Front Immunol. 2022 Apr 19;13:882721. doi: 10.3389/fimmu.2022.882721. eCollection 2022.

ABSTRACT

Allogeneic CD8+ T cells are prominently involved in allograft rejection, but how their effector differentiation and function are regulated at a transcriptional level is not fully understood. Herein, we identified the basic leucine zipper ATF-like transcription factor (BATF) as a key transcription factor that drives the effector program of allogeneic CD8+ T cells. We found that BATF is highly expressed in graft-infiltrating CD8+ T cells, and its ablation in CD8+ T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model. To investigate how BATF dictates allogeneic CD8+ T cell response, BATF-/- and wild-type (WT) CD8+ T cells were mixed in a 1:1 ratio and adoptively transferred into B6.Rag1 -/- mice 1 day prior to skin transplantation. Compared with WT CD8+ T cells at the peak of rejection response, BATF-/- CD8+ T cells displayed a dysfunctional phenotype, evident by their failure to differentiate into CD127-KLRG1+ terminal effectors, impaired proliferative capacity and production of pro-inflammatory cytokines/cytotoxic molecules, and diminished capacity to infiltrate allografts. In association with the failure of effector differentiation, BATF-/- CD8+ T cells largely retained TCF1 expression and expressed significantly low levels of T-bet, TOX, and Ki67. At the memory phase, BATF-deficient CD8+ T cells displayed impaired effector differentiation upon allogeneic antigen re-stimulation. Therefore, BATF is a critical transcriptional determinant that governs the terminal differentiation and memory responses of allogeneic CD8+ T cells in the transplantation setting. Targeting BATF in CD8+ T cells may be an attractive therapeutic approach to promote transplant acceptance.

PMID:35514970 | PMC:PMC9062028 | DOI:10.3389/fimmu.2022.882721

Br J Clin Pharmacol. 2022 May 5. doi: 10.1111/bcp.15387. Online ahead of print.

ABSTRACT

AIMS: To investigate the influence of pharmacogenetic polymorphisms on efavirenz (EFV) exposure and metabolism in HIV-infected Brazilians under treatment with EFV-containing antiretroviral (ART) regimens.

METHODS: HIV-positive adults (n=82) on stable ART regimens containing 600 mg EFV once daily for at least 6 months were recruited at two university hospitals. Blood samples collected at mid-dose interval were used to quantify the plasma concentrations of EFV (denoted [EFV]), its major metabolite 8-OH-EFV ([8-OH-EFV]) and [8-OH-EFV]/[EFV] metabolic ratio, and to genotype single nucleotide polymorphisms (SNPs) in CYP2B6 (rs3745274, c.516G>T; rs28399499, c.983T>C) and ABCB1 (rs3842, c.4036G>A). CYP2B6 metabolic phenotypes were inferred from the CYP2B6 diplotypes. Linear regression modeling was applied to identify sociodemographic, clinical and pharmacogenetic predictors of [EFV] and [8-OH-EFV]/[EFV] metabolic ratio.

RESULTS: Wide (50-fold) interindividual variation in [EFV], [8-OH-EFV] and [8-OH-EFV]/[EFV] was observed; 69.5% of participants had [EFV] within the nominal therapeutic range (1000-4000 ng/ml), while 19.5%, and 11.0% had [EFV] below and above this range, respectively. Multiple regression modeling retained only CYP2B6 metabolic phenotypes or the combined rs3745274 and rs28399499 genotypes, as significant predictors of [EFV] and [8-OH-EFV]/[EFV].

CONCLUSION: EFV exposure and disposition varied widely among HIV-infected Brazilians under stable treatment with EFV-containing ART regimens. About one-tenth of the participants had [EFV] exceeding nominal supratherapeutic concentration (4000 ng/mL), but reported tolerance to the ARV regimens, while one fifth of participants had nominal subtherapeutic [EFV] (<1000 ng/ml) but adequate virological response. Genotype for the two CYP2B6 SNPs studied explained 48% of variation in [EFV] and 35% of variation in [8-OH-EFV]/[EFV].

PMID:35514050 | DOI:10.1111/bcp.15387

Clin Pharmacokinet. 2022 May 6. doi: 10.1007/s40262-022-01128-z. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Vancomycin is frequently used to treat Gram-positive bacterial infections in neonates. However, there is still no consensus on the optimal initial dosing regimen. This study aimed to assess the performance of pharmacokinetic model-based virtual trials to predict the dose-exposure relationship of vancomycin in neonates.

METHODS: The PubMed database was searched for clinical trials of vancomycin in neonates that reported the percentage of target attainment. Monte Carlo simulations were performed using nonlinear mixed-effect modeling to predict the dose-exposure relationship, and the differences in outcomes between virtual trials and real-world data in clinical studies were calculated.

RESULTS: A total of 11 studies with 14 dosing groups were identified from the literature to evaluate dose-exposure relationships. For the ten dosing groups where the surrogate marker for exposure was the trough concentration, the mean ± standard deviation (SD) for the target attainment between original studies and virtual trials was 3.0 ± 7.3%. Deviations between - 10 and 10% accounted for 80% of the included dosing groups. For the other four dosing groups where the surrogate marker for exposure was concentration during continuous infusion, all deviations were between - 10 and 10%, and the mean ± SD value was 2.9 ± 4.5%.

CONCLUSION: The pharmacokinetic model-based virtual trials of vancomycin exhibited good predictive performance for dose-exposure relationships in neonates. These results might be used to assist the optimization of dosing regimens in neonatal practice, avoiding the need for trial and error.

PMID:35513741 | DOI:10.1007/s40262-022-01128-z

J Infect Dis. 2022 May 4:jiac174. doi: 10.1093/infdis/jiac174. Online ahead of print.

ABSTRACT

BACKGROUND: Dolutegravir is a component of preferred antiretroviral therapy (ART) regimens. We characterised the pharmacogenetics of dolutegravir exposure following ART initiation in the ADVANCE trial in South Africa.

METHODS: Genome-wide genotyping followed by imputation was performed. We developed a population pharmacokinetic model for dolutegravir using non-linear mixed-effects modelling. Linear regression models examined associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR).

RESULTS: Genetic associations were evaluable in 284 individuals. Of nine polymorphisms previously associated with dolutegravir pharmacokinetics, the lowest P-value with AUCVAR was UGT1A1 rs887829 (P = 1.8 × 10-4), which was also associated with log10 bilirubin (P = 8.6 × 10-13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = 0.02), as were bilirubin concentrations (P = 7.7 × 10-8). In the population pharmacokinetic model, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively, compared to C/C. The lowest P-value for AUCVAR genome-wide was CAMKMT rs343942 (P = 2.4 × 10-7).

CONCLUSIONS: In South Africa, rs887829 and rs28899168 in the UGT1A locus were independently associated with dolutegravir AUCVAR. The novel rs28899168 association warrants replication. This study enhances understanding of dolutegravir pharmacogenetics in Africa.

PMID:35512135 | DOI:10.1093/infdis/jiac174

Front Med (Lausanne). 2022 Apr 18;9:829304. doi: 10.3389/fmed.2022.829304. eCollection 2022.

ABSTRACT

The vitamin K antagonist is a commonly prescribed effective oral anticoagulant with a narrow therapeutic range, and the dose requirements for different patients varied greatly. In recent years, studies on human intestinal microbiome have provided many valuable insights into disease development and drug reactions. A lot of studies indicated the potential relationship between microbiome and the vitamin K antagonist. Vitamin K is absorbed by the gut, and the intestinal bacteria are a major source of vitamin K in human body. A combined use of the vitamin K antagonist and antibiotics may result in an increase in INR, thus elevating the risk of bleeding, while vitamin K supplementation can improve stability of anticoagulation for oral vitamin K antagonist treatment. Recently, how intestinal bacteria affect the response of the vitamin K antagonist remains unclear. In this review, we reviewed the research, focusing on the physiology of vitamin K in the anticoagulation treatment, and investigated the potential pathways of intestinal bacteria affecting the reaction of the vitamin K antagonist.

PMID:35510250 | PMC:PMC9058076 | DOI:10.3389/fmed.2022.829304

Infect Drug Resist. 2022 Apr 28;15:2271-2286. doi: 10.2147/IDR.S356543. eCollection 2022.

ABSTRACT

BACKGROUND: Infection remains a leading cause of morbidity and mortality in kidney transplant patients. This study aimed to investigate the risk factors of bacterial infection during the perioperative period of transplantation and the effects of infection on long-term clinical outcomes.

METHODS: In total, 295 kidney transplantation recipients were included in this retrospective study and assigned to two groups: non-infected and infected. The tacrolimus concentration, pharmacogenomics, laboratory parameters, and clinical outcomes of both groups were evaluated.

RESULTS: A relatively low incidence of urinary tract infection was observed in our cohort, and lung was identified as the most frequent site of infection. Gram-negative bacteria, such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, were the most common infecting strains in kidney transplant recipients. Patients with diabetes showed greater susceptibility to infection. Compared with the non-infected group, tacrolimus concentration was significantly lower on day 7 and 14 in the infected group. White blood cell count, neutrophil count, and C-reactive protein (CRP) in the infected group were markedly higher post-transplantation, while albumin levels were lower relative to the non-infected group. ABCB1 (rs2032582) genotype showed clear associations with infection. Furthermore, the incidence of delayed graft function (DGF) and early acute rejection (AR) before infection was significantly greater in the infected group. Finally, early post-transplant infection was associated with a marked increase in the incidence of AR, post-transplant diabetes mellitus (PTDM), and secondary infection.

CONCLUSION: Pre-diabetes, longer duration of catheterization, lower albumin, higher CRP, tacrolimus concentration on the day 7 and 14, early AR before infection, and DGF were closely related to postoperative infection in kidney transplantation recipients. Moreover, bacterial infection during the perioperative period was closely associated with AR, PTDM and secondary infection.

PMID:35510155 | PMC:PMC9059986 | DOI:10.2147/IDR.S356543

Oxid Med Cell Longev. 2022 Apr 25;2022:8615242. doi: 10.1155/2022/8615242. eCollection 2022.

ABSTRACT

Bergapten (BP) or 5-methoxypsoralen (5-MOP) is a furocoumarin compound mainly found in bergamot essential oil but also in other citrus essential oils and grapefruit juice. This compound presents antibacterial, anti-inflammatory, hypolipemic, and anticancer effects and is successfully used as a photosensitizing agent. The present review focuses on the research evidence related to the therapeutic properties of bergapten collected in recent years. Many preclinical and in vitro studies have been evidenced the therapeutic action of BP; however, few clinical trials have been carried out to evaluate its efficacy. These clinical trials with BP are mainly focused on patients suffering from skin disorders such as psoriasis or vitiligo. In these trials, the administration of BP (oral or topical) combined with UV irradiation induces relevant lesion clearance rates. In addition, beneficial effects of bergamot extract were also observed in patients with altered serum lipid profiles and in people with nonalcoholic fatty liver. On the contrary, there are no clinical trials that investigate the possible effects on cancer. Although the bioavailability of BP is lower than that of its 8-methoxypsoralen (8-MOP) isomer, it has fewer side effects allowing higher concentrations to be administered. In conclusion, although the use of BP has therapeutic applications on skin disorders as a sensitizing agent and as components of bergamot extract as hypolipemic therapy, more trials are necessary to define the doses and treatment guidelines and its usefulness against other pathologies such as cancer or bacterial infections.

PMID:35509838 | PMC:PMC9060977 | DOI:10.1155/2022/8615242

Croat Med J. 2022 Apr 30;63(2):117-125.

ABSTRACT

AIM: To compare the Croatian and European population in terms of allele frequencies of clinically relevant polymorphisms in drug absorption, distribution, metabolism, and excretion (ADME) genes.

METHODS: In 429 Croatian participants, we genotyped 27 loci in 20 ADME genes. The obtained frequencies were merged with the published frequencies for the Croatian population by sample size weighting. The study sample obtained in this way was compared with the average data for the European population from the gnomAD database.

RESULTS: Variant allele frequencies in the Croatian population were higher in three and lower in two polymorphisms (Benjamini-Hochberg-corrected P values: 0.0027 for CYP2B6*4 rs2279343, CYP2C9*2 rs1799853, and VKORC1 rs9923231; 0.0297 for GSTP1 rs1695; 0.0455 for CYP2A6 rs1801272) compared with the European population. The most marked difference was observed for CYP2B6*4 (9.3% in Europe vs 24.3% in Croatia). The most clinically relevant findings were higher variant allele frequencies in two polymorphisms related to lower warfarin requirements: VKORC1*2 (34.9% in Europe vs 40.1% in Croatia) and CYP2C9*2 (12.3% in Europe vs 14.7% in Croatia). This indicates that three-quarters of Croatian people have at least one variant allele at these loci. Variants in genes GSTP1 and CYP2A6 were significantly less frequently observed in Croatia.

CONCLUSIONS: Croatian population has a higher bleeding and over-anticoagulation risk, which is why we recommend the prescription of lower doses of anticoagulation drugs such as warfarin and acenocoumarol. Lower phenytoin, and higher bupropion and efavirenz doses are also recommended in the Croatian population.

PMID:35505645

Methods Mol Biol. 2022;2449:187-196. doi: 10.1007/978-1-0716-2095-3_7.

ABSTRACT

The prediction of the cancer cell lines sensitivity to a specific treatment is one of the current challenges in precision medicine. With omics and pharmacogenomics data being available for over 1000 cancer cell lines, several machine learning and deep learning algorithms have been proposed for drug sensitivity prediction. However, deciding which omics data to use and which computational methods can efficiently incorporate data from different sources is the challenge which several research groups are working on. In this review, we summarize recent advances in the representative computational methods that have been developed in the last 2 years on three public datasets: COSMIC, CCLE, NCI-60. These methods aim to improve the prediction of the cancer cell lines sensitivity to a given treatment by incorporating drug's chemical information in the input or using a priori feature selection. Finally, we discuss the latest published method which aims to improve the prediction of clinical drug response of real patients starting from cancer cell line molecular profiles.

PMID:35507263 | DOI:10.1007/978-1-0716-2095-3_7

Clin Transl Sci. 2022 May 3. doi: 10.1111/cts.13277. Online ahead of print.

ABSTRACT

Effects of UGT1A1*6 and UGT1A1*28 genetic polymorphisms on irinotecan-induced severe toxicities in Asian cancer patients are inconclusive. Also, ABCC2 c.3972C>T may affect toxicity of irinotecan. It was aimed to assess the aggregated risk of neutropenia or diarrhea in Asian cancer patients taking irinotecan and inherited UGT1A1*6, UGT1A1*28 or ABCC2 c.3972C>T genetic variants. Literature was searched in PubMed for eligible studies. Odds ratios (ORs) were measured using RevMan software where P-values<0.05 were statistically significant. Patients inherited both UGT1A1*6 and UGT1A1*28 genetic variants (heterozygous:UGT1A1*1/*6+*1/*28 and homozygous:UGT1A1*6/*6+*28/*28) were significantly associated with increased risk of neutropenia and diarrhea compared to patients with UGT1A1*1/*1 (Neutropenia: OR 2.89; 95% CI 1.97-4.23; P<0.00001; Diarrhea: OR 2.26; 95% CI 1.71-2.99; P<0.00001). Patients carried homozygous variants had much stronger effects in developing toxicities (Neutropenia: OR 6.23; 95% CI 3.11-12.47; P<0.00001; Diarrhea: OR 3.21; 95% CI 2.13-4.85; P<0.00001) than with heterozygous variants. However, patients carried ABCC2 c.3972C>T genetic variant were not significantly associated with neutropenia (OR 1.67; 95% CI 0.98-2.84; P=0.06) but reduced diarrhea significantly (OR 0.31; 95% CI 0.11-0.81; P=0.02). Both UGT1A1*6 and UGT1A1*28 genetic variants should be screened in Asian cancer patients to reduce substantially irinotecan induced severe toxicities.

PMID:35506159 | DOI:10.1111/cts.13277

Mol Ther Nucleic Acids. 2022 Apr 6;28:464-476. doi: 10.1016/j.omtn.2022.04.001. eCollection 2022 Jun 14.

ABSTRACT

RNA chemical modifications are a new but rapidly developing field. They can directly affect RNA splicing, transport, stability, and translation. Consequently, they are involved in the occurrence and development of diseases that have been studied extensively in recent years. However, few studies have focused on the correlation between chemical modifications and drug effects. Here, we provide a landscape of six RNA modifications in pharmacogene RNA (pharmacoepitranscriptomics) to fully clarify the correlation between chemical modifications and drugs. We performed systematic and comprehensive analyses on pharmacoepitranscriptomics, including basic characteristics of RNA modification and modification-associated mutations and drugs affected by them. Our results show that chemical modifications are common in pharmacogenes, especially N6-methyladenosine (m6A) modification. In addition, we found a very close relationship between chemical modifications and anti-tumor drugs. More interestingly, the results demonstrate the importance of m6A modification for anti-tumor drugs, especially for drugs in triple-negative breast cancer (TNBC), ovarian cancer, and acute myelocytic leukemia (AML). These results indicate that pharmacoepitranscriptomics could be a new source of drug-effect biomarkers, especially for m6A and anti-tumor drugs.

PMID:35505958 | PMC:PMC9044172 | DOI:10.1016/j.omtn.2022.04.001

J Clin Invest. 2022 May 3:e145666. doi: 10.1172/JCI145666. Online ahead of print.

ABSTRACT

Patients with high-risk non muscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical BCG therapy and may have a dismal outcome. Resistance mechanisms to such immunotherapy remain misunderstood. Here, using cancer cell lines, freshly resected human bladder tumors and cohorts of bladder cancer patients pre- and post-BCG therapy, we demonstrate two distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a post-transcriptional downregulation of HLA-I membrane expression via an inhibition of the autophagy flux. Patients with HLA-I deficient cancer cells post-BCG therapy displayed a myeloid immunosuppressive tumor microenvironment with epithelial-to-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I proficient cancer cells post-BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines and inhibitory immune checkpoint molecules. Those patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse post-BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts dismal prognosis. Cancer cells HLA-I scoring by immunohistochemistry (IHC) staining can be easily implemented by pathologists in routine practice in order to stratify future urothelial cancer patient treatment strategies.

PMID:35503263 | DOI:10.1172/JCI145666

Pharmacogenet Genomics. 2022 May 2. doi: 10.1097/FPC.0000000000000473. Online ahead of print.

ABSTRACT

OBJECTIVES: In the era of quality management in clinical laboratories, method validation can be a challenge without appropriate guidelines, such as in the field of pharmacogenetics. The present work describes a method validation for DNA extraction and CYP3A5*3 genotyping, which would meet ISO15189:2012 requirements.

METHODS: DNA extraction was performed using a QIAamp DSP DNA Blood kit, DNA purity and concentration were determined using a Nanodrop, and the genotyping assay was a real-rime PCR using TaqMan reagents. Validation criteria were similar to those usually verified when validating methods in the analytical field: specificity, sensitivity, cross-over contamination, stability of reagents, robustness, lower and upper limits of detection, and between-run and within-run precisions. A comparison to alternate or reference methods was also performed (i.e. QiAamp kit versus DNA extractor and TaqMan genotyping versus Sanger sequencing). Each validation step is described from the pharmacogenetic point of view, as well as acceptance criteria for both DNA extraction [i.e. concentration relative SD (RSD) below 25%, verified purity, and no DNA in blank samples] and genotyping assay (i.e. specificity and diagnostic sensitivity, RSD of mean threshold cycle below 15%, no amplification in blank samples).

RESULTS: Concerning CYP3A5 genotyping following a DNA extraction described as an example, validation criteria were met, allowing routine use of this analytical process. Cost estimation of the overall validation procedure was approximately 290 euros, concerning reagents and consumables.

CONCLUSION: This work aims to provide a reference for method validation for pharmacogenetic analysis using real-time PCR to detect single nucleotide polymorphisms, in accordance with ISO15189:2012.

PMID:35503003 | DOI:10.1097/FPC.0000000000000473

BMC Pediatr. 2022 May 2;22(1):243. doi: 10.1186/s12887-022-03311-4.

ABSTRACT

Hyperbilirubinemia is the main mechanism that causes neonatal jaundice, and genetics is one of the risk factors of hyperbilirubinemia. Therefore, this study aims to explore the correlation between two genes, UGT1A1 and SLCO1B1, and hyperbilirubinemia in Thai neonates. One hundred thirty seven neonates were recruited from Division of Clinical Chemistry, Ramathibodi Hospital. UGT1A1*28 and *6 were determined by pyrosequencing whereas, SLCO1B1 388A > G and 521 T > C genetic variants were determined by TaqMan® real-time polymerase chain reaction. Neonates carrying with homozygous (AA) and heterozygous (GA) variants in UGT1A1*6 were significantly related to hyperbilirubinemia development compared with wild type (GG; P < 0.001). To the combined of UGT1A1, total bilirubin levels in homozygous variant were higher significantly than heterozygous variant and wild type (P = 0.002, P = 0.003, respectively). Moreover, SLCO1B1 combination was significant differences between the hyperbilirubinemia and the control group (P = 0.041). SLCO1B1 521 T > C variant provide protection for Thai neonatal hyperbilirubinemia (P = 0.041). There are no significant differences in UGT1A1*28 and SLCO1B1 388A > G for the different severity of hyperbilirubinemia. The combined UGT1A1*28 and *6 polymorphism is a strong risk factor for the development of severe hyperbilirubinemia in Thai neonates. Therefore, we suggest neonates with this gene should be closely observed to avoid higher severities of bilirubin.

PMID:35501760 | DOI:10.1186/s12887-022-03311-4

Thorax. 2022 May 2:thoraxjnl-2021-217674. doi: 10.1136/thoraxjnl-2021-217674. Online ahead of print.

ABSTRACT

INTRODUCTION: Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults.

METHODS: A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases.

RESULTS: In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10-5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome.

CONCLUSIONS: Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.

PMID:35501119 | DOI:10.1136/thoraxjnl-2021-217674

Evol Bioinform Online. 2022 Apr 24;18:11769343221095834. doi: 10.1177/11769343221095834. eCollection 2022.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx), forming the basis of precision medicine, has revolutionized traditional medical practice. Currently, drug responses such as drug efficacy, drug dosage, and drug adverse reactions can be anticipated based on the genetic makeup of the patients. The pharmacogenomic data of Pakistani populations are limited. This study investigates the frequencies of pharmacogenetic variants and their clinical relevance among ethnic groups in Pakistan.

METHODS: The Pharmacogenomics Knowledge Base (PharmGKB) database was used to extract pharmacogenetic variants that are involved in medical conditions with high (1A + 1B) to moderate (2A + 2B) clinical evidence. Subsequently, the allele frequencies of these variants were searched among multiethnic groups of Pakistan (Balochi, Brahui, Burusho, Hazara, Kalash, Pashtun, Punjabi, and Sindhi) using the 1000 Genomes Project (1KGP) and ALlele FREquency Database (ALFRED). Furthermore, the published Pharmacogenomics literature on the Pakistani population was reviewed in PubMed and Google Scholar.

RESULTS: Our search retrieved (n = 29) pharmacogenetic genes and their (n = 44) variants with high to moderate evidence of clinical association. These pharmacogenetic variants correspond to drug-metabolizing enzymes (n = 22), drug-metabolizing transporters (n = 8), and PGx gene regulators, etc. (n = 14). We found 5 pharmacogenetic variants present at >50% among 8 ethnic groups of Pakistan. These pharmacogenetic variants include CYP2B6 (rs2279345, C; 70%-86%), CYP3A5 (rs776746, C; 64%-88%), FLT3 (rs1933437, T; 54%-74%), CETP (rs1532624, A; 50%-70%), and DPP6 (rs6977820, C; 61%-86%) genes that are involved in drug response for acquired immune deficiency syndrome, transplantation, cancer, heart disease, and mental health therapy, respectively.

CONCLUSIONS: This study highlights the frequency of important clinical pharmacogenetic variants (1A, 1B, 2A, and 2B) among multi-ethnic Pakistani populations. The high prevalence (>50%) of single nucleotide pharmacogenetic variants may contribute to the drug response/diseases outcome. These PGx data could be used as pharmacogenetic markers in the selection of appropriate therapeutic regimens for specific ethnic groups of Pakistan.

PMID:35497687 | PMC:PMC9047794 | DOI:10.1177/11769343221095834

Pharmgenomics Pers Med. 2022 Apr 23;15:409-427. doi: 10.2147/PGPM.S348851. eCollection 2022.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) is the study of how genetic variations for functional proteins, such as metabolizing enzymes and drug receptors, impact drug pharmacokinetics and pharmacodynamics. In theory, pharmacists are well suited to utilize PGx in tailoring medications to patient genetics when providing medication therapy management services. However, PGx education needs to reach pharmacists prior to implementation. The aim of this study is to develop and evaluate a PGx course for pharmacists.

METHODS: A PGx education program was created and offered synchronously (virtual) and asynchronously (self-study) to pharmacists in Alberta, Canada. Lectures were delivered by experts live (virtual) with a question-and-answer period for synchronous sessions. These sessions were recorded for asynchronous delivery. Six case studies were discussed in large and small groups ("breakout rooms") in synchronous sessions, and provided for self-study in the asynchronous subgroup. Topics included genetic and PGx concepts; therapeutic applications; ethical, legal, and social considerations; and practical implementation. Pre- and post-course surveys measured self-rated knowledge using a 5-point Likert Scale and tested objective knowledge with a graded quiz.

RESULTS: Thirty-six pharmacists completed the course and both surveys. Participants reported backgrounds in community (88.9%) and hospital (38.9%) practice. Prior education in PGx was reported by 44.4% from degree programs and 27.8% from continuing education. Overall responses to statements about confidence in PGx moved from a median of "Disagree" at baseline to "Agree" after receiving PGx education (2-point difference [1,2] on 5-point Likert Scale; p < 0.001), indicating an increase in self-assessed competency in PGx. Likewise, mean participant grades on the knowledge quiz improved (20.8±21.9% pre-course vs 70.2±19.1% post-course, p < 0.001). There was no difference in these results between synchronous and asynchronous groups.

CONCLUSION: A didactic and case-based PGx education program was effective at increasing pharmacist knowledge and confidence in PGx in both synchronous and asynchronous environments. Knowledge gained can be utilized in delivery of patient-centered, personalized medication therapy management in the pharmacy setting.

PMID:35496350 | PMC:PMC9045709 | DOI:10.2147/PGPM.S348851

Front Pharmacol. 2022 Apr 12;13:884213. doi: 10.3389/fphar.2022.884213. eCollection 2022.

ABSTRACT

Introduction: Minority groups are underrepresented in pharmacogenomics (PGx) research. Recent sub-analysis of CYP-GUIDES showed reduced length of stay (LOS) in depressed patients with CYP2D6 sub-functional status. Our primary objective was to determine whether PGx guided (G) versus standard treatment (S) influenced LOS among different race/ethnic groups. Secondary objectives included prevalence of drug-gene interactions (DGIs) and readmission rates (RAR). Methods: Retrospective sub-analysis of CYP-GUIDES data comprising CYP2D6 phenotypes was reclassified using standardized CYP2D6 genotype to phenotype recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG). The Mann-Whitney test was used to determine differences in LOS between groups G and S and Kruskal Wallis test to compare LOS among different race/ethnic groups. Logistic regression was used to determine covariates associated with RAR. Results: This study included 1,459 patients with 67.3% in G group (n = 982). The majority of patients were White (57.5%), followed by Latinos (25.6%) and Blacks (12.3%). Although there were no differences in LOS between G and S groups, Latinos had significant shorter LOS than Whites (p = 0.002). LOS was significantly reduced by 5.6 days in poor metabolizers in group G compared to S (p = 0.002). The proportion of supra functional and ultra-rapid metabolizers (UMs) were 6 and 20.3% using CYP-GUIDES and CPIC/DPWG definitions, respectively. Prevalence of DGIs was 40% with significantly fewer DGIs in Blacks (p < 0.001). Race/ethnicity was significantly associated with RAR (aOR 1.30; p = 0.003). Conclusion: A greater number of patients were classified as CYP2D6 UMs using CPIC/DPWG definitions as compared to CYP-GUIDES definitions. This finding may have clinical implications for using psychotropics metabolized by CYP2D6.

PMID:35496293 | PMC:PMC9039251 | DOI:10.3389/fphar.2022.884213

Front Pharmacol. 2022 Apr 14;13:907131. doi: 10.3389/fphar.2022.907131. eCollection 2022.

NO ABSTRACT

PMID:35496282 | PMC:PMC9046651 | DOI:10.3389/fphar.2022.907131

Front Pharmacol. 2022 Apr 14;13:849136. doi: 10.3389/fphar.2022.849136. eCollection 2022.

ABSTRACT

Carbamazepine triggers dermatologic hypersensitivity reactions, associated with specific human leukocyte antigens (HLAs), especially HLA-B*15:02 and HLA-A*31:01. Previous efforts to identify single nucleotide variants (SNVs) with high predictive value as HLA proxies, revealed that rs1061235 and rs17179220 fulfill these requirements for HLA-A*31:01 in some but not all populations. Herein we explored the predictive performance of rs1061235 and rs17179220 as HLA-A*31:01 tags in populations of Native American ancestry, which are largely underrepresented in pharmacogenomic studies. The study cohorts comprised the overall Admixed American superpopulation of the 1000 Genomes Project (1 KG_AMR), a subcohort of individuals with predominant Native American ancestry (1 KG_NAT), the Native American population of the Human Genome Diversity Project (HGDP), plus Kaingang (KRC) and Guarani (GRC and GKW) adults from indigenous reservation areas in Brazil. The diversity of cohorts is reflected in the range of frequencies of HLA-A*31:01 (0.02-0.65), rs1061235 (0.03-0.13) and rs17179220 (0.12-0.66), as well as in the predictive performance of these SNVs as HLA-A*31:01 proxies. NPV (negative predictive value), the metric of primary interest for pharmacogenetic-informed carbamazepine prescription was maximal (NPV = 1.0) for both SNVs in 1 KG_AMR and 1 KG_NAT, for rs17179220, but not rs1061235 (NPV = 0.91) in HGDP, and for rs17179220 in GWK, but not GRC (NPV = 0.88) or KRC (NPV = 0.80). Collectively, the data support the notion that rs1061235 and rs17179220 are not optimal proxies for HLA-A*31:01 across populations of Native American ancestry.

PMID:35496269 | PMC:PMC9046591 | DOI:10.3389/fphar.2022.849136