Pharmacogenetic Testing Research Articles

Developing DPYD Genotyping Method for Personalized Fluoropyrimidines Therapy.

Fluoropyrimidine drugs are widely used in chemotherapy to treat solid tumors. However, severe toxicity has been reported in 10% to 40% of patients. The DPYD gene encodes the rate-limiting enzyme dihydropyrimidine dehydrogenase responsible for fluoropyrimidine catabolism. The DPYD variants resulting in decreased or no enzyme activity are associated with increased risk of fluoropyrimidine toxicity. This study aims to develop a pharmacogenetic test for screening DPYD variants to guide fluoropyrimidine therapy. A multiplex allele-specific polymerase chain reaction (AS-PCR) assay, followed by capillary electrophoresis, was developed to detect 5 common DPYD variants (c.557A > G, c.1129-5923C > G, c.1679T > G, c.1905 + 1G > A, and c.2846A > T). Deidentified population samples were used for screening positive controls and optimizing assay conditions. Proficiency testing samples with known genotypes were analyzed for test validation. All variants detected were confirmed by Sanger sequencing. From the deidentified population samples, 5 samples were heterozygous for c.557A > G, 2 samples were heterozygous for c.1129-5923C > G (HapB3), and 1 sample was heterozygous for c.2846A > T. The 20 proficiency samples matched with their assigned genotypes, including 13 wild-type samples, 3 samples heterozygous for c.1679T > G, 2 samples heterozygous for c.1905 + 1G > A, and 2 samples heterozygous for c.2846A > T. One of the 3 patient samples was heterozygous for c.1129-5923C > G (HapB3). All the variants detected by the multiplex AS-PCR assay were concordant with Sanger sequencing results. A robust multiplex AS-PCR assay was developed to rapidly detect 5 variants in the DPYD gene. It can be used for screening DPYD variants to identify patients with increased risk of toxicity when prescribed fluoropyrimidine therapy.

Pharmacogenetic testing and monitoring of complete blood counts among Veterans newly prescribed thiopurine treatments: a retrospective cohort study

Pharmacogenetic (PGx) testing before initiation of thiopurine treatment and CBC monitoring post-initiation helps avoid adverse events and ensure patient safety. This study aims to evaluate trends in PGx testing and CBC monitoring among Veterans prescribed azathioprine, thioguanine, or mercaptopurine to demonstrate VA’s efforts to improve medication safety after an adverse event. To assess testing patterns, we used VA electronic health report data to identify 20,524 Veterans who first began thiopurine treatment between January 1, 2010, to December 31, 2021. Aggregate monthly counts of thiopurine prescriptions and associated lab tests were tabulated, and the trend in the proportion of patients tested was analyzed using the Mann–Kendall test. The proportion of patients undergoing PGx testing rose from 30.0% in 2010 to 47.5% in late 2014 (July–December). However, PGx testing and overall testing only increased slightly after the sentinel event, and orders levelled off over time at slightly lower levels than before the sentinel event. Very little change was seen in the overall proportion of individuals receiving any testing across all patients with new prescriptions from the time of the sentinel event in 2014 to the end of 2021. A large portion of patients prescribed thiopurine drugs did not receive testing that could help prevent the development of potential adverse events, leading to a predominantly reactive approach. Increased PGx testing may result in a more proactive approach to the prevention of adverse events due to genetic interaction.

Genogeographic technologies of a population biobank as a tool for assessing selection effects (using the example of pharmacogenetic biomarkers of cardiovascular diseases)

Significant differences between the gene pools of Russian peoples require the development of ethno- regional adapted pharmacogenetic tests and the identification of priority regions for their implementation.Aim. To develop a genogeographic technology to identify selection effects using the example of biomarkers that are significant for pharmacotherapy of patients with cardiovascular diseases (CVD), using a population biobank and the Pharmacogenetics of Populations of Russia and Adjacent Countries database.Material and methods. Deoxyribonucleic acid (DNA) samples from the Biobank of Northern Eurasia from 20 metapopulations of the indigenous population of the European Russia were studied using two following data sets: 24 pharmacogenetic markers of CVDs (3170 samples); 1 276 191 polymorphic DNA markers of the autosomal genome (1293 samples). For each data set, estimates of interpopulation variability in the gene pool are provided — the difference between these estimates characterizes the selection pressure on each of the 24 CVD biomarkers. A genogeographic atlas has been created, the maps of which demonstrate the selection pressure on each biomarker according to the degree of deviation from the selective- neutral variability of the gene pool.Results. Twenty-four CVD biomarkers are divided into three following classes: those close to selective- neutral variability, those subject to stabilizing and differentiating selection. For each of the 24 CVD biomarkers, genogeographic maps were created that reveal selection effects in each of the 20 metapopulations. Most maps have identified populations that are under differential selection pressure and therefore a priority for the implementation of ethno- regionally adapted pharmacogenetic protocols.Conclusion. Pharmacogenetic markers and populations under differential selection require the development of ethno- regionally adapted pharmacogenetic tests. The created cartographic atlas of selection can serve as the basis for pharmacogenetic studies carried out using genogeographic methods.

Returning personalized, genetic health test results to individuals of African descent or ancestry in precision medicine research.

Today, many epidemiological studies and biobanks are offering to disclose individual genetic results to their participants, including the National Institutes of Health's All of Us Research Program. Returning hereditary disease risks and pharmacogenetic test results to study participants from racial/ethnic groups that are historically underrepresented in biomedical research poses specific challenges to those participants and the health system writ large. For example, individuals of African descent are underrepresented in research about drug-gene interactions and have a relatively higher proportion of variants of unknown significance, affecting their ability to take clinical action following return of results. In this brief report, we summarize studies published to date concerning the perspectives and/or attitudes of African Americans engaged in genetic research programs to anticipate factors in disclosure protocols that would minimize risks and maximize benefits. A thematic analysis of studies identified (n = 6) lends to themes centered on motivations to engage or disengage in the return of results and integrating research and care. Actionable strategies determined in reaction to these themes center on ensuring adequate system and health education support for participants and personalizing the process for participants engaging in return of results. Overall, we offer these themes and actionable strategies as early guidance to research programs, and provide recommendations to policy makers focused on fair and equitable return of genetic research results to underrepresented research participants.

Feasibility of preemptive pharmacogenetic testing and improvement of medication treatment satisfaction among medically underserved patients.

Previous findings suggest that medically underserved patients are prescribed medications with pharmacogenetic (PGx) guidelines at a high frequency. Thus, underserved patients may especially benefit from PGx testing, but little evidence exists regarding the effect of testing in this population. This pilot study aimed to generate key feasibility data and explore clinical outcomes of PGx implementation in underserved populations. Black and Latino patients were recruited from an outpatient clinic and underwent PGx testing. Feasibility measures included enrollment metrics and actionable genotype frequencies. The primary clinical outcome was patient medication treatment satisfaction 6 months after testing. Implementation outcomes included the number of healthcare provider encounters and medication changes within the 6-month follow-up. Effectiveness outcomes included medication adherence, patient-perceived test value, and time spent discussing medications with providers. Ninety-nine patients completed the study. Proton-pump inhibitors were the most frequent PGx drug class prescribed at baseline (61%) followed by nonsteroidal anti-inflammatory drugs (36%). Patients with an actionable genotype constituted 96% of the population, whereas 28% had an actionable genotype related to their PGx drug. Patient treatment satisfaction significantly increased over the 6 months after PGx testing. In addition, medication adherence and the number of provider encounters significantly increased over the study period. In a pilot study, preemptive PGx testing was feasible in primary care clinics, improved patient treatment satisfaction and adherence, and increased the number of provider encounters in medically underserved patients. Future clinical trials are warranted to assess the long-term effects of PGx testing in a larger diverse patient population.

Caffeine, Lorazepam, and Morphine Use in Neonatal Intensive Care Unit Population and Potential Relevance of Pharmacogenomics

Abstract Medications are critical for managing acutely ill infants in neonatal intensive care unit (NICU). Tailoring therapies to individual differences in response and dose requirements might help improve outcomes. However, tools for optimizing pharmacotherapy remain limited. In this retrospective study, we explored the potential utility of pharmacogenetics for commonly prescribed NICU medications. All patients admitted to our local NICU March-December, 2022 were eligible for inclusion in the study. In infants who received at least three doses of one or more medications, we extracted DNA from residual EDTA blood collected for routine clinical care according to IRB-approved study protocols. Demographic, pharmacy, and clinical information was recorded retrospectively. Targeted pharmacogenetics testing was performed with a custom TaqMan OpenArray and a QuantStudio 12K Flex (ThermoFisher Scientific) with DNA normalized to 50 ng/mL. Results were analyzed using Genotyper Software version 1.3 and allele calls were made based on the combination of variants detected and consensus nomenclature. For drugs administered to at least 30 NICU patients, pharmacogenes were evaluated for variant allele frequency and potential clinical relevance. Of the 132 patients enrolled, 81 were male. Average length of stay was 47 days. Of the 64 different medications prescribed to at least one infant, for 15 of them are described clinical annotations with specific pharmacogenes by the PharmGKB and/or Clinical Pharmacogenetics Implementation Consortium. Of those 15 medications, three were administered at least three times to at least 30 infants: caffeine (n=102), morphine (n=56), and lorazepam (n=31). The associated pharmacogenes were CYP1A2 (caffeine); CYP3A4, OPRM1, COMT, ABCB1 (morphine); and UGT2B15 (lorazepam). Relevant to the rate of clearance of caffeine, rs2069514 (CYP1A2) was heterozygous in 18% of patients, and homozygous in 5%. Relevant to the rate of clearance of morphine, CYP3A4*22 was heterozygous in 5%. The common variants associated with response to morphine, c.472G>A (COMT) and c.118A>G (OPRM1) were heterozygous in 43% and 26%, and were homozygous in 22% and 8%, respectively. The transporter variant ABCB1*2 was heterozygous in 6% and homozygous in 11%. Relevant to the rate of clearance of lorazepam, UGT2B15*2 (rs1902023) was heterozygous in 45%, and homozygous in 31%. Correlation of pharmacogenetic results to specific clinical phenotypes is currently in progress. Pharmacogenetic variants relevant to commonly prescribed medications in the NICU are prevalent. Further clinical correlation of pharmacogenetic results may help inform selection and dosing of medications for critically ill NICU infants. This research may also facilitate detection and definition of new drug-gene associations unique to this patient population.

The role of pharmacogenetics in the treatment of major depressive disorder: a critical review.

Pharmacological therapy represents one of the essential approaches to treatment of Major Depressive Disorder (MDD). However, currently available antidepressant medications show high rates of first-level treatment non-response, and several attempts are often required to find an effective molecule for a specific patient in clinical practice. In this context, pharmacogenetic analyses could represent a valuable tool to identify appropriate pharmacological treatment quickly and more effectively. However, the usefulness and the practical effectiveness of pharmacogenetic testing currently remains an object of scientific debate. The present narrative and critical review focuses on exploring the available evidence supporting the usefulness of pharmacogenetic testing for the treatment of MDD in clinical practice, highlighting both the points of strength and the limitations of the available studies and of currently used tests. Future research directions and suggestions to improve the quality of available evidence, as well as consideration on the potential use of pharmacogenetic tests in everyday clinical practice are also presented.

Abstract 14482: Low Utilization of Guideline-Recommended Genetic and Pharmacogenetic Testing Among Patients With Cardiovascular Conditions in the United States (US)

Introduction: Cardiovascular disease (CVD) continues to be the leading cause of death in the US and globally. Clinical practice guidelines recommend genetic testing for the diagnosis of select CVDs to improve disease management, reduce incidence of cardiac events, and positively impact major cardiac adverse events. Professional guidelines also recommend pharmacogenomic (PGx) testing for patients being prescribed certain medications. Research Question: What is the utilization of genetic diagnosis and PGx testing in patients with CVD in the US? Methods: This study used data from the Optum Labs Data Warehouse, composed of de-identified administrative claims data for both commercially insured and Medicare Advantage enrollees to assess rates of genetic testing among adult patients diagnosed with 4 major types of CVD conditions (arrhythmias (N=518,316), familial hypercholesterolemia (FH) (N=38,068), cardiomyopathies (CM) (N=74,597), and aortopathies (N=58,316)) and PGx testing rates in patients prescribed CVD medications with PGx test recommendations (per CPIC guidelines) between January 1, 2017 to December 31, 2021. Patients were required to have ≥12 months of continuous enrollment prior (baseline) to diagnosis (index date) and ≥12 months post-index period unless they died (follow-up). Genetic and PGx testing was captured using Current Procedural Terminology (CPT®) codes in both baseline and follow-up periods. Results: Low genetic testing utilization was found across the 4 major types of CVD conditions. Genetic testing rates were 1.3% in the arrythmia cohort, 1.9% in the CM cohort, 2.0% in the aortopathy cohort and 1.9% in the FH cohort. PGx testing rates in patients prescribed with CVD relevant medications were 0.6% (N=2,094/377,111) in the arrhythmia cohort, 0.8% (N=501/60,632) in the CM cohort, 0.7% (N=247/37,344) in the aortopathy cohort, and 1.3% (N=329/25,835) in FH cohort. Conclusions: Despite clinical practice guidelines, genetic and PGx testing in patients with CVD conditions remains underutilized. Future work will help us understand the barriers to guideline adherence both for genetic diagnosis and PGx testing that could impact clinical management and patient outcomes.

The Correlation of Two Different Real-Time PCR Devices for the Analysis of CYP2C19 Pharmacogenetic Results

CYP2C19 is a highly polymorphic gene responsible for the metabolism of commonly used drugs. CYP2C19*1, the wild-type allele, is associated with normal enzyme activity, whereas CYP2C19*2 and CYP2C19*17 lead to null and increased enzyme activity, respectively. The use of different instruments to perform the same pharmacogenetic tests should not affect the reliability of the results reported to clinicians, as required by the ISO 15189 standard. Genotyping assays allowed for the identification of gene variants corresponding to the CYP2C19*2 and CYP2C19*17 haplotypes in 44 selected samples. Each sample was analyzed in duplicate using the Thermo Fisher Taqman Drug Metabolism probes CYP2C19*2: c_25986767_70 (rs4244285) and CYP2C19*17: c_469857_10 (rs12248560). The experiments were performed on two widely used types of real-time PCR analyzers: ABI PRSIM™7500 and QuantStudioTM12KFlex (both from Applied Biosystems, Thermofisher). The data were analyzed in a Thermo Fisher Cloud facility. The analysis was performed independently by two qualified professionals. Both different instruments and analysts’ interpretations were consistent in identifying the native homozygous, heterozygous, and mutant homozygous variants for CYP2C19*2 and CYP2C19*17. The results provided by both the primary and backup analyzers showed a perfect correlation. This would allow for the use of the backup analyzer in case the main one is not available.

Characterization of CYP2C19 pharmacogenetic variation in African populations and comparison with other global populations.

Background: CYP2C19 is important in the metabolism of clopidogrel and several antidepressants. This study aimed to characterize the distribution of CYP2C19 star alleles (haplotypes) across diverse African populations compared with global populations. Methods: CYP2C19 star alleles and diplotypes were called from high coverage genomes using the StellarPGx pipeline. Results: CYP2C19*1 (51%), *2 (17%) and *17 (22%) were the most common star alleles across African populations in this study. It was observed that 3% of African participants had potentially novel CYP2C19 haplotypes. Conclusion: This study supports the necessity for CYP2C19 pharmacogenetic testing in African and global clinical settings, as well as the importance of comprehensive star allele characterization in the African context.

MODERN ASPECTS OF PHARMACOGENETICS: FROM THEORY TO PRACTICE IN PERINATOLOGY AND PEDIATRICS

Pharmacogenetic testing (PT) is a modern tool in the doctor’s practice, which allows to make the right clinical decision indiffi cult cases, when the expected result of medical measures is not achieved. It is clear that certain metabolic processes in the human body, as well as a number of diseases, are genetically programmed. Therefore, despite the large number of unexplained mechanisms of individual response to drugs, genetic testing occupies one of the leading positions among methods of selecting drug therapy in complex clinical cases. However, the successful implementation of this promising method must overcome a number of obstacles, including limited evidence of eff ectiveness, ethical, legal, and social factors. The purpose of this review is to highlight modern concepts and practical aspects of the use of PT. The article addresses the problem of expanding the indications for PT when it is not limited to preventive use only. PT allows to identify drugs associated with an increased risk of causing side eff ects, with a narrow therapeutic index, to reduce the number of drugs in treatment, to choose the dosage of the drug. A variety of PT platforms can be used in a physician’s offi ce, which can be broadly divided into two categories – genotyping- based tests and sequencing- based tests. Depending on the gene being tested, diff erent algorithms can be used to generate results. Some gene variants can be described in terms of metabolic activity or general function, while others can only be described as present or absent. Results for gene variants can also be reported as normal, intermediate or low function for the corresponding gene. Pharmacogenetic clinical decision support systems (CDSS) are computer- based systems that assist healthcare providers in prescribing medications at the point of care. These systems provide physicians and other healthcare providers with appropriately fi ltered pharmacogenetic information, such as drug-gene interaction alerts or patient- specifi c treatment recommendations. A pharmacogenetic CDSS can either be integrated into a local hospital information system or used as a stand- alone application such as a web service or mobile application. Pharmacogenetics can increase the quantity and quality of information available to pregnant women and their physicians about medication use during pregnancy. Implementation of PT recommendations intoroutine pediatric practice requires carefully coordinated strategies at the national, regional, and health system levels. To date, pharmacogenetics provides mosaic information on the association between response to drug therapy and genetic background. It is expected that the next step will be a study in a larger group of participants to investigate the contribution of epigenetic factors and to provide clinical recommendations for adjusting or selecting therapy based on the personal characteristics of the patient.

DPYD variant testing in candidates for fluoropyrimidine treatment: A study protocol

ObjectiveThe main purpose of this study is to evaluate the potential clinical impact of pharmacogenetic testing on the reduction of the toxicity in patients treated with fluoropyrimidines. This will be achieved by comparing the frequency of adverse events and the incidence of toxicity of two groups of patients that will differ from each other only in that one will receive pharmacogenetic counseling. The hypothesis is that availability of a pharmacogenetic report prior to treatment initiation has a positive effect. One of the main secondary goals is to analyze allele frequencies and the association of polymorphisms rs895819 (miR27A) and rs1801160 (DPYD*6) with toxicity by conducting an observational study to determine their clinical relevance and standardize a dose adjustment recommendation. MethodThe study has an single-center ambispective, quasi-experimental design and is based on a multidisciplinary protocol involving implementation and standardization of DPYD*2A; DPYD*13; c.2846A>T; and HapB3 measurements. Following these measurements, pharmacogenetic counseling will be carried out and its clinical impact will be evaluated. The primary endpoint of the study is severe toxicity and/or mortality. The toxicity observed in two groups with similar epidemiological characteristics will be compared: the intervention group (candidates for treatment with fluoropyrimidines who will be subjected to the protocol) and the control group (retrospective cohort). Additionally, rs895819 (MIR27A) and rs1801160 (DPYD*6) will be determined. Testing for these variants is not part of the hospital's daily practice, nor are they included in clinical guidelines. However, according to recently published studies, the activity of dihydropyrimidine dehydrogenase might be affected by these variants, as they may be associated with toxicity. The results of the measurements of these two variants will not be incorporated to pharmacogenetics counseling until their association with toxicity is determined by means of the observational study to be conducted. The project, as well as the patient information sheet and the informed consent form, were approved by the Ethics Committee of the participating center (code 20/006).

Advancing pharmacogenetic testing in a tertiary hospital: a retrospective analysis after 10 years of activity.

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing. A head-to-head comparison with previously published activity results within the same pharmacogenetic laboratory was also conducted to contrast the progress made after 10years. The analysis revealed significant utilization of pharmacogenetic testing in daily clinical practice, with 1,145 pharmacogenetic tests performed over a 1-year period and showing a 35% growth rate increase over time. Of the 17 different medical departments that sought PGx tests, the Oncology department accounted for the highest number, representing 58.47% of all genotyped patients. A total of 1,000 PGx tests were requested for individuals susceptible to receive a dose modification based on genotype, and 76 individuals received a genotype-guided dose adjustment. This study presents a comprehensive descriptive analysis of real-world data obtained from a public tertiary hospital laboratory specialized in pharmacogenetic testing, and presents data that strongly endorse the integration of pharmacogenetic testing into everyday clinical practice.

Psychiatric mental health nurse practitioner student knowledge and perceptions of pharmacogenetic testing.

Psychotropic medications are typically prescribed in a trial-and-error fashion, and some providers are beginning to utilize pharmacogenetic testing (PGx) as a supplemental prescribing tool in treatment decision making. PGx testing shows potential in enhancing provider insights into personalized prescribing for patients by examining genetic information related to drug metabolism. Literature points to providers' lack of knowledge in PGx interpretation as a main barrier, including psychiatric mental health nurse practitioners (PMHNPs). The aim of this study was to measure a difference, if any, in the knowledge and perceptions of PGx after implementation using a pre-post design. This study implemented an educational intervention on graduate nursing students (n = 15). Data were collected by using a pre- and post-interventional questionnaire. Results demonstrated a significant difference in findings related to students' knowledge (p < 0.001), students' skills related to pharmacogenetics, (p < 0.001), as well as students' perceived ability to implement pharmacogenetics into their practice, (p = 0.028). The authors propose that the knowledge gained from the study demonstrates the importance of introducing PGx education into the PMHNP curricula and to prepare future PMHNPs to confidently utilize PGx in their clinical practice.

Influence of pharmacogenetics on the diversity of response to statins associated with adverse drug reactions.

Statins are one of the most prescribed medications in developed countries as the treatment of choice for reducing cholesterol and preventing cardiovascular diseases. However, a large proportion of patients experience adverse drug reactions, especially myotoxicity. Among the factors that influence the diversity of response, pharmacogenetics emerges as a relevant factor of influence in inter-individual differences in response to statins and can be useful in the prevention of adverse drug effects. A systematic review was performed of current knowledge of the influence of pharmacogenetics on the occurrence and prevention of statin-associated adverse reactions and clinical benefits of preemptive pharmacogenetics testing. Genetic variants SLCO1B1 (rs4149056) for all statins; ABCG2 (rs2231142) for rosuvastatin; or CYP2C9 (rs1799853 and rs1057910) for fluvastatin are associated with an increase in muscle-related adverse effects and poor treatment adherence. Besides, various inhibitors of these transporters and biotransformation enzymes increase the systemic exposure of statins, thereby favoring the occurrence of adverse drug reactions. The clinical preemptive testing of this pharmacogenetic panel would largely prevent the incidence of adverse drug reactions. Standardized methods should be used for the identification of adverse effects and the performance and interpretation of genotyping test results. Standardization would allow to obtain more conclusive results about the association between SLCO1B1, ABCG and CYP2C9 variants and the occurrence of adverse drug reactions. As a result, more personalized recommendations could be established for each statin.

Analytical validation of GenoPharm a clinical genotyping open array panel of 46 pharmacogenes inclusive of variants unique to people of African ancestry.

Pharmacogenomic testing may be used to improve treatment outcomes and reduce the frequency of adverse drug reactions (ADRs). Population specific, targeted pharmacogenetics (PGx) panel-based testing methods enable sensitive, accurate and economical implementation of precision medicine. We evaluated the analytical performance of the GenoPharm® custom open array platform which evaluates 120 SNPs across 46 pharmacogenes. Using commercially available reference samples (Coriell Biorepository) and in-house extracted DNA, we assessed accuracy, precision, and linearity of GenoPharm®. We then used GenoPharm® on 218 samples from two Southern African black populations and determined allele and genotype frequencies for selected actionable variants. Across all assays, the GenoPharm® panel demonstrated 99.5% concordance with the Coriell reference samples, with 98.9% reproducibility. We observed high frequencies of key genetic variants in people of African ancestry: CYP2B6*6 (0.35), CYP2C9*8, *11 (0.13, 0.03), CYP2D6*17 (0.21) and *29 (0.11). GenoPharm® open array is therefore an accurate, reproducible and sensitive test that can be used for clinical pharmacogenetic testing and is inclusive of variants specific to the people of African ancestry.

Pharmacogenetic Testing in Patients with Autism Spectrum Disorder Evaluated in a Precision Medicine Clinic.

This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored associations between patient characteristics and pharmacogenomic testing results. Records for patients diagnosed with ASD and subsequently referred to a pediatric hospital's precision medicine clinic between July 1, 2010, and June 30, 2020, were reviewed. Pharmacogenetic testing results were abstracted focusing on CYP2D6 and CYP2C19. In addition, we compiled counts of patients' co-occurring diagnoses, histories of adverse drug reactions (ADRs), previously trialed ineffective medications, and previous psychiatric medication changes. Logistic regression models were fit to examine CYP2C19 and CYP2D6 metabolizer status as functions of patient demographics and prereferral medication histories. Of 202 patients (mean age = 12.18 yrs), 66% were referred to precision medicine because of poor medication response. Among patients with pharmacogenomic testing results for CYP2D6, 9% were classified as poor metabolizers; among patients with results for CYP2C19, 10% were classified as rapid/ultrarapid metabolizers. Patient demographics and medication response history did not predict pharmacogenomic results. However, the number of co-occurring diagnoses positively predicted the number of nonpsychiatric ADRs and a higher probability of CYP2D6 poor metabolizer status; moreover, nonpsychiatric ADRs positively predicted CYP2C19 rapid/ultrarapid metabolizer status. In one of the largest reported samples of youth with ASD clinically referred for pharmacogenetic testing, we observed high variability in medication response and yield for actionable results. Our findings suggest potential clinical utility for pharmacogenetic testing and introduce possible clinical profiles associated with metabolizer status.

EDUCATION DAY: PHARMACOGENETICS TESTING

EDUCATION DAY: PHARMACOGENETICS TESTING

Unexpected High Need for Genetic Testing in Rheumatology: A Cross-Sectional Cohort Study.

Genetic testing may provide information for diagnostic, prognostic and pharmacogenetic purposes. The PREPARE study recently showed that the number of clinically relevant adverse drug reactions could be reduced via genotype-guided treatment. The aim of this work was to assess the relevance of genetic testing and its actual use in consecutive rheumatic outpatients. A retrospective cross-sectional analysis was performed with data from a prospectively designed observational project with outpatients consecutively recruited from a university clinic of rheumatology. In this cohort of 2490 patients, the potential need for genetic testing is immense, with 57.3% of patients having the potential to benefit from genetic testing according to their diagnosis and treatment and 53.3% of patients with actually performed genetic testing for diagnostic, prognostic or pharmacogenetic purposes. In detail, patients would potentially benefit from genetic testing especially for therapeutic (28.0%) and diagnostic (26.9%) purposes. Genetic testing was performed for diagnostic purposes in 51.6% of subjects, for pharmacogenetic purposes in 3.7% and for prognostic purposes in 0.1%. The ratio between the number of patients who had had tests performed to those with a potential need for genetic testing decreased with age, from 127.1% for 20 to <30-year-old patients to 46.1% for 80 to <90-year-old patients. Pharmacogenetic testing was only performed for disease-related medications. Genetic testing is frequently needed in patients with rheumatic diseases. The value of pharmacogenetic testing is certainly underestimated, especially in case of medications for comorbidities.

Utility of pharmacogenetic testing to optimise antidepressant pharmacotherapy in youth: a narrative literature review.

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals' genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current "one-size-fits-all" approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth.