BACKGROUND: Kratom use is rising, increasing the need for safety and tolerability studies of high-quality and well-characterized kratom products in humans. Kratom's risk-benefit ratio, recommended dose, treatment-emergent adverse events (TEAEs), abuse potential, and withdrawal require evaluation. Thus, the safety and tolerability of 4 escalating single and 15 daily dried kratom leaf powder doses in human volunteers were evaluated over 47 days in the largest controlled kratom-administration study to date. METHODS: A randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of MitraLeaf kratom powder after single doses (SD), during 15 daily doses (multiple doses; MD), and a 23-day follow-up was conducted in 116 volunteers (49 MitraLeaf and 67 placebo). Twelve participants each received a SD of either 6.65, 13.3, 26.6, or 53.2 mg (n = 13) mitragynine in 500, 1000, 2000, or 4000 mg of MitraLeaf, respectively, with a 10-day follow-up. The same participants received 15 daily doses at the same concentration of SD mitragynine received, with a 27-day follow-up period. Inclusion criteria were nonsmoking healthy males and females who never used kratom or had not used kratom for ≥12 months, 18-55 years old, and BMI ≥18.5 and ≤29.9 kg/m 2 . Participants were excluded if they had known CYP3A4, CYP2D6, or CYP1A2 genetic polymorphisms. RESULTS: No serious adverse events or deaths were reported. TEAEs after SD or MD generally increased as the dose increased. Dizziness, nausea, and feeling of relaxation were the most commonly reported TEAEs after SD, and headache, feeling hot, increased alanine aminotransferase level, and nausea were most common after MD. CONCLUSIONS: This SD and first MD controlled study shows that Mitragyna speciosa -derived MitraLeaf kratom powder was safe and well tolerated at the dose ranges tested, with no evidence of meaningful abuse potential or withdrawal.

Humans↗

PubMed2026

Whole-Exome and Whole-Genome Sequencing of Candidate Pharmacogenomic and Schizophrenia-Related Genes in Sudanese Families with Schizophrenia.

BACKGROUND: Schizophrenia is considered a neuro-developmental disorder leading to disastrous lifelong disability of the patients and their families. There is a lack of data regarding pharmacogenomics of schizophrenia in Sudan. This study aimed to identify different genes affecting the treatment outcomes in Sudanese patients with schizophrenia. METHODS: A case-control study was conducted on seven families having more than one member diagnosed with schizophrenia. This was a small exploratory family-based sequencing study involving 18 affected individuals and 8 controls from seven families. Ethical clearance and informed consent were obtained. Demographic data were collected using a standardized data collection sheet. DNA was extracted from blood samples collected from patients and control groups. Then, whole-exome and genome sequencing were performed. Sixty-six genes associated with schizophrenia, treatment, and treatment resistance were selected from the variant calling file. Variants showing single-nucleotide polymorphisms (SNPs) were identified. These variants were then classified based on their impact on the protein-coding sequence into high- and moderate-impact. Moreover, indel mutations were also identified. RESULTS: Twelve variants of seven genes (COMT, FMO1, LPL, CYP2E1, ABCC1, GRM3, CYP2C9) were identified as genes with impact and potential association with schizophrenia (p-value=0.006632). Forty-three genes had a moderate impact, and they showed a potential association with schizophrenia (p-value=0.0004436). Two variants were indel mutations (CYP2D6, DTNBP1) and showed association with schizophrenia (p-value=0.004741). The p-values were generated from different databases. CONCLUSION: This exploratory family-based sequencing study identified several potentially relevant pharmacogenomic and schizophrenia-associated variants in Sudanese families, warranting validation in larger and ethnically diverse cohorts.

antipsychotics↗

PubMed2026

A minimal three-arm oral regimen for healthspan: mechanistic alignment with transcriptomic signals from a large parental-lifespan GWAS.

A large genome-wide association study of parental lifespan was reported in 2019. A later transcriptome-wide association study (TWAS) based on those summary statistics identified a set of transcriptional programs associated with longer genetically predicted survival, including increased brain NAD + salvage, especially NMNAT2, reduced glucose-stimulated insulin secretion, a shift toward synaptic pruning with less broad plasticity, and a glial pattern characterized by relatively greater microglial and lower astrocytic signatures, with only weak pan-tissue senescence signals. Building on those directional findings, this short communication proposes a minimal three-arm oral regimen with unequal evidentiary weight: first, the Cheung Glutamatergic Regimen, consisting of low-dose dextromethorphan potentiated by a CYP2D6 inhibitor together with piracetam and L-glutamine, as an exploratory adjunct aimed at preserving residual functional connectivity; second, daily nicotinamide mononucleotide and N-acetylcysteine with pulsed senolytics for NAD + salvage and senescence modulation; and third, GLP-1 receptor agonism for metabolic reprogramming. The NAD+/senescence arm is the primary mechanistic anchor, GLP-1 receptor agonism provides secondary metabolic support, and the glutamatergic arm is exploratory. Each arm targets a separate node within the pruning-plasticity-metabolic triad. The regimen is fully oral, uses conservative dosing, and draws on prior therapeutic or human-exposure data, although the proposed combination has no established safety profile. Although direct combination data are lacking and the foundational TWAS remains a preprint, the components show plausible but uneven mechanistic alignment with the TWAS signals and may justify carefully designed, safety-focused pilot evaluation.

GLP-1↗