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AbstractLiquid biopsy is a non-invasive method of detecting cancer-related mutations from circulating cell-free DNA (cfDNA) and has emerged as a promising alternative to traditional tissue biopsies. However, its utility has so far been limited to the detection of somatic mutations in cancer cells. Our study examined germline mutations that are associated with pharmacogenetics in 19 patients diagnosed with colorectal cancer and 12 patients with non-small cell lung carcinoma, utilizing the highly advanced and non-invasive technique of liquid biopsy, followed by subsequent next-generation sequencing for comprehensive analysis. Despite the relatively modest sample size of patients under consideration, our results indicated a noteworthy correlation between the presence of adverse effects and the identified germline mutations. We have identified the following mutations with significant implications for pharmacogenetics: MTHFR c.1286A > C, MTHFR c.665C > T, DPYD c.2194G > A, DPYD c.85C > T, XPC c.2815C > A, UMPS c.638G > C, SLC22A2 c.808T > G, EGFR c.1562G > A, ABCB1 2677 T > G, GSTP1 c.313A > G, ERCC2 c.2251A > C, and SLC19A1 c.80A > G. In addition, we observed various adverse drug reactions in our patient cohort, encompassing myelosuppression, hepatotoxicity, neurotoxicity and gastrointestinal toxicity. Liquid biopsy has the potential to revolutionize cancer diagnosis and treatment by detecting both somatic and germline mutations. The preliminary results of studies on germline mutations are promising, but further research is needed to address the remaining challenges and to establish the utility of liquid biopsy as a reliable diagnostic tool for germline mutations.

Introduction: Pharmacogenomics (PGx) aims to maximize drug benefits while minimizing risk of toxicity. Although PGx has proven beneficial in many settings, clinical uptake lags. Lack of clinician confidence and limited availability of PGx testing can deter patients from completing PGx testing. A few novel PGx clinic models have been described as a way to incorporate PGx testing into the standard of care. Background: A PGx clinic was implemented to fill an identified gap in provider availability, confidence, and utilization of PGx across our health system. Through a joint pharmacist and Advanced Practice Provider (APP) collaborative clinic, patients received counseling and PGx medication recommendations both before and after PGx testing. The clinic serves patients both in-person and virtually across four states in the upper Midwest. Results: The majority of patients seen in the PGx clinic during the early months were clinician referred (77%, n = 102) with the remainder being self-referred. Patients were, on average, taking two medications with Clinical Pharmacogenetics Implementation Consortium guidelines. Visits were split almost equally between in-person and virtual visits. Conclusion: Herein, we describe the successful implementation of an interdisciplinary PGx clinic to further enhance our PGx program. Throughout the implementation of the PGx clinic we have learned valuable lessons that may be of interest to other implementors. Clinicians were actively engaged in clinic referrals and early adoption of telemedicine was key to the clinic's early successes. [ABSTRACT FROM AUTHOR]

Background: Osimertinib has shown greater efficacy than standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and fewer grade 3 or higher adverse drug reactions (ADRs) in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the clinical outcomes of osimertinib treatment vary depending on the patient's ethnicity. Therefore, further research is necessary to evaluate the impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) and drug transporters on the therapeutic outcomes and ADRs to osimertinib in Thai patients, to provide improved pharmacological treatments for cancer patients. Methods: This retrospective and prospective cohort study enrolled 63 Thai patients with NSCLC treated with 80 mg of osimertinib once daily as monotherapy. Seventeen SNPs in candidate genes related to drug metabolism and transport pathways were analyzed in each patient. Chi-square or Fisher's exact tests were used to evaluate the associations between SNPs and clinical outcomes, including ADR incidence and objective response rate (ORR). In addition, the correlation between the genotype and median time to treatment failure (TTF) or progression-free survival (PFS) was assessed using Kaplan-Meier analysis and a log-rank test. Results: We identified six SNPs (rs2231142 and rs2622604 in ABCG2, rs762551 in CYP1A2, rs1057910 in CYP2C9, rs28371759 in CYP3A4, and CYP2A6 deletion polymorphism (CYP2A6*4)) that significantly increased the incidence of ADRs. In addition, we found two SNPs (rs2069514 in CYP1A2 and rs1057910 in CYP2C9) that significantly decreased the median TTF, and two SNPs (rs28399433 in CYP2A6 and rs1057910 in CYP2C9) that significantly decreased the median progression-free survival (PFS). Specifically, we found that one of these SNPs (rs1057910 in CYP2C9) influenced ADRs, TTF, and PFS. Additionally, SNPs in the CYP2A6 heterozygous variant (non4/*4) significantly increased ADR incidence, leading to a high frequency of dose reduction (27.0%). Conclusion: Our study demonstrated significant SNPs associated with increased ADR incidence, decreased PFS, and decreased TTF in Thai patients with NSCLC treated with osimertinib. The CYP2C9 (*3) and CYP2A6 (*4) allele frequencies differed between ethnicities and were associated with an increased incidence of ADRs. These findings highlight the importance of considering genetic factors in NSCLC treatment and may facilitate personalized medicine approaches. Moreover, our study showed a higher incidence of ADRs than the previous trials, including FLAURA and AURA2, and a higher frequency of dose reduction than reported in the AURA 3 trial, possibly due to genetic differences among the study populations. [ABSTRACT FROM AUTHOR]

With the trend towards promoting personalised medicine (PM), the application of pharmacogenetics and pharmacogenomics (PGx) is of growing importance. For the purposes of clinical trials, the inclusion of PGx is an additional tool that should be considered for improving our knowledge about the effectiveness and safety of new drugs. A search of available clinical trials containing pharmacogenetic and PGx information was conducted on ClinicalTrials.gov. The results show there has been an increase in the number of trials containing PGx information since the 2000 s, with particular relevance in the areas of Oncology (28.43%) and Mental Health (10.66%). Most of the clinical trials focus on treatment as their primary purpose. In those clinical trials entries where the specific genes considered for study are detailed, the most frequently explored genes are CYP2D6 (especially in Mental Health and Pain), CYP2C9 (in Hematology), CYP2C19 (in Cardiology and Mental Health) and ABCB1 and CYP3A5 (particularly prominent in Transplantation and Cardiology), among others. Researchers and clinicans should be trained in pharmacogenetics and PGx in order to be able to make a proper interpretation of this data, contributing to better prescribing decisions and an improvement in patients' care, which would lead to the performance of PM. [ABSTRACT FROM AUTHOR]

Tadalafil and finasteride are used in combination for the management of benign prostatic hyperplasia (BPH). Genetic variations in genes involved in the metabolism and transport of tadalafil or finasteride (i.e., pharmacogenes) could affect their pharmacokinetic processes altering their drug exposure, efficacy, and toxicity. The main objective of this study was to investigate the effects of variants in pharmacogenes on the pharmacokinetics of tadalafil and finasteride. An exploratory candidate gene study involving 120 variants in 33 genes was performed with 66 male healthy volunteers from two bioequivalence clinical trials after administration of tadalafil/finasteride 5 mg/5 mg under fed or fasting conditions. Afterwards, a confirmatory study was conducted with 189 male and female volunteers receiving tadalafil 20 mg formulations in seven additional bioequivalence clinical trials. Regarding tadalafil, fed volunteers showed higher area in the time-concentration curve (AUC∞), maximum plasma concentration (Cmax), and time to reach Cmax (tmax) compared to fasting volunteers; male volunteers also showed higher AUC∞ and Cmax compared to female volunteers. Furthermore, fed volunteers presented higher finasteride AUC∞, Cmax and tmax compared to fasting individuals. Variants in ABCC3, CYP1A2, CES1, NUDT15, SLC22A1/A2 and UGT2B10 were nominally associated with pharmacokinetic variation in tadalafil and/or finasteride but did not remain significant after correction for multiple comparisons. Genetic variation did not demonstrate to clinically impact on the pharmacokinetics of finasteride and tadalafil; however, additional studies with larger sample sizes are needed to assess the effect of rare variants, such as CYP3A4*20 or *22, on tadalafil and finasteride pharmacokinetics. [ABSTRACT FROM AUTHOR]

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is part of the standard treatment of colorectal cancer (CRC). Severe adverse dose limiting reactions that impair treatment safety and lead to treatment suspension remain a relevant concern. Single-nucleotide polymorphisms (SNPs) in genes involved in the activation of capecitabine may alter the bioavailability of 5-FU and thereby affect therapy outcomes. The aim of this study was to evaluate the association of these SNPs with severe toxicity and treatment suspension in patients with CRC treated with capecitabine-based therapy. An ambispective cohort study was conducted, including 161 patients with CRC. SNPs were analyzed using real-time PCR with TaqMan® probes. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. CES1 rs71647871-A was associated with a severe hand–foot syndrome (p = 0.030; OR = 11.92; 95% CI = 1.46–73.47; GG vs. A). CDA rs1048977-CC (p = 0.030; OR = 2.30; 95% CI 1.09–5.00; T vs. CC) and capecitabine monotherapy (p = 0.003; OR = 3.13; 95% CI 1.49–6.81) were associated with treatment suspension due to toxicity. SNPs CES1 rs71647871 and CDA rs1048977 may act as potential predictive biomarkers of safety in patients with CRC under capecitabine-based adjuvant therapy. [ABSTRACT FROM AUTHOR]

The modalities for prescribing a psychotropic (dose and choice of molecule) are currently unsatisfactory, which can lead to a lack of efficacy of the treatment associated with prolonged exposure of the patient to the symptoms of his or her illness and the side effects of the molecule. In order to improve the quality of treatment prescription, a part of the current biomedical research is dedicated to the development of pharmacogenetic tools for individualized prescription. In this guideline, we will present the genes of interest with level 1 clinical recommendations according to PharmGKB for the two major families of psychotropics: antipsychotics and antidepressants. For antipsychotics, there are CYP2D6 and CYP3A4, and for antidepressants, CYP2B6, CYP2D6, and CYP2C19. The study will focus on describing the role of each gene, presenting the variants that cause functional changes, and discussing the implications for prescriptions in clinical practice. [ABSTRACT FROM AUTHOR]

Background: A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs. Hypothesis: PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet‐rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results. Animals: Fifty‐two privately owned CKCS with no or preclinical MMVD. Methods: Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate‐induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography. Results: Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 μM (P <.0001) and Vel at 0.03 μM (P <.001). PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response. Conclusions and Clinical Importance: The PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment. [ABSTRACT FROM AUTHOR]

This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active and inactive metabolites that influence their therapeutic effects. The research examines the role of genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) in predicting the therapeutic response and adverse effects of thiopurine treatment. The TPMT genotype variations impact the individual responses to thiopurines. Patients with reduced TPMT activity are more susceptible to adverse reactions (AEs), such leukopenia, hepatotoxicity, pancreatitis, and nausea, which are common adverse effects of thiopurine therapy. The therapeutic monitoring of the metabolites 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP) is proposed to optimize treatment and minimize AEs. Patients with higher 6-TGN levels tend to have better clinical responses, while elevated 6-MMP levels are linked to hepatotoxicity. Genotyping for TPMT before or during treatment initiation is suggested to tailor dosing strategies and enhance treatment efficacy while reducing the risk of myelosuppression. In conclusion, this study highlights the importance of considering genetic variations and metabolite levels in optimizing thiopurine therapy for IBD patients, focusing on balance therapeutic efficacy with the prevention of adverse effects and contributing to personalized treatment and better patient outcomes. [ABSTRACT FROM AUTHOR]

Purpose of Review: Advances in pharmacogenomics have paved the way for personalized medicine. Cardiovascular diseases still represent the leading cause of mortality in the world. The aim of this review is to summarize the background, rationale, and evidence of pharmacogenomics in cardiovascular medicine, in particular, the use of antiplatelet drugs, anticoagulants, and drugs used for the treatment of dyslipidemia. Recent findings: Randomized clinical trials have supported the role of a genotype-guided approach for antiplatelet therapy in patients with coronary heart disease undergoing percutaneous coronary interventions. Numerous studies demonstrate how the risk of ineffectiveness of new oral anticoagulants and vitamin K anticoagulants is linked to various genetic polymorphisms. Furthermore, there is growing evidence to support the association of some genetic variants and poor adherence to statin therapy, for example, due to the appearance of muscular symptoms. There is evidence for resistance to some drugs for the treatment of dyslipidemia, such as anti-PCSK9. Summary: Pharmacogenomics has the potential to improve patient care by providing the right drug to the right patient and could guide the identification of new drug therapies for cardiovascular disease. This is very important in cardiovascular diseases, which have high morbidity and mortality. The improvement in therapy could be reflected in the reduction of healthcare costs and patient mortality. [ABSTRACT FROM AUTHOR]

Background: Imatinib is presently the first-line choice for the treatment of chronic myeloid leukemia. However, there are limited real-world data on Chinese patients to support individualized medicine. This work aims to characterize population pharmacokinetics in Chinese patients with chronic myeloid leukemia, investigate the effects of several covariates on imatinib exposure, and provide support for personalized medicine and dose reduction. Methods: A total of 230 patients with chronic myeloid leukemia were enrolled, and 424 steady-state concentration measurements were taken to perform the population pharmacokinetic analysis and Monte Carlo simulations with Phoenix NLME software. The effects of the demographic, biological, and pharmacogenetic (ten SNP corresponding to CYP3A4, CYP3A5, ABCB1, ABCG2, SCL22A1 and POR) covariates on clearance were evaluated. Results: A one-compartmental model best-described imatinib pharmacokinetics. The hemoglobin and the estimated glomerular filtration rate (< 85 mL⋅min−1⋅1.73 m2) were associated with imatinib clearance. The genetic polymorphisms related to pharmacokinetics were not found to have a significant effect on the clearance of imatinib. The final model estimates of parameters are: ka (h−1) = 0.329; Vd/F (L) = 270; CL/F (L⋅h−1) = 7.60. Conclusions: Key covariates in the study population accounting for variability in imatinib exposure are hemoglobin and the estimated glomerular filtration rate. There is some need for caution when treating patients with moderate-to-severe renal impairment and significant hemoglobin changes. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) is the leading cause of late-onset blindness in elderly. The occurrence and development of AMD is a multifactorial complex process where autophagy plays an important role. The first-line drugs for neovascular AMD (nAMD) are inhibitors of VEGF, with up to 30% of patients having an incomplete response to treatment. Genetic factors may influence the response to anti-VEGF therapy and explain treatment outcome variability. We aimed to estimate the role of polymorphic markers of the MTOR (rs1064261, rs1057079, rs11121704, rs2295080), SQSTM1 (rs10277), ULK1 (rs11246867, rs3088051), MAP1LC3A (rs73105013) and ATG5 (rs573775) genes in the development of nAMD and the efficacy of anti-VEGF therapy response. Methods: Genotyping by allele-specific PCR was performed in 317 controls and 315 nAMD patients in the Russian population. Of them, 196 treatment-naive nAMD patients underwent three monthly intravitreal injections (IVIs) of aflibercept. Genotypic frequencies were compared with OCT markers of therapy effectiveness and best-corrected visual acuity (BCVA) measures. The main outcomes were the BCVA gain and decrease in central retinal thickness (CRT). Results: MTOR-rs1057079-C, MTOR-rs11121704-C and MTOR-rs2295080-G alleles were associated with an increased risk of nAMD. The BCVA was increased in 117 (59.7%) patients by 10 [5–20] letters, did not changed in 59 (30.1%), and was decreased in 20 (10.2%) patients. ULK1-rs3088051 was associated with BCVA change. Among patients with the TT and CT genotypes for ULK1-rs3088051, an improvement in visual acuity was noted in 67.6% and 53.8% of cases, while in patients with the CC genotype, an increase in BCVA was recorded in 37.5% of cases (p = 0.01). The decrease in CRT was associated with SQSTM1-rs10277 (p = 0.001): it was significantly higher in TT (93 [58–122] mkm) and CT (66 [30–105] mkm) carriers compared to the CC genotype (47 [24–68] mkm). Other SNPs did not show significant associations with the outcome of anti-VEGF treatment. Conclusions: MTOR gene polymorphisms are moderately associated with the risk of nAMD. SQSTM1-rs10277 and ULK1-rs3088051 may influence short-term response to intravitreal anti-VEGF treatment. The results suggest that autophagy could be a target for future drugs to overcome resistance to anti-VEGF therapy. [ABSTRACT FROM AUTHOR]

Introduction: Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir, allopurinol, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, or flucloxacillin. Transplant patients are genotyped for HLA as a routine practice to match a potential donor to a recipient. This study aims to investigate the feasibility and potential impact of repurposing these HLA genotype data from kidney transplant patients to prevent drug hypersensitivity reactions. Methods: A cohort of 1347 kidney transplant recipients has been genotyped in the Leiden University Medical Center (LUMC) using next-generation sequencing (NGS). The risk alleles HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*57:01, and HLA-B*58:01 were retrieved from the NGS data. Medical history, medication use, and allergic reactions were obtained from the patient's medical records. Carrier frequencies found were compared to a LUMC blood donor population. Results: A total of 13.1% of transplant cohort patients carried at least one of the five HLA risk alleles and therefore had an increased risk of drug-induced hypersensitivity for specific drugs. HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01 were found in carrier frequencies of 4.61%, 1.19%, 4.46%, and 3.35% respectively. No HLA-B*15:11 carrier was found. In total nine HLA-B*57:01 carriers received flucloxacillin and seven HLA-B*58:01 carriers within our cohort received allopurinol. Discussion: Our study shows that repurposing HLA genotype data from transplantation patients for the assignment of HLA risk alleles associated with drug hypersensitivity is feasible. The use of these data by physicians while prescribing drugs or by the pharmacist when dispensing drugs holds the potential to prevent drug hypersensitivity reactions. The utility of this method was highlighted by 13.1% of the transplant cohort patients carrying an actionable HLA allele. [ABSTRACT FROM AUTHOR]

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters' genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, β = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, β = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics. [ABSTRACT FROM AUTHOR]

Pharmacogenomics (PGx) is an integral part of precision medicine and contributes to the maximization of drug efficacy and reduction of adverse drug event risk. Accurate information on PGx allele frequencies improves the implementation of PGx. Nonetheless, curating such information from published allele data is time and resource intensive. The limited number of allelic variants in most studies leads to an underestimation of certain alleles. We applied the Pharmacogenomics Clinical Annotation Tool (PharmCAT) on an integrated 200K UK Biobank genetic dataset (N = 200,044). Based on PharmCAT results, we estimated PGx frequencies (alleles, diplotypes, phenotypes, and activity scores) for 17 pharmacogenes in five biogeographic groups: European, Central/South Asian, East Asian, Afro-Caribbean, and Sub-Saharan African. PGx frequencies were distinct for each biogeographic group. Even biogeographic groups with similar proportions of phenotypes were driven by different sets of dominant PGx alleles. PharmCAT also identified "no-function" alleles that were rare or seldom tested in certain groups by previous studies, e.g., SLCO1B1 ∗31 in the Afro-Caribbean (3.0%) and Sub-Saharan African (3.9%) groups. Estimated PGx frequencies are disseminated via the PharmGKB (The Pharmacogenomics Knowledgebase: www.pharmgkb.org). We demonstrate that genetic biobanks such as the UK Biobank are a robust resource for estimating PGx frequencies. Improving our understanding of PGx allele and phenotype frequencies provides guidance for future PGx studies and clinical genetic test panel design, and better serves individuals from wider biogeographic backgrounds. The frequencies of pharmacogenomic alleles/haplotypes, diplotypes, and phenotypes in five biogeographic groups were estimated using an integrated UK Biobank genetic data set and the Pharmacogenomics Clinical Annotation Tool (PharmCAT). Rare partial alleles and combinations of known pharmacogenomic alleles were reported. The frequencies will be disseminated via the Pharmacogenomics Knowledgebase (PharmGKB). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Tamoxifen is the most used hormonal therapy for oestrogen receptor‐positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC‐MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/mL, and in 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold of 5.97 ng/mL. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (P = 0.0151) and with endoxifen to N‐desmethyl‐tamoxifen ratios (P = 0.0006). [ABSTRACT FROM AUTHOR]

Introduction: Up to 73% of individuals with autism spectrum disorder (ASD) and intellectual disability (ID) currently have prescriptions for psychotropic drugs. This is explained by a higher prevalence of medical and psychiatric chronic comorbidities, which favors polypharmacy, increasing the probability of the appearance of adverse events (AEs). These could be a preventable cause of harm to patients with ASD and an unnecessary waste of healthcare resources. Objective: To study the impact of pharmacogenetic markers on the prevention of AE appearance in a population with ASD and ID. Methods: This is a cross-sectional, observational study (n = 118, 72 participants completed all information) in the ASD population. Sociodemographic and pharmacological data were gathered. The Udvalg for Kliniske Undersøgelser Scale (UKU Scale) was used to identify AEs related to the use of psychotropic medication. Polymorphisms of DOP2, ABCB1, and COMT were genotyped and correlated with the AE to find candidate genes. Furthermore, a review of all medications assessed in a clinical trial for adults with autism was performed to enrich the search for potential pharmacogenetic markers, keeping in mind the usual medications. Results: The majority of the study population were men (75%) with multiple comorbidities and polypharmacy, the most frequently prescribed drugs were antipsychotics (69%); 21% of the participants had four or more AEs related to psychotropic drugs. The most common were "Neurological" and" Psychiatric" (both 41%). Statistical analysis results suggested a significant correlation between the neurological symptoms and the DOP2 genotype, given that they are not equally distributed among its allelic variants. The final review considered 19 manuscripts of medications for adults with ASD, and the confirmed genetic markers for those medications were consulted in databases. Conclusion: A possible correlation between neurologic AEs and polymorphisms of DOP2 was observed; therefore, studying this gene could contribute to the safety of this population's prescriptions. The following studies are underway to maximize statistical power and have a better representation of the population. [ABSTRACT FROM AUTHOR]

Aims: Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration. Methods: PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. Results: The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients. Conclusions: This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly. [ABSTRACT FROM AUTHOR]

Personalized medicine is a desideratum that presents the advantages of increased efficacy and superior tolerability, which would improve the therapeutic adherence, the quality of life and the functional recovery of the patient. Integrating anamnestic, clinical, laboratory, genetic and imaging data in the case management also allows for evidence-based choice of optimal treatment in patients with psychiatric disorders. This case study illustrates how pharmacogenetic testing can guide medication choice in first-line agent non-responsiveness and how augmentation agents can be selected for situations of partial response in a patient with recurrent major depressive disorder (MDD). Although it is desirable that the introduction of pharmacogenetic testing in the clinical practice of the psychiatrist become routine, there are still undeniable economic and procedural aspects that prevent the generalization of this recommendation. Changing the physician’s perspective on selecting drugs for difficult-to-treat psychiatric conditions is another goal of this case report. Despite the aforementioned impediments, it is recommended to perform a pharmacogenetic test in cases where there is an insufficient response to the current psychotropic medication, there are tolerability issues even though the doses used are within the therapeutic range, or a history of lack of response to treatment is detected during the previous episodes. [ABSTRACT FROM AUTHOR]

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β‐adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross‐sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self‐described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p =.0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p =.0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions. [ABSTRACT FROM AUTHOR]

Pharmacogenomic (PGx) testing to inform antidepressant medication selection and dosing is gaining attention from healthcare professionals, patients, and payors in Australia. However, there is often uncertainty regarding which test is most suitable for a particular patient. Here, we identified and evaluated the coverage of CYP2D6 and CYP2C19 variants in commercial antidepressant PGx testing panels in Victoria, a large and ethnically diverse state of Australia. Test characteristics and star alleles tested for both genes were obtained directly from pathology laboratories offering PGx testing and compared against the Association of Molecular Pathology's recommended minimum (Tier 1) and extended (Tier 2) allele sets. Although all tests covered the minimum recommended alleles for CYP2C19, this was not the case for CYP2D6. This study emphasizes that PGx tests might not be suitable for all individuals in Australia due to the limited range of star alleles assessed. Inadequate haplotype coverage may risk misclassification of an individual's predicted metabolizer phenotype, which has ramifications for depression medication selection and dosage. This study underscores the urgent need for greater standardization in PGx testing and emphasizes the importance of considering genetic ancestry when choosing a PGx testing panel to ensure optimal clinical applicability. [ABSTRACT FROM AUTHOR]

Pharmacogenetics (PGx) can explain/predict drug therapy outcomes. There is, however, unclarity about the use and usefulness of PGx in primary care. In this study, we investigated PGx tests ordered by general practitioners (GPs) in 2021 at Dept. Clinical Chemistry, Erasmus MC, and analyzed the gene tests ordered, drugs/drug groups, reasons for testing and single-gene versus panel testing. Additionally, a survey was sent to 90 GPs asking about their experiences and barriers to implementing PGx. In total, 1206 patients and 6300 PGx tests were requested by GPs. CYP2C19 was requested most frequently (17%), and clopidogrel was the most commonly indicated drug (23%). Regarding drug groups, antidepressants (51%) were the main driver for requesting PGx, followed by antihypertensives (26%). Side effects (79%) and non-response (27%) were the main indicators. Panel testing was preferred over single-gene testing. The survey revealed knowledge on when and how to use PGx as one of the main barriers. In conclusion, PGx is currently used by GPs in clinical practice in the Netherlands. Side effects are the main reason for testing, which mostly involves antidepressants. Lack of knowledge is indicated as a major barrier, indicating the need for more education on PGx for GPs. [ABSTRACT FROM AUTHOR]

Background The clinical heterogeneity in major depressive disorder (MDD), variable treatment response, and conflicting findings limit the ability of genomics toward the discovery of evidence-based diagnosis and treatment regimen. This study attempts to curate all genetic association findings to evaluate potential variants for clinical translation. Methods We systematically reviewed all candidates and genome-wide association studies for both MDD susceptibility and antidepressant response, independently, using MEDLINE, particularly to identify replicated findings. These variants were evaluated for functional consequences using different in silico tools and further estimated their diagnostic predictability by calculating positive predictive values. Results A total of 217 significantly associated studies comprising 1200 variants across 545 genes and 128 studies including 921 variants across 412 genes were included with MDD susceptibility and antidepressant response, respectively. Although the majority of associations were confirmed by a single study, we identified 31 and 18 replicated variants (in at least 2 studies) for MDD and antidepressant response. Functional annotation of these 31 variants predicted 20% coding variants as deleterious/damaging and 80.6% variants with regulatory effect. Similarly, the response-related 18 variants revealed 25% coding variant as damaging and 88.2% with substantial regulatory potential. Finally, we could calculate the diagnostic predictability of 19 and 5 variants whose positive predictive values ranges from 0.49 to 0.66 for MDD and 0.36 to 0.66 for response. Conclusions The replicated variants presented in our data are promising for disease diagnosis and improved response outcomes. Although these quantitative assessment measures are solely directive of available observational evidence, robust homogenous validation studies are required to strengthen these variants for molecular diagnostic application. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result interpretation could maximize its potential benefits. However, studies on genetics of pharmacokinetic genes including the functional enzyme status are lacking. Aim: The retrospective analyses of clinical routine data aimed to investigating how the CYP2D6 functional enzyme status affects serum concentrations and metabolite-to-parent ratios of seven common psychotropic drugs and allows an evaluation of the relevance of this information for patient care. Method: Two patient cohorts (total n = 316; 44.2 ± 15.4 years) were investigated for the CYP2D6 functional enzyme status and its associations with drug exposure and metabolism of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone and quetiapine. Results: We found an increase in intermediate and poor metabolizers, as well as a decrease in normal metabolizers of CYP2D6 when including PC. Moreover, we found associations between amitriptyline exposure with the phenoconversion-corrected activity score of CYP2D6 (Spearman correlation; p = 0.03), and risperidone exposure with CYP2D6 functional enzyme status (Kruskal–Wallis test; p = 0.01), as well as between metabolite-to-parent ratio of venlafaxine and risperidone with CYP2D6 functional enzyme status (Kruskal–Wallis test; p < 0.001; p = 0.05). Conclusion: The data stress the relevance of PC-informed PGx in psychopharmacological treatment and suggest that PC should be included in PGx result interpretation when PGx is implemented in routine clinical care, especially before initiating amitriptyline- or risperidone-treatment, to start with a dose adequate to the respective CYP2D6 functional enzyme status. Moreover, PGx and therapeutic drug monitoring should be used complementary but not alternatively. [ABSTRACT FROM AUTHOR]

Purpose of Review: Axial spondyloarthritis (AxSpA) is among the rheumatology's most heritable complex diseases, yet precision medicine at clinics still needs to be explored. We reviewed the emerging concepts and recent developments in polygenic risk scores, Mendelian randomization, pharmacogenomics, single-cell sequencing, and spatial transcriptomics. Recent Findings: Polygenic risk score has resulted in encouraging results with potential diagnostic utility as it appears to outperform current diagnostic tools. Its performance and generalizability vary with ethnicity. Mendelian randomization has elucidated multiple causal associations, particularly between inflammatory bowel disease and AxSpA. Single-cell transcriptomics (particularly scRNA-seq and scATAC-seq) has identified numerous cell types, including synovial and blood immunological cells, to understand the contribution of both innate and adaptative immunity in AxSpA. Summary: Current molecular tools provide an exciting opportunity to advance precision medicine for AxSpA patients. However, extensive research and implementation strategies are still required before they can have an impact in the clinic. [ABSTRACT FROM AUTHOR]

Background: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is an X-linked disorder affecting over 400 million people worldwide. Individuals with molecular variants associated with reduced enzymatic activity are susceptible to oxidative stress in red blood cells, thereby increasing the risk of pathophysiological conditions and toxicity to anti-malarial treatments. Globally, the prevalence of G6PDd varies among populations. Accordingly, this study aims to characterize G6PDd distribution within the Ecuadorian population and to describe the spatial distribution of reported malaria cases. Methods: Molecular variants associated with G6PDd were genotyped in 581 individuals from Afro-Ecuadorian, Indigenous, Mestizo, and Montubio ethnic groups. Additionally, spatial analysis was conducted to identify significant malaria clusters with high incidence rates across Ecuador, using data collected from 2010 to 2021. Results: The A- c.202G > A and A- c.968T > C variants underpin the genetic basis of G6PDd in the studied population. The overall prevalence of G6PDd was 4.6% in the entire population. However, this frequency increased to 19.2% among Afro-Ecuadorian people. Spatial analysis revealed 12 malaria clusters, primarily located in the north of the country and its Amazon region, with relative risks of infection of 2.02 to 87.88. Conclusions: The findings of this study hold significant implications for public health interventions, treatment strategies, and targeted efforts to mitigate the burden of malaria in Ecuador. The high prevalence of G6PDd among Afro-Ecuadorian groups in the northern endemic areas necessitates the development of comprehensive malaria eradication strategies tailored to this geographical region. [ABSTRACT FROM AUTHOR]

Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade =3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. Conclusion: DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia. [ABSTRACT FROM AUTHOR]

Background: Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of life and survivorship in affected patients. Genetic polymorphisms in the CYP3A family have been investigated but the findings have been inconsistent and contradictory. Methods: A systematic review identified 12 pharmacogenetic studies investigating genetic variation in CYP3A4*22 and CYP3A5*3 and TIPN. In our candidate gene study, 288 eligible participants (211 taxane participants receiving docetaxel or paclitaxel, and 77 control participants receiving oxaliplatin) were successfully genotyped for CYP3A4*22 and CYP3A5*3. Genotyping data was transformed into a combined CYP3A metaboliser phenotype: Poor metabolisers, intermediate metabolisers and extensive metabolisers. Individual genotypes and combined CYP3A metaboliser phenotypes were assessed in relation to neurotoxicity, including by meta-analysis where possible. Results: In the systematic review, no significant association was found between CYP3A5*3 and TIPN in seven studies, with one study reporting a protective association. For CYP3A4*22, one study has reported an association with TIPN, while four other studies failed to show an association. Evaluation of our patient cohort showed that paclitaxel was found to be more neurotoxic than docetaxel (p < 0.001). Diabetes was also significantly associated with the development of TIPN. The candidate gene analysis showed no significant association between either SNP (CYP3A5*3 and CYP3A4*22) and the development of TIPN overall, or severe TIPN. Meta-analysis showed no association between these two variants and TIPN. Transformed into combined CYP3A metaboliser phenotypes, 30 taxane recipients were poor metabolisers, 159 were intermediate metabolisers, and 22 were extensive metabolisers. No significant association was observed between metaboliser status and case-control status. Summary: We have shown that the risk of peripheral neuropathy during taxane chemotherapy is greater in patients who have diabetes. CYP3A genotype or phenotype was not identified as a risk factor in either the candidate gene analysis or the systematic review/meta-analysis, although we cannot exclude the possibility of a minor contribution, which would require a larger sample size. [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of neurodegenerative disorders has increased, yet reliable, pre-symptomatic biomarkers for early detection and subsequent preventive interventions remain elusive. The aim of our study was to understand the interplay between DNA methylation, a crucial biological process that modifies DNA activity, genetic composition, and the impact of drugs on neurodegenerative diseases. We distinguished two patient groups based on their DNA methylation levels and found unique drug-response patterns and gene-interaction dynamics within each group. These variations in gene interactions produced differential treatment responses that correlated with temporal changes in DNA methylation. Our findings highlight the critical role of specific genes, including CYP1A2, CYP2E1, CHAT, and various transporter genes, in shaping DNA methylation and treatment outcomes. Moreover, gene variants such as APOE and NBEA influenced disease progression and treatment response. The complexity of these interactions was further underscored by the varied responses of other genes such as the drug metabolizing genes CYP4F2, NAT2, and COMT. Our study highlights the potential of precision medicine in managing neurodegenerative disorders by tailoring treatments to individual genetic and epigenetic profiles. By deepening our understanding of these interactions, we can potentially improve treatment efficacy, thereby reducing the societal burden of neurodegenerative diseases. Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including CYP1A2, CYP2C9, CYP4F2, GSTP1, and NAT2, that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolizers compared to patients in Group A, did not show an improvement in 5mC levels during follow-up. Furthermore, there were significant differences in phenotype distribution between patient Groups A and B for several SNPs associated with transporter genes (ABCB1, ABCC2, SLC2A9, SLC39A8, and SLCO1B1) and pathogenic genes (APOE, NBEA, and PTGS2). These findings appear to suggest that the interplay between pharmacogenomics and DNA methylation has important implications for improving treatment outcomes in patients with brain-related disorders. [ABSTRACT FROM AUTHOR]

Tumor Necrosis Factor-alpha (TNFα) rs1800629 (-308G>A) is a single nucleotide polymorphism (SNP) related to variable responses to anti-TNFα therapy. This therapy is efficient in severe and refractory manifestation of Behçet syndrome (BS), an auto-inflammatory systemic vasculitis. We investigated (1) the association between rs1800629 genotypes and responses to therapy and (2) the correlation between SNP and clinical patterns in a cohort of 74 BS Italian patients receiving anti-TNFα therapy with a follow-up of at least 12 months. The rs1800629 was genotyped through amplification, direct sequencing and bioinformatics analyses. The rs1800629 GG and GA genotypes were assessed as predictors of outcomes dividing the patients between therapy responders and non-responders. The rs1800629 GG and GA genotypes were found, respectively, in 59/74 (79.7%) and 15/74 BS patients (21.3%) (p < 0.05). We identified 16/74 (21.9%) non-responder patients, of which 9/16 (56.3%) showed the GG genotype and 7/16 (43.7%) the GA genotype. A total of 50/58 (86.2%) responder patients showed the GG genotype, and 8/58 (13.8%) the GA genotype (p < 0.05). The percentage of non-responder females (68.8%) was significantly higher than non-responder males (31.2%) (p < 0.05). No correlation between SNP and clinical patterns was observed. To successfully include rs1800629 as a predictive biomarker of TNFα inhibitor response, genome-wide association studies in larger, well-characterised cohorts are required. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used psychopharmaceutical treatment for major depressive disorder (MDD), but individual responses to SSRIs vary greatly. CYP2C19 is a key enzyme involved in the metabolism of several drugs, including SSRIs. Variations in the CYP2C19 gene are associated with differential metabolic activity, and thus differential SSRI exposure; accordingly, the CYP2C19 genotype may affect the therapeutic response and clinical outcomes, though existing evidence of this link is not entirely consistent. Therefore, we analysed data from the UK Biobank, a large, deeply phenotyped prospective study, to investigate the effects of CYP2C19 metaboliser phenotypes on several clinical outcomes derived from primary care records, including multiple measures of antidepressant switching, discontinuation, duration, and side effects. In this dataset, 24,729 individuals were prescribed citalopram, 3012 individuals were prescribed escitalopram, and 12,544 individuals were prescribed sertraline. Consistent with pharmacological expectations, CYP2C19 poor metabolisers on escitalopram were more likely to switch antidepressants, have side effects following first prescription, and be on escitalopram for a shorter duration compared to normal metabolisers. CYP2C19 poor and intermediate metabolisers on citalopram also exhibited increased odds of discontinuation and shorter durations relative to normal metabolisers. Generally, no associations were found between metabolic phenotypes and proxies of response to sertraline. Sensitivity analyses in a depression subgroup and metabolic activity scores corroborated results from the primary analysis. In summary, our findings suggest that CYP2C19 genotypes, and thus metabolic phenotypes, may have utility in determining clinical responses to SSRIs, particularly escitalopram and citalopram, though further investigation of such a relationship is warranted. [ABSTRACT FROM AUTHOR]

Objective: To examine whether serotonin (5-HT) related genetic variants moderate the effects of selective serotonin reuptake inhibitors (SSRIs) on skeletal outcomes. Methods: Trabecular bone mineral density (BMD) at the radius, lumbar spine (LS) BMD, total body less head (TBLH) bone mineral content (BMC) and markers of bone metabolism (osteocalcin, C-terminal telopeptide of type I collagen [CTX-1], and bone specific alkaline phosphatase to CTX-1 ratio) were examined in an observational study, enrolling 15- to 20-year-old participants, unmedicated or within a month of SSRI initiation. Variants in HTR1A (rs6295), HTR1B (rs6296), HTR1D (rs6300), HTR2A (rs6311 and rs6314), HTR2B (rs6736017), and the serotonin transporter intron 2 variable number tandem repeat (STin2 VNTR) were genotyped. Linear mixed-effects regression analysis examined associations between SSRI use, genetic variants, and skeletal outcomes. Results: After adjusting for relevant covariates, rs6295 CC and GC genotypes in 262 participants (60% female, mean ± SD age = 18.9 ± 1.6 years) were significantly associated with higher LS BMD compared to the GG genotype. Rs6311 GG SSRI users had greater LS BMD compared to nonusers (β = 0.18, p = <0.0001). Female SSRI users with the combination of rs6295 CC+GC and rs6311 GG genotypes had greater LS BMD than female SSRI nonusers (β = 0.29, p < 0.0001). SSRI users with the rs6295 GG genotype had higher trabecular BMD compared to nonusers (β = 3.60, p = 0.05). No significant interactions were found for TBLH BMC or bone turnover markers. After correcting for multiple comparisons, none of the results retained significance. Conclusions: In older adolescents and young adults, HTR1A (rs6295) and HTR2A (rs6311) variants may moderate the effect of SSRIs on BMD. Sex differences may exist and require further examination. Further research with larger sample sizes is needed to confirm our preliminary findings. Clinical Trial Registration: clinicaltrials.gov NCT02147184. [ABSTRACT FROM AUTHOR]

Background: Methotrexate (MTX) is one of the most extensively used drugs in the treatment of moderate-to-severe psoriasis (PS). However, it frequently must be suspended owing to the toxicity in certain patients. Objective: To evaluate the influence of ABCC1, ABCG2, and FOXP3 in the development of MTX toxicity in PS. Methods: Retrospective cohort study with 101 patients. Five single-nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction with TaqMan probes. Results: Patients carrying ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.04; 95% CI = 1.48–46.78; p = 0.015); FOXP3 rs376154-GT and GG genotypes (GT vs. TT/GG: OR = 3.86; 95% CI = 1.17–13.92; p = 0.031) and ABCG2 rs13120400-T allele (T vs. CC: OR = 8.33; 95% CI = 1.24–164.79; p = 0.059) showed a higher risk of developing more than one adverse effect. The toxicity analysis by subtypes showed that the ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.10; 95% CI = 1.69–46.63; p = 0.011) and FOXP3 rs376154-GT genotype (OR = 4.11; 95% CI = 1.22–15.30; p = 0.027) were associated with the appearance of asthenia. No association of the other ABCC1 polymorphisms (rs35592 and rs246240) with MTX toxicity was found. Conclusion: ABCC1, ABCG2, and FOXP3 polymorphisms can be considered to be risk biomarkers of toxicities in PS patients treated with MTX. [ABSTRACT FROM AUTHOR]

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.

BackgroundThe randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine.MethodsThere were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients.ResultsNone of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant.ConclusionsWe found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.