Living with respiratory viruses: The next saga in human/viral coexistence?

Testing for respiratory viruses and SARS-CoV-2 in clinical and epidemiological settings has contrasting purposes and utility. Symptomatic patients are best tested with respiratory virus panels to establish the pathogen and guide personalized treatment. Asymptomatic patients are tested for a single infectious pathogen to establish carrier status and guide containment.

Personalized health and the coronavirus vaccines-Do individual genetics matter?

Vaccines represent preventative interventions amenable to immunogenetic prediction of how human variability will influence their safety and efficacy. The genetic polymorphism among individuals within any population can render possible that the immunity elicited by a vaccine is variable in length and strength. The same immune challenge (virus and/or vaccine) could provoke partial, complete or even failed protection for some individuals treated under the same conditions. We review genetic variants and mechanistic relationships among chemokines, chemokine receptors, interleukins, interferons, interferon receptors, toll-like receptors, histocompatibility antigens, various immunoglobulins and major histocompatibility complex antigens. These are the targets for variation among macrophages, dendritic cells, natural killer cells, T- and B-lymphocytes, and complement. The technology platforms (mRNA, viral vectors, proteins) utilized to produce vaccines against SARS-CoV-2 infections may each trigger genetically distinct immune reactogenic profiles. With DNA biobanking and immunoprofiling of recipients, global COVID-19 vaccinations could launch a new era of personalized healthcare.

Pharmacogenomics: an Update for Child and Adolescent Psychiatry.

PURPOSE OF REVIEW: This paper aims to acquaint child and adolescent psychiatrists with the field of pharmacogenomics (PGX) and review the most up-to-date evidence-based practices to guide the application of this field in clinical care. RECENT FINDINGS: Despite much research being done in this area, the field of PGX continues to yield controversial findings. In the adult world, studies have focused on the impact of combinatorial gene panels that guide medication selection by providing reports that estimate the impact of multiple pharmacodynamic and pharmacokinetic genes, but to date, these have not been directly examined in younger patient populations. Pharmacokinetic genes, CYP2D6 and CYP2C19, and hypersensitivity genes, HLA-A and HLA-B, have the strongest evidence base for application to pharmacotherapy in children. Although the field is evolving, and the evidence is mixed, there may be a role for PGX testing in children to help guide dosing and monitoring strategies. However, evidence-based medicine, rather than PGX testing, continues to play the lead role in guiding medication selection in pediatric psychopharmacology.

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia.

The brain's default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging-genetic relationships. ICA identified three DMNs. Hypo-connectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases.

Pharmacogenetic association study of warfarin safety endpoints in Puerto Ricans.

OBJECTIVE: This study was intended to determine the incidence rate of warfarin-related adverse events (e.g., bleeding) in Puerto Ricans and whether a genetic association between warfarin pharmacogenes and any of these adverse events was observed over the initiation period (i.e., the first 90 days of therapy). METHODS: We conducted an observational, retrospective cohort study of pharmacogenetic association in 122 warfarin-treated, male, Puerto Rican patients (69.9 +/- 9.6 years) from the Veterans Affair Caribbean Healthcare System (VACHS) who consented to participate. Genotyping was performed using the CYP2C9 and VKORC1 assays by Luminex. Event-free survival curves were estimated using the Kaplan-Meier method and analyzed by log-rank test. Cox regression models were constructed and hazard ratios (HR) calculated. RESULTS: Carriers of functional CYP2C9 and VKORC1 polymorphisms demonstrated a higher incidence rate of multiple adverse events (i.e., 5.2 vs. 1.0 cases per 100 patient-months; RR = 4.8, p = 0.12) than did wild types. A significant association was observed between multiple adverse events and carrier status (HR = 2.5; 95% CI: 1.0-6.3, p = 0.04). However, no significant associations between genotypes and individual outcomes over the first 90 days of therapy were found. CONCLUSION: The association of CYP2C9 and VKORC1 genotypes and risks for adverse events due to exposure to warfarin was examined for the first time in Puerto Ricans. Despite a lack of association with individual events in this study population, our findings revealed a potential utility of genotyping for the prevention of multiple adverse events during warfarin therapy.

Pharmacogenetics in Child and Adolescent Psychiatry: Background and Evidence-Based Clinical Applications.

The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic factors. Pharmacogenetics (PGx) in child and adolescent psychiatry can potentially improve treatment outcomes and minimize adverse drug reactions. This article reviews key pharmacokinetic and pharmacodynamic genes and principles of pharmacogenetic testing and discusses the evidence base for clinical decision-making concerning PGx testing. This article reviews current guidelines from the United States Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Dutch Pharmacogenetics Working Group (DPWG) and explores potential future directions. This review discusses key clinical considerations for clinicians prescribing psychotropic medications in children and adolescents, focusing on antidepressants, antipsychotics, stimulants, norepinephrine reuptake inhibitors, and alpha-2 agonists. Finally, this review synthesizes the practical use of pharmacogenetic testing and clinical decision support systems.

Implementing a pharmacogenomic-driven algorithm to guide antiplatelet therapy among Caribbean Hispanics: a non-randomised clinical trial.

OBJECTIVES: To assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the rate of major adverse cardiovascular and cerebrovascular events (MACCEs) among Caribbean Hispanic patients, after 6 months. DESIGN: An open-label, multicentre, non-randomised clinical trial. SETTING: Eight secondary and tertiary care hospitals (public and private) in Puerto Rico. PARTICIPANTS: 300 Caribbean Hispanic patients on clopidogrel, both genders, underwent percutaneous coronary intervention (PCI) for acute coronary syndromes, stable ischaemic heart disease and documented extracardiac vascular diseases. INTERVENTIONS: Patients were separated into standard-of-care (SoC) and genotype-guided (pharmacogenetic (PGx)-CDS) groups (150 each) and stratified by risk scores. Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Individual platelet function, genotypes, clinical and demographic data were included. Ticagrelor was recommended for patients with a high-risk score ≥2 in the PGx-CDS group only, the rest were kept or de-escalated to clopidogrel. The intervention took place within 3-5 days after PCI. Adherence medication score was also measured. PRIMARY AND SECONDARY OUTCOMES: The occurrence rate of MACCEs (primary) and bleeding episodes (secondary). Statistical associations between patient time free of events and predictor variables (ie, treatment groups, risk scores) were tested using Kaplan-Meier survival analyses and Cox proportional-hazards regression models. RESULTS: The genotype-guided group had a clinically lower but not significantly different risk of MACCEs compared with the SoC group (8.7% vs 10.7%, p=0.56; HR=0.56). Among high-risk score patients, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in reducing MACCE incidence 6 months postcoronary stenting (adjusted HR=0.104; p< 0.0001). CONCLUSIONS: The potential benefit of implementing our PGx-CDS algorithm to significantly reduce the incidence rate of MACCEs in post-PCI Caribbean Hispanic patients on clopidogrel was observed exclusively among high-risk patients, with apparently no evident effect in other patient groups. TRIAL REGISTRATION NUMBER: NCT03419325.

Contrasting ABCB1 pharmacogenetics and psychotropic responses in child and adolescent psychiatry: a case comparison.

This case comparison illustrates pharmacogenetic testing in psychotropic and clinical management in relation to the ABCB1 gene, which encodes the P-glycoprotein transporter affecting blood-brain barrier (BBB) permeability. Two pediatric patients (9 and 11 years old) were selected for similar clinical presentations with opposing ABCB1 genotype, while they were identically matched for key CYP450, dopaminergic and serotonergic genes (CYP2C9, CYP2C19, DRD2, SLC6A4, 5HTR2A). Case A was functional for the ABCB1 gene (G/G rs1045642), suggesting that the BBB had a functional P-glycoprotein transporter. Case B was subfunctional for the ABCB1 gene (A/A rs1045642), suggesting that the patient's BBB may be permeable to psychotropic drugs. Case A had more medication trials and dose adjustments than Case B. Case A had two inpatient admissions and interspersed emergency room visits, while case B had none.

The focus of this case comparison report is the ABCB1 gene in child psychiatry and its role in drug efficacy and side effects. ABCB1 encodes the P-glycoprotein transporter of the blood­brain barrier (BBB). As antidepressants must cross the BBB to act on the brain, differences in the functionality of ABCB1 may lead to variable brain concentrations of antidepressants and subsequent variability in therapeutic response. Selecting the cases for comparison with opposing functionality at the ABCB1 gene, while matching for key CYP450, dopaminergic and serotonergic genes (CYP2C9, CYP2C19, DRD2, SLC6A4, 5HTR2A), was the approach utilized. The outcomes of case A and case B reflected pharmacogenetic and clinical contrasts, including patient responses to antidepressants and antipsychotics, susceptibility to adverse effects and differences in the severity of symptoms. These effects on antidepressants and antipsychotics are important because a permeable BBB will allow these drugs to cross into the brain to exert their effect, thus improving clinical outcomes, reducing hospitalizations and emergency room visits and minimizing drug trials and dosage changes. More clinical attention and research are needed for the BBB's involvement in psychiatric disease and for the P-glycoprotein transporter as a chemical gatekeeper to the brain. Pharmacogenetic testing for ABCB1 polymorphisms could be considered to inform psychotropic prescribing for the most vulnerable patients in child and adolescent psychiatry in the near future.

PharmVar Tutorial on CYP2D6 Structural Variation Testing and Recommendations on Reporting.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus and a comprehensive summary of structural variation. CYP2D6 contributes to the metabolism of numerous drugs and, thus, genetic variation in its gene impacts drug efficacy and safety. To accurately predict a patient's CYP2D6 phenotype, testing must include structural variants including gene deletions, duplications, hybrid genes, and combinations thereof. This tutorial offers a comprehensive overview of CYP2D6 structural variation, terms, and definitions, a review of methods suitable for their detection and characterization, and practical examples to address the lack of standards to describe CYP2D6 structural variants or any other pharmacogene. This PharmVar tutorial offers practical guidance on how to detect the many, often complex, structural variants, as well as recommends terms and definitions for clinical and research reporting. Uniform reporting is not only essential for electronic health record-keeping but also for accurate translation of a patient's genotype into phenotype which is typically utilized to guide drug therapy.

Discovery of Ancestry-specific Variants Associated with Clopidogrel Response among Caribbean Hispanics.

Background: High on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. This study aimed to identify genetic predictors of HTPR in a cohort of Caribbean Hispanic cardiovascular patients from Puerto Rico. Methods: Local Ancestry inference (LAI) and traditional GWASs were performed on a cohort of 511 clopidogrel-treated patients, stratified based on their P2Y12 reaction units (PRU) into responders and non-responders (HTPR). Results: The LAI GWAS identified variants within the CYP2C19 region associated with HTPR, predominantly driven by individuals of European ancestry and absent in those with native ancestry. Incorporating local ancestry adjustment notably enhanced our ability to detect associations. While no loci reached traditional GWAS significance, three variants showed suggestive significance at chromosomes 3, 14 and 22 (OSBPL10 rs1376606, DERL3 rs5030613, and RGS6 rs9323567). In addition, a variant in the UNC5C gene on chromosome 4 was associated with an increased risk of HTPR. These findings were not identified in other cohorts, highlighting the unique genetic landscape of Caribbean Hispanics. Conclusion: This is the first GWAS of clopidogrel response in Hispanics, confirming the relevance of the CYP2C19 cluster, particularly among those with European ancestry, and also identifying novel markers in a diverse patient population. Further studies are warranted to replicate our findings in other diverse cohorts and meta-analyses.

Implementing a Pharmacogenomic-driven Algorithm to Guide Antiplatelet Therapy among Caribbean Hispanics: A non-randomized prospective cohort study.

Background: After percutaneous coronary intervention (PCI), clopidogrel resistant patients are at an increased risk of major adverse cardiovascular and cerebrovascular events (MACCEs). We aimed to assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the occurrence of these ischemic events and improves outcomes among Caribbean Hispanic patients from Puerto Rico, who are underrepresented in clinical pharmacogenomic (PGx)-guided implementation studies. Methods: Individual platelet function testing (PRU) measures, CYP2C19*2 and PON1 rs662 genotypes, clinical and demographic data from 8 medical facilities were included. Patients were separated into standard of care (SoC) and genotype-guided groups (150 each). Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Alternative therapy with ticagrelor was recommended for patients with a high risk score ≥2. Statistical associations between patient time free of MACCEs and predictor variables (i.e., treatment groups, risk scores) were tested in this population using Kaplan-Meier survival analyses and Cox proportional-hazards regression models. Results: Median age of participants is 67 years; BMI: 27.8; 48% women; 14% smokers; 59% with type-2 diabetes mellitus (T2DM). Among patients with high-risk scores who were free from MACCE events 6 months after coronary stenting, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in terms of reducing the incidence rate of atherothrombotic events. Conclusions: The clinical utility of our PGx-driven CDS algorithm to reduce the incidence rate of MACCEs among post-PCI Caribbean Hispanic patients on clopidogrel was externally demonstrated. Clinical Trial Registration Unique Identifier: NCT03419325.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.

Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes.

BACKGROUND: The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients. OBJECTIVE: To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm. METHODS: A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested. RESULTS: Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients. CONCLUSIONS: This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.

CYP2C19 genotype-guided antiplatelet therapy in a patient with clopidogrel resistance.

We report a switch in antiplatelet medication based on platelet function and CYP2C19 genotype test results in a 74-year-old man with severe coronary arterial disease. Upon bare metal stent implantation at age 66, clopidogrel therapy (75 mg/ day) was initiated to supplement aspirin. Over the next eight years, the patient required multiple percutaneous coronary interventions for de novo coronary stenosis and in-stent restenosis. Platelet reactivity measured while on clopidogrel therapy was high, consistent with clopidogrel resistance. CYP2C19 genotype testing then revealed homozygosity for the *2 null allele. The *2/*2 designation indicates poor metabolizer status, indicating deficient capacity of the cytochrome p450 2C19 enzyme for activation of clopidogrel. A medication switch to prasugrel,which does not rely on activation by the 2C19 enzyme, reduced platelet reactivity by 86%. The patient has suffered no cardiovascular events in the 18 months since initiation of prasugrel therapy.

Automated Extraction of Pain Symptoms: A Natural Language Approach using Electronic Health Records.

BACKGROUND: Pain costs more than $600 billion annually and affects more than 100 million Americans, but is still a poorly understood problem and one for which there is very often limited effective treatment. Electronic health records (EHRs) are the only databases with a high volume of granular pain information that allows for documentation of detailed clinical notes on a patient's subjective experience. OBJECTIVES: This study applied natural language processing (NLP) technology to an EHR dataset as part of a pilot study to capture pain information from clinical notes and prove its feasibility as an efficient method. STUDY DESIGN: Retrospective study. SETTING: All data were from UConn Health John Dempsey Hospital (JDH) in Farmington, CT. METHODS: The JDH EHR dataset contains 611,355 clinical narratives from 359,854 patients from diverse demographic backgrounds from 2010 through 2019. These data were processed through a customized NLP pipeline. A training set of 100 notes was annotated based on focus group-generated ontology and used to generate and evaluate an NLP model that was later tested on the remaining notes. Validation of the model was evaluated externally and performance was analyzed. RESULTS: The model identified back pain as the most common location of experienced pain with 40,369 term frequencies. Patients most commonly experienced decreased mobility with their pain with 7,375 term frequencies. Pain was most commonly found to be radiating with 26,967 term frequencies and patients most commonly rated their pain as 8/10 with 2,375 term frequencies. All parameters studied had statistical F-scores greater than 0.85. LIMITATIONS: A single-center, pilot study subject to reporting bias, recording bias, and missing patient data. CONCLUSIONS: Our customized NLP model demonstrated good and successful performance in extracting granular pain information from clinical notes in electronic health records.

Subanalysis of the CYP-GUIDES Trial: CYP2D6 Functional Stratification and Operational Timeline Selection.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) was a Randomized Controlled Trial comparing 2 outcomes in hospitalized patients with major depressive disorder treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary was Re-Admission Rate (RAR) 30 days after discharge. Methodology, total results and database of the trial have been published. Here we present a subanalysis that isolated 3 confounders to assess the impact of CYP2D6 therapeutic guidance on LOS: a single Electronic Medical Record, a minimum 3-day LOS, and CYP2D6 functional stratification of patients. CYP2D6 functional stratification enabled subgrouping patients and comparing outcomes according to CYP2D6 functionality within Group G and Group S. Subfunctional patients evidenced a 2-day shorter LOS in Group G compared to Group S. Drug administration for subfunctional patients in Group S evidenced a higher percentage of CYP2D6 substrate psychotropics being prescribed as well as a greater number of prescriptions than in functional patients. We conclude that there was an effect of pharmacogenetic clinical decision support that reduced LOS in patients with CYP2D6 subfunctional status and reduced prescribing of CYP2D6 substrate dependent drugs.

Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach.

This multicenter clinical study was aimed at conducting a targeted pharmacogenomic association analysis of residual on-clopidogrel platelet reactivity in 474 Caribbean Hispanic patients. Platelet reactivity was measured using the VerifyNow P2Y12 assay and clopidogrel resistance was defined as P2Y12 reaction units (PRUs) greater than or equal to 208. Genotyping was performed using the whole-genome Infinium MEGA BeadChip array. An ancestry-adjusted, weighted polygenic risk score (wPGxRS) was developed to account for the effect of multiple variants on PRU and compared between clopidogrel responders and nonresponders. The mean PRU across the study cohort was 173.8 ± 68.5 and 33.5% of patients were defined as clopidogrel resistant. Multivariate linear regression showed that 19% of PRU variability was attributed to nine independent predictors, with CYP2C19*2 (rs4244285) accounting for ~ 7% of observed PRU variation (p < 0.001). PON1 rs662, ABCB1/MDR1 rs2032582, PEAR1 rs12041331 carrier status, and the interaction between African ancestry and rs12041331 carriers also predicted PRU among the participants (p ≤ 0.05). A clear gene-dose effect was detected between PRU and CYP2C19*2 genotype, consistent with previous studies in European patient populations, as well as rs12777823. Importantly, a significant positive correlation was detected between our novel wPGxRS (4 variants) and PRU among the Hispanic patient population (rp  = 0.35, p < 0.001). Moreover, the wPGxRS discriminated between nonresponders and responders (p = 0.003), indicating that this multigene-based score is a useful predictor of clopidogrel resistance among Caribbean Hispanics. Taken together, these results help close the gap of knowledge on clopidogrel pharmacogenomics and its potential clinical implementation in this under-represented population.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.

Exposure to non-therapeutic INR in a high risk cardiovascular patient: potential hazard reduction with genotype-guided warfarin (Coumadin) dosing.

A case to illustrate the utility of genetic screening in warfarin (Coumadin) management is reported. A 45 year-old woman of Puerto Rican ancestry was admitted to the emergency room twice within one month with chest pain. She was diagnosed with congestive heart failure, which was stabilized both times. At her second release, warfarin therapy was initiated at 5 mg/ day to prevent thrombus formation and was lowered to 3.75 mg/day at day 7 by her primary physician. International Normalized Ratio (INR) test results in the follow-up period at days 1, 7, and 10 of warfarin therapy were 4.5, 6.5, and 7.3, respectively-far in excess of the therapeutic range, despite the lower dosage in effect from day 7 onward. The patient achieved target INR over the next 43 days after downward adjustment of the dose to a dose of 1.5 mg/day by trial and error. DNA-typing specific for the CYP2C9*2,*3,*4,*5,*6 alleles and seven variants in the VKORC1 gene, including the VKORC1-1639 G > A polymorphism, revealed the presence of combinatorial CYP2C9*2/*3 and VKORC1-1639 G/A genotypes in this patient. Entering the patient's demographic and genotype status data into independent algorithms available in the public domain to predict effective warfarin dose yielded predicted doses which ranged from 1.5 to 1.8 mg/day. Notably, the prediction of 1.5 mg/day, which was generated by the online resource www.warfarindosing.org, coincided with the patient's actual effective warfarin dose. We conclude that the rapid rise in INR observed upon the initiation of warfarin therapy and the final effective warfarin dose of 1.5 mg/day, are attributable in some part to the presence of two minor alleles in CYP2C9, which together significantly reduce warfarin metabolism. Warfarin genotyping can therefore inform the clinician of the predicted effective warfarin dose. The results highlight the potential for warfarin genetic testing to improve patient care.