搜索结果：Pharmacogenetics and genomics

Scientific advances and cost efficiencies in genetics and genomics are expanding clinical application for prevention, diagnosis, and treatment. PCORnet®, a research network that includes participation from 78 health systems nationally and is linked to more than 47 million unique patients with at least one encounter annually, can help (1) understand the ability of genetics/genomics to predict health outcomes, (2) identify diseases impacted by genetic/genomic factors, (3) evaluate pharmacogenomics' role in medication optimization, (4) evaluate emerging gene therapies, and (5) compare clinical genetic or genomic strategies within learning health systems to improve outcomes, while (6) facilitating patient and other partner engagement across these areas. The breadth of data accessible via PCORnet represents a unique opportunity to study relationships among genetic markers and clinical and exposome-based disease risk factors, particularly as more genomic data become available. The network's experience developing computable phenotypes for identifying specific diseases can be leveraged to evaluate the role of genetics/genomics in health. The PCORnet infrastructure can be used to identify patients with particular conditions for predictive modeling or comparative clinical effectiveness research using electronic health record data. The network can also recruit patients for observational cohorts or pragmatic clinical trials on pharmacogenomics or the return of genetic results, evaluation of emerging gene therapies, or embedded research into learning health systems to compare clinical genetics/genomics implementation approaches in health care. The partner engagement focus of the PCORnet® Network Partners can enrich research and improve health care delivery and outcomes. The rise of clinical genetics and genomics will profoundly impact health care in the next decade, and the PCORnet® Network Partners are primed to make a leading contribution in this area.

Pharmacogenetics is considered a promising method to improve pharmacotherapy, yet its implementation in clinical practice is hampered, limiting its potential benefits to the public. Previously, its uptake has been investigated within a variety of healthcare professional groups. Commonly cited barriers by prescribing physicians are lack of knowledge and insurance coverage. An important occupational group who may support physicians due to their expert knowledge are pharmacists. However, they have been understudied in research on pharmacogenetics implementation thus far. Therefore, we investigated the experience and attitudes of pharmacists regarding pharmacogenetics using an online questionnaire. Using Qualtrics software, an online survey was distributed nationally from April 1st to December 1st 2024. Respondents were recruited during a national conference organized by the Dutch pharmacy residents, through email-invites, and via newsletters of national pharmacist-associations. In total, data of n = 281 respondents were analyzed in the study, the majority of which were working professionals (±15.8 years of experience). Although only 44.4% had ever requested a pharmacogenetic test, 88.6% of respondents had experience with test result interpretation. Cost, lack of reimbursement through insurance, and lack of availability of pharmacogenetic guidelines including clinical evidence, were found as key barriers. Importantly, respondents generally felt confident regarding their own pharmacogenetics-related knowledge and skills, while maintaining caution in situations where pharmacogenetic evidence is limited. Successful adoption of pharmacogenetics in practice may benefit from interprofessional collaboration, expanding the pharmacogenetics evidence base, and prioritizing pharmacogenetics in updated health policy.

Adverse drug reactions (ADRs) are responsible for a significant proportion of hospitalizations globally, and represent a significant, yet partially preventable, burden on public health systems, particularly in resource-limited and low- and middle-income countries (LMICs), where chronic diseases and polypharmacy are highly prevalent. Pharmacogenomics (PGx), through targeted gene panels on drug-gene interactions, has shown potential to reduce ADRs, and improve prescription safety in health systems. The central hypothesis of this article is that the gradual implementation of panel-based pharmacogenomics within public health services in LMICs is possible, ethically justifiable, and potentially cost-effective, when adapted within regulatory, epidemiological, and infrastructural conditions in each region. Using Mexico as a representative case study within the global context, this manuscript synthesizes the international implementation experience and proposes a conceptual and operational framework for the gradual integration of PGx in Public Health Institutions. Estimated hypothetical projections of the clinical and economic potential impact discussed in this article-such as the potential reduction in preventable ADR-related hospitalizations and associated costs-are illustrative and inferential, based on international evidence, and not as empirically demonstrated results within the Mexican health system. The proposed model puts emphasis on scalability, regulatory framework, ethical oversight, and equity-oriented implementation as its core principles. Through the development of a hypothetical policy-relevant model, this article seeks to serve as a basis for the implementation of future pilot programs, empirical evaluations and evidence-based decisions regarding the integration of pharmacogenomics into public health services in Mexico and in similar regions of resource-limited LMICS.

Pharmacogenomic (PGx) variants associated with opioid metabolism and reward pathways may influence pain response and risk of opioid dependence. Infants undergoing surgery routinely receive opioids, and prolonged exposure impacts health outcomes. This study evaluated relationships between PGx variants and opioid utilization in infants undergoing surgery for congenital heart disease (CHD). This retrospective cohort study included infants <1 year who underwent CHD surgery and had exome sequencing at a quaternary children's hospital from 2009 to 2020. PGx variants associated with opioid-response (COMT, DRD2/ANKK1, ABCB1, OPRM1, and CYP2D6) were evaluated. Median cumulative morphine milliequivalents (MMEs) administered were calculated over each hospitalization, and median MMEs corresponding with each variant were analyzed using Kruskal-Wallis tests. Overall, 48 infants were identified (54.2% male, 47.9% Hispanic/Latino, and 6.3% preterm). Most (n&#x2005;=&#x2005;34, 70.8%) underwent open surgery, and 14 (29.2%) underwent minimally invasive procedures. Forty infants (83%) were homozygous for at least one opioid-related PGx variant. Infants who underwent open surgery and were homozygous for OPRM1: rs1799971, COMT: rs4633, rs4680, and ABCB1: rs1045642 demonstrated increased cumulative MMEs compared to wild type. Infants who underwent minimally invasive surgery and were homozygous for ABCB1: rs1045642 also had increased cumulative MMEs. No relationship between CYP2D6 metabolizer phenotypes and MMEs was observed. Most infants undergoing CHD surgery who had exome sequencing were homozygous for an opioid-related PGx variant. Additionally, infants who were homozygous received increased MMEs during hospitalization. Routine reporting of PGx variants could inform future innovation in precision medicine and opioid stewardship efforts.

Genomics is perceived to impact healthcare in the United Kingdom and pharmacy professionals are believed to have a key role in the delivery of pharmacogenomic services. To compare the delivery of genomic education within pharmacy undergraduate training between the UK and other countries. Six electronic databases were searched including MEDLINE, EMBASE and Cochrane Library using variations of the terms pharmacogenomic, genomics and education, looking at all levels of education. No date restrictions were applied. Studies were then screened for duplicates and eligibility for inclusion. Fifty studies were included and categorised into three main themes: identifying training requirements, training methods, and curriculum design/review. Most studies (n&#xa0;=&#xa0;30) were from the United States. Many international studies highlighted the need to improve pharmacy undergraduate pharmacogenomic training. The pharmacist pharmacogenomic focussed competencies available in the United States have underpinned the development of pharmacist pharmacogenomic education and many studies described a mixed-methods approach to education delivery to ensure pharmacy student pharmacogenomic competence. The curricula evaluation in the Unites States and Australia demonstrated improved pharmacogenomic content within school of pharmacy curriculums but lacks nationwide standardisation. This review demonstrates global growth in pharmacy pharmacogenomic education, particularly in the US, where competencies and delivery methods have been defined and explored across institutions. The United Kingdom should develop its own competency framework to guide pharmacogenomic education for pharmacy undergraduates. This would support efforts to standardise genomic content in UK pharmacy curricula and promote the creation of standardised tools for effective training across all pharmacy schools.

Recent regulatory and guideline changes have established pretreatment DPYD genotyping as a critical strategy to prevent severe fluoropyrimidine toxicity. Following earlier European leadership by the European Medicines Agency, the US Food and Drug Administration added boxed warnings to capecitabine and 5-fluorouracil labels recommending genetic testing before therapy. Concurrent updates from the National Comprehensive Cancer Network and ASCO align US with European practice supporting universal testing. Fluoropyrimidines remain foundational treatments across multiple cancers but can cause life-threatening toxicity in patients with dihydropyrimidine dehydrogenase (DPD) deficiency, most commonly because of inherited DPYD variants. DPYD variant carriers receiving standard doses experience markedly increased risk of severe toxicity and treatment-related mortality, emphasizing the clinical importance of DPYD testing and genotype-guided dosing. Evidence demonstrates that dose individualization based on guidance from the Clinical Pharmacogenetics Implementation Consortium reduces toxicity risk while maintaining treatment effectiveness and potentially reducing overall costs. Patient advocacy, particularly efforts led by Advocates for Universal DPD/DPYD Testing, has accelerated policy change, increased clinician awareness, and highlighted ethical implications of preventable harm. Despite growing adoption, implementation challenges persist, including workflow integration, clinician education, and equitable access. Integrated health systems such as the Veterans Health Administration demonstrate how centralized infrastructure and clinical decision support can facilitate uptake. Barriers are more pronounced in resource-constrained settings, where limited infrastructure, reimbursement uncertainty, and insufficient pharmacogenomic education hinder implementation. Regional initiatives illustrate education-focused, context-adapted strategies to expand testing and address population-specific variant knowledge gaps. Collectively, emerging evidence, regulatory alignment, and advocacy efforts position DPYD genotyping as a patient-safety imperative necessary to achieve safer, more equitable fluoropyrimidine therapy worldwide.

Major depressive disorder (MDD) and bipolar disorder (BD) are common, disabling conditions. Despite associated morbidity and premature mortality, current treatments have modest efficacy and response to treatment highly variable. Contributing factors to variability in response include influence of common genetic variations in the pharmacokinetic and/or pharmacodynamic action of medications. As such, attention has turned toward the identification of genetic markers that could assist with determining who will respond or not to psychotropic treatment. Results of studies to date are promising but primarily have been small. This study aims to evaluate the efficacy of a pharmacogenetic (PGx)-based decision support tool among adults with MDD and BD. This single-site, single (rater) blinded, randomized controlled trial with two arms evaluates the 24-week efficacy of a PGx-based support tool for adults with MDD or BD. Participants are randomized to receive PGx testing or standard prescribing. Participants provide DNA samples at baseline, but only those (including clinicians) randomized to the former receive the results at the start of their study participation. It is not mandatory for clinicians to follow the test recommendations. Remission rate (primary outcome), change in depression symptoms, drop-out rate, medication adherence, and medication side effects (secondary outcomes) are assessed at 4-, 8-, 12-, and 24-week postbaseline by a blinded rater. Analyses will follow an intention-to-treat approach and use mixed models for repeated measures. Treatment response to medication for severe mood disorders is highly variable and less than optimal. This trial will provide evidence as to whether a PGx-based support tool is an efficacious strategy to inform selection and dosing of pharmacotherapy among adults with severe mood disorders. Importantly, it will do so independently and with a larger sample size than previous studies. This trial is registered under the number ACTRN12621001374853 (11 Oct 2021).

Pharmacogenomics (PGx) can potentially tailor medication prescriptions to the genetic profiles of individuals, enhancing treatment outcomes and minimizing adverse drug reactions. This study assessed cardiovascular disease (CVD) patients' knowledge and views toward PGx testing in the United Arab Emirates (UAE). A cross-sectional study was conducted among CVD patients attending multiple clinics using a validated, culturally adapted, and piloted bilingual questionnaire. Participants were invited via phone calls or in-person contact at clinics. Data analysis was conducted using SPSS V.29, incorporating descriptive statistics and multivariable logistic regression. A total of 425 responses were analyzed; 67.5% were over 50&#x2009;years old, and 67.5% held a bachelor's degree. Chronic diseases, excluding CVD, affected 65.2%, with 58.1% reporting medication side effects and 36.5% was hospitalized due to these effects. Knowledge varied, with 55.3% demonstrating good knowledge; 75.3% recognized DNA as gene-based, while 47.5% understood PGx for predicting medication responses. Participants were grouped into three PGx perception clusters: Cluster 1 (33.17%) concerned about risks but valued PGx, Cluster 2 (40.23%) worried about privacy/costs, and Cluster 3 (26.58%) confident in PGx benefits. Safety was the top priority for 60.2% of respondents, 34.8% would not pay for PGx tets, and 35.3% preferred preemptive testing. Regression linked higher PGx knowledge to females, non-healthcare workers, those with genetic diseases, and those hospitalized for side effects (p&#x2009;<&#x2009;0.05). The study highlights a need for educational initiatives in the UAE to improve PGx literacy among CVD patients. The findings suggest that targeted awareness campaigns, policy interventions addressing privacy, and financial support could promote PGx wider adoption.

To characterize the allelic and diplotype variability of TPMT and NUDT15 in pediatric patients with B-cell acute lymphoblastic leukemia from the central-southern region of Mexico. Samples from 275 pediatric B-cell acute lymphoblastic leukemia patients were analyzed. Next-generation sequencing was used for TPMT and NUDT15 genotyping. Alleles and diplotypes were assessed according to the Clinical Pharmacogenetics Implementation Consortium guidelines. Their geographic distribution was compared across Mexican states and global populations. In-silico analyses were conducted to assess the structural and functional impact of TPMT variants not associated with star alleles. The wild-type *1 allele, associated with normal enzymatic activity, was predominant in both genes: TPMT (94.15%) and NUDT15 (90.45%). TPMT showed greater allelic diversity compared with previous studies in Mexican populations. Alleles conferring absent or indeterminate enzymatic activity in TPMT were distributed across six diplotypes (11.62%), with *3A allele (4.73%) and *1 / *3A diplotype (9.45%) being the most frequent. Additionally, two unclassified TPMT variants, p.G126A and p.D137Y, were identified. For NUDT15 , three non-wild-type diplotypes were observed (19.09%), with the *2 allele (6.74%) and *1* / 2 diplotype (13.48%) being the most prevalent. Approximately 28% of patients carried TPMT and/or NUDT15 variants associated with non-wild-type enzymatic activity, increasing the risk of mercaptopurine-induced myelotoxicity. Preemptive genotyping is essential to reduce toxicity, optimize treatment, and advance precision medicine in this population. Additionally, the two TPMT variants p.G126A and p.D137Y, currently not classified within Clinical Pharmacogenetics Implementation Consortium-defined star alleles, highlight the need for functional validation and potential clinical classification to improve pharmacogenetic interpretation in diverse populations.

Dehydroepiandrosterone (DHEA) is considered an endogenous steroid hormone precursor, and 17-&#xdf; estradiol (E2) is one of the estrogen steroid hormones. Of the 13 known human cytosolic sulfotransferases (SULTs), SULT2B1a has been shown to be expressed in steroid hormone-responsive tissues such as the prostate, ovary, and placenta, as well as the fetal brain. Previous studies have demonstrated that SULT2B1a is capable of sulfating 3&#x3b2;-hydroxysteroids such as DHEA and pregnenolone. The present study aimed to investigate the effects of human SULT2B1 single-nucleotide polymorphisms (SNPs) on the enzymatic characteristics of SULT2B1a allozymes in mediating the sulfation of DHEA and E2. To inspect the effects of SNPs of the SULT2B1 gene on the sulfation of DHEA and E2 by SULT2B1a allozymes, 13 recombinant SULT2B1a allozymes were produced, expressed, and purified using established procedures. Thirteen SULT 2B1a nonsynonymous missense coding SNPs (cSNPs) were selected among numerous identified human SULT 2B1a SNPs by a comprehensive database search. The corresponding cDNAs, packaged in pGEX-2TK expression vector, and encoding the selected 13 SULT2B1a allozymes, have been generated by performing site-directed mutagenesis. These were then bacterially expressed in BL21 E. coli cells and purified using glutathione-Sepharose affinity chromatography. The purified allozymes were tested for their ability to sulfonate DHEA and E2. In terms of the kinetic parameters, the wild-type SULT2B1a exhibited higher enzyme affinity toward DHEA than with E2. In comparison with the wild-type SULT2B1a, the purified allozymes displayed differential sulfating activities toward DHEA and E2. Accordingly, these findings indicate an apparent effect of SULT2B1 cSNPs on the sulfating activities of SULT2B1a allozymes toward DHEA and E2, and may provide for a better understanding of the pharmacokinetics of DHEA and E2 in individuals with differing SULT2B1a genotypes.

Pharmacogenomics (PGx) is a scientific field that aims to understand how an individual's genetic code regulates drug metabolism and response. The response to many anesthetic drugs varies widely among patients due to many factors including, but not limited to, age, gender, and comorbidities. However, PGx contributes to this variability, particularly regarding adverse drug reactions. This review explores the influence of PGx on five commonly used induction agents in anesthesia: propofol, midazolam, ketamine, etomidate, and thiopental. Propofol metabolism is significantly affected by polymorphisms in CYP2B6, CYP2C9, and UGT1A9, influencing both efficacy and toxicity. Midazolam's PGx is mainly mediated by variations in CYP3A4, CYP3A5, and UDP-glucuronosyltransferase enzymes, with implications for sedation depth and drug clearance. Ketamine response is modulated by polymorphisms in metabolic enzymes (e.g. CYP2B6), as well as neurobiological targets such as brain-derived neurotrophic factor and gamma-aminobutyric acid (GABA) receptors, particularly in psychiatric applications. Etomidate shows less studied but emerging PGx associations, including single-nucleotide polymorphisms in GABA receptor subunits and metabolic enzymes, which may affect both sedative depth and cardiovascular stability. Thiopental is a rapid-acting metabolite whose effect stems from GABA-A receptor potentiation; no studies have yet identified specific genetic polymorphisms influencing its action. Overall, PGx provides a promising avenue for tailoring anesthetic management to improve patient safety and outcomes. However, clinical integration remains limited due to practical and infrastructural barriers. This review highlights the potential and current limitations of pharmacogenomic-guided anesthesia, underscoring its relevance in the era of precision medicine.

Pharmacogenetic testing is increasingly implemented clinically, which is effectively supported by both pharmacists and genetic counselors to counsel patients on these results. However, pharmacogenetic specialists are limited, and alternative service delivery methods need to be evaluated, including patient preferences and comprehension with pharmacogenetic counseling. This study assessed patients' views in relation to their health literacy and genetics knowledge on the communication of pharmacogenetic results through electronic health record (EHR) patient portals. Participants in a large, diverse biobank were electronically surveyed. Eighty-five percent of the cohort (580/682) indicated that they wanted their pharmacogenetic results added to the patient portal. Participants with a higher genetics knowledge were more likely to want their results added (p&#x202f;=&#x202f;0.004), while health literacy did not have a significant impact. Participants with greater pharmacogenetic terminology familiarity (p&#x202f;=&#x202f;0.004), better understanding of a mock patient-facing clinical pharmacogenetic report (p&#x202f;=&#x202f;0.02), and greater self-reported ease of understanding the mock report (p&#x202f;<&#x202f;0.0001), were more likely to want their results added to the patient portal. Furthermore, participants with higher health literacy (p&#x202f;<&#x202f;0.0001), genetics knowledge (p&#x202f;<&#x202f;0.0001), and familiarity with pharmacogenetic terminology (p&#x202f;<&#x202f;0.0001) had greater understanding of the mock report. Taken together, this novel EHR-based pharmacogenetic survey of diverse patients determined that most participants favor using patient portals to communicate pharmacogenetic results. However, these results are counterbalanced by the importance of considering patient literacy in health and genetics when delivering pharmacogenetic results as well as the need for additional educational resources to support clinical pharmacogenetics implementation. Integrating pharmacogenetic results into patient portals offers a scalable approach to result delivery but should be paired with tailored education and support to ensure equitable patient understanding and engagement.

Clinical genomics and pharmacogenomics have largely remained separate fields, though some genetic variants have overlapping disease risk and drug implications. However, the extent of this overlap is not well studied. To explore this gap, we cross-referenced genes from the American College of Medical Genetics Secondary Findings v3.2 list with genomic databases and drug labeling to identify gene-phenotype pairs with overlapping clinical genomics and pharmacogenomic implications. We searched GeneReviews and PharmGKB (now called ClinPGx) for each gene-phenotype pair and reviewed the FDALabel database contraindications or warnings. Targeted therapies for specific germline/somatic variants were excluded. PGx-trained pharmacists and a genetic counselor classified gene-phenotype pairs into three levels: Level 1 (Food and Drug Administration's or guideline-driven recommendations), Level 2 (potential pharmacotherapy implication), and Level 3 (no/weak interactions). Among 97 gene-phenotype pairs reviewed, 22 (23%) were Level 1, 31 (32%) were Level 2, and 44 (45%) were Level 3. Pharmacotherapy implications included risks inferred by disease pathology (e.g., anticoagulants and hereditary hemorrhagic telangiectasia) and less obvious associations (e.g., Marfan syndrome and fluoroquinolones). Unrecognized medication implications may pose patient safety risks. Greater research, information consolidation and dissemination, and multidisciplinary collaboration among clinical genomics specialists, pharmacogenomic specialists, and other practitioners are essential as genetic testing becomes routine in clinical care.

Pharmacogenetics has become increasingly important in pharmaceutical practice. This study assessed pharmacists' knowledge, perceptions, and confidence regarding the application of pharmacogenetics in Saudi Arabia. It also explored their readiness to integrate pharmacogenetics into practice and identified barriers to implementation. A pre-validated questionnaire consisting of six sections was used: demographics; pharmacogenetic training and counseling; knowledge, perception, and confidence toward pharmacogenetic application; preferred learning methods for future pharmacogenetic education; and perceived barriers to implementation. The survey was conducted in August 2023 and included 757 participants. Male pharmacists constituted the majority of respondents (62.8%), and the median age was 34 years. The median scores were 3 for knowledge (71% demonstrated good knowledge), 5 for perception (79% expressed positive perceptions), and 2 for confidence (only 44% reported high confidence). Pharmacists who had counseled patients on pharmacogenetic testing results were significantly more likely to have higher knowledge [odds ratio (OR): 2.376, 95% confidence interval (CI): 1.181-4.778], more positive perceptions (OR: 4.331, 95% CI: 1.514-12.392), and greater confidence. In contrast, pharmacists working in general or other specialty areas had lower perception scores (OR: 0.531, 95% CI: 0.305-0.924). High confidence was also associated with older age and prior pharmacogenetic training. These findings suggest that pharmacists in Saudi Arabia are ready to incorporate pharmacogenetics into practice and that patient counseling plays a key role in enhancing their knowledge, perceptions, and confidence.

To investigate the association between CFTR genotypes and clinical and nutritional outcomes in children and adolescents with cystic fibrosis (CF) receiving care within the public health system of Esp&#xed;rito Santo, Brazil. This cross-sectional study retrospectively analyzed clinical and genetic data from 110 individuals under 18 years with confirmed CF, followed at a state reference center between 2007 and 2024. CFTR variants were classified by functional consequence and grouped by severity. Outcomes included pancreatic insufficiency, forced expiratory volume in 1 s (FEV1%), Shwachman-Kulczycki score, nutritional status, and chronic airway colonization by Pseudomonas aeruginosa . Associations were assessed using appropriate statistical tests. A high degree of CFTR genotypic heterogeneity was observed, with predominance of the F508del variant (72.7%) alongside a substantial proportion of non-F508del and rare pathogenic variants. Individuals carrying two class I-III variants had a higher frequency of pancreatic insufficiency ( P = 0.026). The presence of p.Phe508del was associated with worse pulmonary function ( P = 0.031) and bone demineralization ( P = 0.026). The Shwachman-Kulczycki score correlated negatively with age and age at diagnosis and positively with BMI z -score and FEV1%. No significant associations were found between genotype and chronic P. aeruginosa colonization, liver disease, or overall disease severity. CFTR genotypic heterogeneity was high, with minimal function variants associated with poorer clinical outcomes. The notable presence of rare variants underscores the need for regional studies to better characterize phenotypic variability and support precision medicine strategies in middle-income settings.

Pharmacogenomics (PGx) is a rapidly evolving field that aims to personalize medicine by identifying genetic variations that influence drug response. While next-generation sequencing (NGS)-based applications are not yet widely adopted in clinical routine, this study aimed to validate 9 genes of the NGS-based Ion AmpliSeq Pharmacogenomics Panel on 28 samples with known diplotypes for routine clinical implementation at Bumrungrad International Hospital (BIH). The panel was evaluated for accuracy (>&#x2009;96.77%), sensitivity (100%), specificity (>&#x2009;95.31%), positive predictive value (PPV; >&#x2009;90.63%), negative predictive value (NPV; 100%), and reproducibility (>&#x2009;99.85%). A novel bioinformatics pipeline, BIH-protocol, was specifically developed and designed to mitigate errors across all measurement metrics, ensuring reliability and accuracy of test results, even in individuals with complex genetic backgrounds. These results demonstrate 100% precision and reliability of the Ion AmpliSeq Pharmacogenomics Panel together with BIH-protocol for genetic variation detection. These findings demonstrate the panel's suitability for integration into routine clinical practice and its potential to advance personalized medicine.

The pathogenic mechanisms of antituberculosis drug-induced liver injury (AT-DILI) remain unclear. Isoniazid and rifampicin may lead to hepatic accumulation of protoporphyrin IX in which heme synthesis ferrochelatase (FECH), a key rate-limiting enzyme, potentially plays an important role. This study aimed to investigate the combined effects of FECH gene polymorphisms and promoter methylation on AT-DILI risk in the Eastern Chinese population. A 1&#x2005;:&#x2005;1 matched case-control study was conducted, detecting one CpG island in the FECH promoter and four single-nucleotide polymorphisms (SNPs). A multivariate conditional logistic regression was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (OR) with 95% confidence intervals (CIs). Additive and multiplicative interactions between methylation status and SNPs were further analyzed: additive interactions via the relative excess risk due to interaction (RERI) with 95% CIs, and multiplicative interactions by incorporating methylation-SNP product terms into regression models. Overall, 182 cases and 182 controls were included. Neither FECH promoter methylation (adjusted OR: 0.978, 95% CI: 0.408-1.560, P &#x2005;=&#x2005;0.509) nor the four SNPs showed individual associations with AT-DILI risk ( P &#x2005;>&#x2005;0.05). Crossover analyses revealed no significant genotype-methylation interactions ( P &#x2005;>&#x2005;0.05). Both additive (rs17063905 RERI: -0.556, P &#x2005;=&#x2005;0.691) and multiplicative interaction models (rs17063905, OR: 0.723, P &#x2005;=&#x2005;0.615) demonstrated no synergistic effects between methylation and polymorphisms. This research finds no significant association between FECH promoter methylation status in the CpG island, polymorphisms, or their interactions and the risk of AT-DILI.

The aim of this study was to elucidate cardiovascular prescriber access, uptake, and attitudes toward CYP2C19 and CYP2D6 genetic testing to guide prescribing of commonly used medications such as clopidogrel, antiarrhythmics, proton pump inhibitors, and antidepressants. A survey, designed in collaboration with the European Society of Cardiology (ESC) WG on Cardiovascular Pharmacotherapy and external experts was disseminated to ESC members using SurveyMonkey. 265 prescribers from 68 countries participated. Most respondents thought testing would be beneficial, though CYP2C19 testing was perceived as more beneficial (73%) and desirable than CYP2D6 (61%). Access to CYP2C19 testing was more common (30%) than CYP2D6 testing (19%), but mostly outside of public funded health systems. Uptake in those who had access was higher for CYP2C19 (67%), than for CYP2D6 (33%). Confidence in interpreting results to prescribe was also higher with CYP2C19 (69%) than with CYP2D6 (53%), but most respondents wanted information prior to prescribing. One third of respondents highlighted the need for a turnaround time that matched their clinical practice. Unsolicited Pharmacogenomic (PGx) information from a patient was uncommon, but most prescribers acted on the information. A minority of respondents had undertaken PGx testing themselves, but most wanted testing for relevant medications. Respondents' experiences as patients made them more likely to believe that PGx testing was warranted. A minority (&#x2009;~&#x2009;15%) were aware of either local prescriber guidance or patient information materials regarding PGx testing. Prescribers want access to pharmacogenomics data regarding CYP2C19 and CYP2D6 for prescribing cardiovascular medicines. However, there are barriers which hamper implementation. Prescribers lived experience with medication use as patients impacted their views of PGx. 265 prescribers responded to the ESC survey from 68 countries. Most prescribers wanted access to pharmacogenomic testing for CYP2C19 and CYP2D6 for their patients and for themselves. Though most prescribers thought these pharmacogenomic tests would be useful and could improve the risk/benefit profile of relevant medications, prescribers responded more positively to CYP2C19 compared with CYP2D6 testing. Guidance and information for both prescribers and patients were lacking.

Antidepressants exhibit a considerable variation in efficacy, and increasing evidence suggests that individual genetics contribute to antidepressant treatment response. Here, we combined data on antidepressant non-response measured using rating scales for depressive symptoms, questionnaires of treatment effect, and data from electronic health records, to increase statistical power to detect genomic loci associated with non-response to antidepressants in a total sample of 135,471 individuals prescribed antidepressants (25,255 non-responders and 110,216 responders). We performed genome-wide association meta-analyses, genetic correlation analyses, leave-one-out polygenic prediction, and bioinformatics analyses for genetically informed drug prioritization. We identified one novel locus (rs1106260) associated with non-response to selective serotonin reuptake inhibitors (SSRIs), and one novel locus (rs60847828) associated with non-response to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) and showed significant polygenic prediction in independent samples. Genetic correlation analyses show positive associations between non-response to antidepressants and most psychiatric traits, and negative associations with cognitive traits and subjective well-being. In addition, we investigated drugs that target proteins likely involved in mechanisms underlying antidepressant non-response, and shortlisted drugs that warrant further replication and validation of their potential to reduce depressive symptoms in individuals who do not respond to first-line antidepressant medications. These results suggest that meta-analyses of GWAS utilizing real-world measures of treatment outcomes can increase sample sizes to improve the discovery of variants associated with non-response to antidepressants.