Front Med (Lausanne). 2022 Aug 18;9:945352. doi: 10.3389/fmed.2022.945352. eCollection 2022.

ABSTRACT

Several healthcare organizations have developed pre-emptive pharmacogenetic testing programs, where testing is undertaken prior to the prescription of a medicine. This review characterizes the barriers and facilitators which influenced the development of these programs. A bidirectional citation searching strategy identified relevant publications before a standardized data extraction approach was applied. Publications were grouped by program and data synthesis was undertaken using the Consolidated Framework for Implementation Research (CFIR). 104 publications were identified from 40 programs and 4 multi-center initiatives. 26 (66%) of the programs were based in the United States and 95% in high-income countries. The programs were heterogeneous in their design and scale. The Characteristics of the Intervention, Inner Setting, and Process domains were referenced by 92.5, 80, and 77.5% of programs, respectively. A positive institutional culture, leadership engagement, engaging stakeholders, and the use of clinical champions were frequently described as facilitators to implementation. Clinician self-efficacy, lack of stakeholder knowledge, and the cost of the intervention were commonly cited barriers. Despite variation between the programs, there were several similarities in approach which could be categorized via the CFIR. These form a resource for organizations planning the development of pharmacogenetic programs, highlighting key facilitators which can be leveraged to promote successful implementation.

PMID:36059837 | PMC:PMC9433561 | DOI:10.3389/fmed.2022.945352

Hum Mutat. 2022 Sep 4. doi: 10.1002/humu.24457. Online ahead of print.

ABSTRACT

To determine the phase of NUDT15 sequence variants for more comprehensive star (*) allele diplotyping, we developed a novel long-read single molecule real-time HiFi amplicon sequencing method. A 10.5 kb NUDT15 amplicon assay was validated using reference material positive controls and additional samples for specimen type and blinded accuracy assessment. Triplicate NUDT15 HiFi sequencing of two reference material samples had non-reference genotype concordances of >99.9%, indicating that the assay is robust. Notably, short-read genome sequencing of a subset of samples was unable to determine the phase of star (*) allele-defining NUDT15 variants, resulting in ambiguous diplotype results. In contrast, long-read HiFi sequencing phased all variants across the NUDT15 amplicons, including a *2/*9 diplotype that previously was characterized as *1/*2 in the 1000 Genomes Project v3 dataset. Assay throughput was also tested using 8.5 kb amplicons from 100 Ashkenazi Jewish individuals, which identified a novel NUDT15 *1 sub-allele (c.-121G>A) and a rare likely-deleterious coding variant (p.Pro129Arg). Both novel alleles were Sanger confirmed and assigned as *1.007 and *20, respectively, by the PharmVar Consortium. Taken together, NUDT15 HiFi amplicon sequencing is an innovative method for phased full-gene characterization and novel allele discovery, which could improve NUDT15 pharmacogenomic testing and subsequent phenotype prediction. This article is protected by copyright. All rights reserved.

PMID:36057977 | DOI:10.1002/humu.24457

Eur J Hum Genet. 2022 Sep 2. doi: 10.1038/s41431-022-01180-0. Online ahead of print.

ABSTRACT

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.

PMID:36056234 | DOI:10.1038/s41431-022-01180-0

Alcohol Clin Exp Res. 2022 Sep 2. doi: 10.1111/acer.14932. Online ahead of print.

ABSTRACT

BACKGROUND: In a previous study, ondansetron, a serotonin 5-HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4), and 5-HT3A (HTR3A) and 5-HT3B (HTR3B) receptors. We tested whether 1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA) and 2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B.

METHODS: In this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" vs. "non-responsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across 16 weeks of treatment.

RESULTS: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent-to-treat analysis, the ondansetron group averaged 0.40 more DPDD (p=0.51), 1.35 times as many HDD (p=0.16), and 1.06 times as many DPD (p=0.59) as the placebo group. There were no significant interactions with genotype. There were no study-related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems.

CONCLUSIONS: We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.

PMID:36055978 | DOI:10.1111/acer.14932

Mol Metab. 2022 Aug 30:101588. doi: 10.1016/j.molmet.2022.101588. Online ahead of print.

ABSTRACT

Thermogenic fat differentiation and function can be promoted through multiple pathways, resulting in a common cell phenotype characterized by the expression of Uncoupling Protein-1 and the ability to dissipate energy, but local and systemic stimuli are necessary to promote adequate thermogenic fat vascularization, which is a precondition for the transport of substrate and the dissipation of heat. Angiopoietin-2 is an important driver of vascularization, and its transcription is in part promoted by estrogen signaling. In this study we demonstrate that adipose tissue-specific knock out of Angiopoietin-2 causes a female-specific reduced thermogenic fat differentiation and function, resulting in obesity and impaired glucose tolerance with end-organ features consistent with metabolic syndrome. In humans, angiopoietin-2 levels are higher in females than in males, and are inversely correlated with adiposity and age more strongly in pre-menopause when compared to post-menopause. Collectively, these data indicate a novel and important role for estrogen-mediated Angiopoietin-2 adipose tissue production in the protection against calorie overload in females, and potentially in the development of postmenopausal weight gain.

PMID:36055577 | DOI:10.1016/j.molmet.2022.101588

Am J Hum Genet. 2022 Sep 1;109(9):1638-1652. doi: 10.1016/j.ajhg.2022.08.004.

ABSTRACT

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

PMID:36055212 | DOI:10.1016/j.ajhg.2022.08.004

Tuberculosis (Edinb). 2022 Aug 25;136:102248. doi: 10.1016/j.tube.2022.102248. Online ahead of print.

ABSTRACT

Rifampicin is one of the most important drugs for the treatment of tuberculosis (TB). Polymorphisms in SLCO1B1 and SLC10A1 genes are associated with impaired transporter function of drug compounds such as rifampicin. The relationship between genetic variation, clinical comorbidities, and rifampicin exposures in TB patients has not been completely elucidated. The aim of this study was to investigate the prevalence of SLCO1A1 and SLCO1B1 polymorphisms in TB and TB-DM patients and to determine their relationship with rifampicin pharmacokinetics on patients from México. Blood samples were collected in two hospitals in Baja California, Mexico from February through December 2017. Sampling included 19 patients with TB, 11 with T2DM and 17 healthy individuals. Polymorphisms genotype rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs72559746,rs2291075 and rs4603354 of SLCO1B1 and rs4646285 and rs138880008 of SLC10A1 were analyzed by Sanger's sequencing. None of the SLCO1B1 and SLC10A1 variants were significantly associated with rifampicin Cmax. TB and T2DM patients with suboptimal Cmax rifampicin levels showed wild alleles in rs11045819 and rs2291075 in SLCO1B1 SLC10A1 and SLC10A1. This is the first study to analyze SLC10A1 and SLCO1B1 polymorphisms in TB and TB-T2DM patients and healthy individuals in Mexico. Further research to confirm and extend these findings is necessary.

PMID:36055153 | DOI:10.1016/j.tube.2022.102248

Ther Adv Psychopharmacol. 2022 Aug 23;12:20451253221112587. doi: 10.1177/20451253221112587. eCollection 2022.

ABSTRACT

BACKGROUND: Antipsychotic polypharmacy (APP) prescribing and clozapine underuse are considered inappropriate prescribing in schizophrenia. Psychiatric hospitalisations may be suitable occasions to re-evaluate patient pharmacotherapy and to switch to monotherapy.

OBJECTIVES: To explore the evolution of APP and other psychotropic prescribing patterns during psychiatric hospitalisations, to detect characteristics associated with APP on admission and at discharge, and to examine clozapine prescribing patterns.

DESIGN: We performed a retrospective observational study based on electronic health records.

METHODS: Data on adult inpatients diagnosed with schizophrenia spectrum disorders were collected retrospectively from 6 Belgian hospitals in 2020-2021.

RESULTS: Of the 516 patients included, APP prescribing increased significantly from 47.9% on hospital admission to 59.1% at discharge. On admission and at discharge, APP was associated with prior clozapine use (ORadmission = 2.53, CI = 1.1-5.84, ORdischarge = 11.01, CI = 4.45-27.28), treatment with a first-generation antipsychotic (ORadmission = 26.79, CI = 13.08-54.86, ORdischarge = 25.2, CI = 12.2-52.04), increased antipsychotic exposure (ORadmission = 8.93, CI = 5.13-15.56, ORdischarge = 19.89, CI = 10-39.54), and a greater number of hypno-sedatives (ORadmission = 1.88, CI = 1.23-2.88, ORdischarge = 4.18, CI = 2.53-6.91). APP was negatively associated with involuntary admission (ORadmission = 0.31, CI = 0.14-0.7, ORdischarge = 0.3, CI = 0.13-0.68). When using an alternative definition of monotherapy (i.e. including patients with an add-on low-dose antipsychotic for sleep disorders), alcohol use disorder (ORadmission = 0.26, CI = 0.13-0.54) and higher age (ORdischarge = 0.53, CI = 0.29-0.95) were negatively associated with APP, and living in a residential facility (ORdischarge = 2.39 CI = 1.21-4.71) and a higher daily dosage of benzodiazepines during the stay (ORdischarge = 1.32 CI = 1.03-1.69) increased the odds of being discharged on APP. On admission, 9.3% of patients were being treated with clozapine. Although 28.1% of patients were eligible for clozapine treatment, only 11% of patients were discharged with a clozapine prescription. For 7 of the 10 patients with a new clozapine prescription, it was directly prescribed in combination with another antipsychotic, without a prior trial of clozapine monotherapy.

CONCLUSION: Suboptimal prescriptions of antipsychotics in patients with schizophrenia persist after psychiatric hospitalisations and are associated with identifiable characteristics.

PMID:36051501 | PMC:PMC9425880 | DOI:10.1177/20451253221112587

Sci Rep. 2022 Sep 1;12(1):14858. doi: 10.1038/s41598-022-19318-x.

ABSTRACT

Organic anion transporting polypeptides (OATP), which are encoded by SLCO genes, participate in the hepatic elimination of drugs and xenobiotics. SLCO1B1 is an important pharmacogenomic gene (encoding OATP1B1) associated with response to the uptake of endogenous compounds, such as statin and bilirubin. Ethnicity of the patient modulates the response to these drugs; the frequency and haplotype data for SLCO1B1 genetic variants in the Arab population is lacking. Therefore, we determined the frequencies of two well-characterized SLCO1B1 single nucleotide polymorphisms (SNP) and haplotypes that affect the OATP1B1 drugs transportation activity in Qatari population. Genotyping data for two SLCO1B1 SNPs (c.388A > G, c.521 T > C) were extracted from whole exome data of 1050 Qatari individuals, who were divided into three ancestry groups, namely Bedouins, Persians/South Asians, and Africans. By way of using Fisher's exact and Chi-square tests, we evaluated the differences in minor allele frequency (MAF) of the two functional SNPs and haplotype frequencies (HF) among the three ancestry groups. The OATP1B1 phenotypes were assigned according to their function by following the guidelines from the Clinical Pharmacogenetics Implementation Consortium for SLCO1B1 and Simvastatin-Induced Myopathy.The MAF of SLCO1B1:c.388A > G was higher compared to that of SLCO1B1:c.521 T > C in the study cohort. It was significantly high in the African ancestry group compared with the other two groups, whereas SLCO1B1:c.521 T > C was significantly low in the African ancestry group compared with the other two groups. The SLCO1B1 *15 haplotype had the highest HF, followed by *1b, *1a, and *5. Only the SLCO1B1 *5 haplotype showed no significant difference in frequency across the three ancestry groups. Furthermore, we observed that the OATP1B1 normal function phenotype accounted for 58% of the Qatari individuals, the intermediate function phenotype accounted for 35% with significant differences across the ancestry groups, and the low function phenotype accounted for 6% of the total Qatari individuals with a higher trend observed in the Bedouin group.The results indicate that the phenotype frequencies of the OATP1B1 intermediate and low function in the Qatari population appear at the higher end of the frequency range seen worldwide. Thus, a pharmacogenetic screening program for SLCO1B1 variants may be necessary for the Qatari population.

PMID:36050458 | DOI:10.1038/s41598-022-19318-x

Clin Pharmacol Ther. 2022 Sep 1. doi: 10.1002/cpt.2735. Online ahead of print.

ABSTRACT

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia in the setting of oxidative stress, which can be caused by medication exposure. Regulatory agencies worldwide warn against the use of certain medications in G6PD deficient persons, but in many cases, this information is conflicting, and the clinical evidence is sparse. This guideline provides information on using G6PD genotype as part of the diagnosis of G6PD deficiency and classifies medications that have been previously implicated as unsafe in G6PD deficient individuals by one or more sources. We classify these medications as high, medium, or low-to-no risk based on a systematic review of the published evidence of the gene-drug associations and regulatory warnings. In patients with G6PD deficiency, high risk medications should be avoided, medium risk medications should be used with caution, and low-to-no risk medications can be used with standard precautions, without regard to G6PD phenotype. This new document replaces the prior Clinical Pharmacogenetics Implementation Consortium guideline for rasburicase therapy in the context of G6PD genotype (updates at www.cpicpgx.org).

PMID:36049896 | DOI:10.1002/cpt.2735

Front Psychiatry. 2022 Aug 10;13:947583. doi: 10.3389/fpsyt.2022.947583. eCollection 2022.

ABSTRACT

INTRODUCTION: Few studies have objectively evaluated cognitive deficits after the acute phase of COVID-19 disease. Moreover, the role of apolipoprotein E (APOE) genotypes in cognitive decline in patients with COVID-19 has not been evaluated yet.

METHODS: This cross-sectional study was conducted in confirmed cases of COVID-19 patients with neurological symptoms that persisted for more than 3 months from the onset. We determined APOE genotypes.

RESULTS: The final sample consisted of 141 patients. The most frequent APOE genotype was E3/E3 (N = 95; 67.3%). In total, 93 patients (65.9%) had memory impairment symptoms as the main complaint, objectively confirmed through screening tests in 25 patients (17.7%). Patients with cognitive impairment had a lower frequency of anosmia than the normal and subjective cognitive decline (SCD) groups (p = 0.005). In addition, depression was recurrent in the cognitive impairment group and the SCD group (p = 0.046). Cognitive impairment was significantly more frequent in hospitalized patients and those with a lower education level. Cognitive status was not associated with APOE genotypes.

DISCUSSION: Hospitalized patients had more severe infection with a greater possibility of systemic complications, greater inflammatory response, and prolonged hospitalization, which could impact cognitive performance. Cognitive impairment in patients with COVID-19 does not necessarily involve specific APOE polymorphisms. However, psychiatric disorders may also be responsible for cognitive complaints. Cognitive complaints are frequent in patients with COVID-19, even after the acute phase of the disease and in mild cases. Hospitalized participants and depressed patients may have a higher risk of cognitive impairment. APOE genotypes or haplotypes may not significantly play a role in COVID-19 cognitive impairment.

PMID:36046159 | PMC:PMC9423011 | DOI:10.3389/fpsyt.2022.947583

Front Oncol. 2022 Aug 4;12:961014. doi: 10.3389/fonc.2022.961014. eCollection 2022.

ABSTRACT

BACKGROUND: Glioblastoma is characterized by rich vasculature and abnormal vascular structure and function. Currently, there is no standard treatment for recurrent glioblastoma (rGBM). Bevacizumab (BEV) has established role of inhibiting neovascularization, alleviating hypoxia in the tumor area and activating the immune microenvironment. BEV may exert synergistic effects with re-irradiation (re-RT) to improve the tumor microenvironment for rGBM.

PURPOSE: The purpose of this study was to evaluate the safety, tolerability, and efficacy of a combination of BEV and re-RT for rGBM treatment.

METHODS: In this retrospective study, a total of 26 rGBM patients with surgical pathologically confirmed glioblastoma and at least one event of recurrence were enrolled. All patients were treated with re-RT in combination with BEV. BEV was administered until progression or serious adverse events.

RESULTS: Median follow-up was 21.9 months for all patients, whereas median progression-free survival (PFS) was 8.0 months (95% confidence interval [CI]: 6.5-9.5 months). In addition, the 6-month and 1-year PFS rates were 65.4% and 28.2%, respectively. The median overall survival (OS), 6-month OS rate, and 1-year OS rate were 13.6 months (95% CI: 10.2-17.0 months), 92.3%, and 67.5%, respectively. The patient showed good tolerance during the treatment with no grade > 3 grade side event and radiation necrosis occurrence rate of 0%. Combined treatment of gross total resection (GTR) before re-RT and concurrent temozolomide during re-RT was an independent prognostic factor that affected both OS and PFS in the whole cohort (OS: 0.067, 95% CI: 0.009-0.521, p = 0.010; PFS: 0.238, 95% CI: 0.076-0.744, p = 0.038).

CONCLUSION: In this study, re-RT combined with concurrent and maintenance BEV treatment was safe, tolerable, and effective in rGBM patients. Moreover, GTR before re-RT and selective concurrent temozolomide could further improve patient PFS and OS.

PMID:36046037 | PMC:PMC9423039 | DOI:10.3389/fonc.2022.961014

Clin Transl Sci. 2022 Aug 31. doi: 10.1111/cts.13398. Online ahead of print.

ABSTRACT

The cytochrome P450 3As (CYP3As) are abundantly expressed in the liver and metabolize many commonly prescribed medications. Their expression is highly variable between individuals with little known genetic cause. Despite extensive investigation, cis-acting genetic elements that control the expression of the CYP3As remain uncharacterized. Using chromatin conformation capture (4C assays), we detected reciprocal interaction between a distal regulatory region (DRR) and the CYP3A4 promoter. The DRR colocalizes with a variety of enhancer marks and was found to promote transcription in reporter assays. CRISPR-mediated deletion of the DRR decreased expression of CYP3A4, CYP3A5, and CYP3A7, supporting its role as a shared enhancer regulating the expression of three CYP3A genes. Using reporter gene assays, we identified two SNPs (rs115025140 and rs776744/rs776742) that increased DRR-driven luciferase reporter expression. In a liver cohort (n=246), rs115025140 was associated with increased expression of CYP3A4 mRNA (1.8-fold) and protein (1.6-fold) and rs776744/rs776742 was associated with 1.39-fold increased expression of CYP3A5 mRNA. rs115025140 is unique to the African population and in a clinical cohort of African Americans taking statins for lipid control rs115025140 carriers showed a trend towards reduced statin-mediated lipid reduction. Also, using a published cohort of Chinese renal transplant patients taking tacrolimus, rs776744/rs776742 carriers were associated with reduced tacrolimus concentration after adjusting for CYP3A5*3. Our results elucidate a complex regulatory network controlling expression of three CYP3A genes and identify two novel regulatory variants with potential clinical relevance for predicting CYP3A4 and CYP3A5 expression.

PMID:36045613 | DOI:10.1111/cts.13398

Acta Biomed. 2022 Aug 31;93(4):e2022051. doi: 10.23750/abm.v93i4.11695.

ABSTRACT

BACKGROUND AND AIM OF THE WORK: BRCA1/2 are tumour-suppressor genes involved in DNA homologous recombination and ovarian cancer development. The study evaluated the risk of tumor cancer in women presenting the BRCA mutations.

METHODS: Risk-reducing surgery (RRS) was performed in 100 patients carrying BRCA1 (aged between 30-73 years, median age was 51 years) and BRCA 2 mutation (aged between 36-70 years, median age was 53 years). Fifty-eight patients had previous history of breast cancer.

RESULTS: Between the 100 patients, 82 women underwent risk-reducing salpingo-oophorectomy (RRSO) through a laparoscopic minimally invasive approach, 7 (7 %) underwent laparoscopic RRSO and contextual hysterectomy, 1 woman (1 %) underwent RRSO through a laparotomic approach and 10 women (10 %) laparotomic RRSO and hysterectomy. During 5 (5 %) laparoscopic RRSO, prophylactic bilateral mastectomy was also performed. Early and late complication occurred in 3 patients (3 %). Two patients (2 %) were found to have occult Serous Tubal Intraepithelial Carcinoma (STIC) and three patients (3 %) occult cancer.

CONCLUSIONS: RRSO is safe and feasible in BRCA mutation carriers. The procedure is effective for genetic prevention of ovarian cancer.

PMID:36043985 | DOI:10.23750/abm.v93i4.11695

Pharmacogenomics. 2022 Aug 31. doi: 10.2217/pgs-2022-0082. Online ahead of print.

ABSTRACT

Background & aim: POR is an enzyme that mediates electron transfer to enable the drug-metabolizing activity of CYP450 proteins. However, POR has been understudied in pharmacogenomics despite this vital role. This study aimed to characterize the genetic variation in POR across African populations and to compare the star allele (haplotype) distribution with that in other global populations. Materials & methods: POR star alleles were called from whole-genome sequencing data using the StellarPGx pipeline. Results: In addition to the common POR*1 and *28 (defined by rs1057868), five novel rare haplotypes were computationally inferred. No significant frequency differences were observed among the majority of African populations. However, POR*28 was observed at a higher frequency in individuals of non-African ancestry. Conclusion: This study highlights the distribution of POR alleles in Africa and across global populations with a view toward informing future precision medicine implementation.

PMID:36043428 | DOI:10.2217/pgs-2022-0082

Pharmacogenomics. 2022 Aug 31. doi: 10.2217/pgs-2022-0085. Online ahead of print.

ABSTRACT

Background: Germline sequencing of individual genomes can detect alleles responsible for adverse drug reactions (ADRs) in relation to chemotherapy, targeted agents, antiemetics or pain treatment. Materials & methods: To evaluate the interest of such pharmacogenetic information, the authors retrospectively analyzed genes known to have an impact on cancer therapy in a cohort of 445 solid cancers patients. Results: Six patients treated with 5-fluorouracil carrying one DPYD variant classified as 1A showed decreased drug mean clearance (p = 0.01). Regarding CYP2D6, all patients (n = 5) with predicted CYP2D6 poor or ultra-rapid metabolizer status experienced adverse drug reactions related to opioid therapy. Conclusion: Genomic germline sequencing performed for theragnostic issues in patients with a solid tumor, can provide relevant information about common pharmacogenetic alleles.

PMID:36043386 | DOI:10.2217/pgs-2022-0085

BMC Psychiatry. 2022 Aug 30;22(1):576. doi: 10.1186/s12888-022-04225-2.

ABSTRACT

OBJECTIVE: The main goal of this work was to identify, describe, characterize, and classify the scientific evidence regarding the use of pharmacogenomic biomarkers in antidepressant treatment.

METHODS: The work was developed in two phases: i) a search for pharmacogenomic biomarkers in summaries of antidepressant drugs with marketing authorization in Portugal; and ii) a systematic literature review based on the data obtained in the first phase, with the main objective of finding international literature that could describe and characterize previously reported biomarkers and identify other relevant biomarkers. Finally, the levels of evidence and recommendation grades were classified.

RESULTS: Among the 26 drugs with marketing authorization in Portugal, only 16 had pharmacogenomic information. The most widely studied pharmacogenomic biomarker was CYP2D6. These results were mostly supported by the systematic literature review, which yielded 103 papers, 63 of which were ultimately included in the review. The systematic literature review also revealed the existence of other relevant biomarkers. Most of the included studies show a good level of evidence, which guarantees reliability and good recommendation grades. For the database (built during phase i), the results were informative but resulted in no specific recommendations.

CONCLUSIONS: Most pharmacogenomic variants are not studied or acknowledged by genetic tests, and more scientific research is needed to confirm their usefulness. Therefore, only a small number of variants are considered when prescribing antidepressant drugs. In addition, genotyping of patients is not common in clinical practice.

PMID:36042420 | DOI:10.1186/s12888-022-04225-2

PLoS One. 2022 Aug 30;17(8):e0273582. doi: 10.1371/journal.pone.0273582. eCollection 2022.

ABSTRACT

The number of adverse drug events in the United States is critically high, with annual rates exceeding 1 million cases over the last nine years. One cause of adverse drug events is the underlying genetic variation that can alter drug responses. Pharmacogenomics is a growing field that seeks to better understand the relationship between a patient's genetics and drug efficacy. Currently, pharmacogenomics relies largely on human trials, as there is not a well-developed animal model for studying preventative measures and alternative treatments. Here, we analyzed pharmacogene expression at two developmental time points in zebrafish to demonstrate the potential of using this model organism for high-throughput pharmacogenomics research. We found that 76% of tiered human pharmacogenes have a zebrafish ortholog, and of these, many have highly conserved amino acid sequences. Additional gene ontology analysis was used to classify pharmacogenes and identify candidate pathways for future modeling in zebrafish. As precision medicine burgeons, adopting a high-throughput in vivo model such as the zebrafish could greatly increase our understanding of the molecular pathology underlying adverse drug events.

PMID:36040978 | DOI:10.1371/journal.pone.0273582

Epilepsia. 2022 Aug 21. doi: 10.1111/epi.17399. Online ahead of print.

ABSTRACT

OBJECTIVE: Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity.

METHODS: Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected.

RESULTS: The serum LCM concentration showed a linear correlation with the daily dose (r = .66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p = .01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 μg/ml, p = .024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1 μg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9 μg/ml).

SIGNIFICANCE: Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.

PMID:36039802 | DOI:10.1111/epi.17399

Lancet Reg Health Eur. 2022 Aug 19;22:100493. doi: 10.1016/j.lanepe.2022.100493. eCollection 2022 Nov.

ABSTRACT

BACKGROUND: Cardiometabolic dysfunction is common in young people with psychosis. Recently, the Psychosis Metabolic Risk Calculator (PsyMetRiC) was developed and externally validated in the UK, predicting up-to six-year risk of metabolic syndrome (MetS) from routinely collected data. The full-model includes age, sex, ethnicity, body-mass index, smoking status, prescription of metabolically-active antipsychotic medication, high-density lipoprotein, and triglyceride concentrations; the partial-model excludes biochemical predictors.

METHODS: To move toward a future internationally-useful tool, we externally validated PsyMetRiC in two independent European samples. We used data from the PsyMetab (Lausanne, Switzerland) and PAFIP (Cantabria, Spain) cohorts, including participants aged 16-35y without MetS at baseline who had 1-6y follow-up. Predictive performance was assessed primarily via discrimination (C-statistic), calibration (calibration plots), and decision curve analysis. Site-specific recalibration was considered.

FINDINGS: We included 1024 participants (PsyMetab n=558, male=62%, outcome prevalence=19%, mean follow-up=2.48y; PAFIP n=466, male=65%, outcome prevalence=14%, mean follow-up=2.59y). Discrimination was better in the full- compared with partial-model (PsyMetab=full-model C=0.73, 95% C.I., 0.68-0.79, partial-model C=0.68, 95% C.I., 0.62-0.74; PAFIP=full-model C=0.72, 95% C.I., 0.66-0.78; partial-model C=0.66, 95% C.I., 0.60-0.71). As expected, calibration plots revealed varying degrees of miscalibration, which recovered following site-specific recalibration. PsyMetRiC showed net benefit in both new cohorts, more so after recalibration.

INTERPRETATION: The study provides evidence of PsyMetRiC's generalizability in Western Europe, although further local and international validation studies are required. In future, PsyMetRiC could help clinicians internationally to identify young people with psychosis who are at higher cardiometabolic risk, so interventions can be directed effectively to reduce long-term morbidity and mortality.

FUNDING: NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); The Wellcome Trust (201486/Z/16/Z); Swiss National Research Foundation (320030-120686, 324730- 144064, and 320030-173211); The Carlos III Health Institute (CM20/00015, FIS00/3095, PI020499, PI050427, and PI060507); IDIVAL (INT/A21/10 and INT/A20/04); The Andalusian Regional Government (A1-0055-2020 and A1-0005-2021); SENY Fundacion Research (2005-0308007); Fundacion Marques de Valdecilla (A/02/07, API07/011); Ministry of Economy and Competitiveness and the European Fund for Regional Development (SAF2016-76046-R and SAF2013-46292-R).For the Spanish and French translation of the abstract see Supplementary Materials section.

PMID:36039146 | PMC:PMC9418905 | DOI:10.1016/j.lanepe.2022.100493