Diabetes Obes Metab. 2023 Jun 1. doi: 10.1111/dom.15143. Online ahead of print.

ABSTRACT

AIM: Glucagon-like peptide-1 receptor agonists provide multiple benefits to patients with type 2 diabetes, including improved glycaemic control, weight loss and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.

METHODS: Exenatide (5 μg, subcutaneously) or saline (0.2 ml, subcutaneously) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was a crossover design in which participants received exenatide and saline in random order.

RESULTS: Exenatide increased first phase insulin secretion 1.9-fold (p = 1.9 × 10-9 ) and accelerated the rate of glucose disappearance 2.4-fold (p = 2 × 10-10 ). Minimal model analysis showed that exenatide increased glucose effectiveness (Sg ) by 32% (p = .0008) but did not significantly affect insulin sensitivity (Si ). The exenatide-induced increase in insulin secretion made the largest contribution to interindividual variation in exenatide-induced acceleration of glucose disappearance while interindividual variation in the drug effect on Sg contributed to a lesser extent (β = 0.58 or 0.27, respectively).

CONCLUSIONS: This pilot study provides validation for the value of a frequently sampled intravenous glucose tolerance test (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide (NCT05071898). Three endpoints provide quantitative assessments of the effects of glucagon-like peptide-1 receptor agonists on glucose metabolism: first phase insulin secretion, glucose disappearance rates and glucose effectiveness.

PMID:37264484 | DOI:10.1111/dom.15143

Front Pharmacol. 2023 May 16;14:1069854. doi: 10.3389/fphar.2023.1069854. eCollection 2023.

ABSTRACT

Objective: Deferasirox is an iron-chelating agent prescribed to patients with iron overload. Due to the interindividual variability of deferasirox responses reported in various populations, this study aims to determine the genetic polymorphisms that influence drug responses. Methods: A systematic search was performed from inception to March 2022 on electronic databases. All studies investigating genetic associations of deferasirox in humans were included, and the outcomes of interest included pharmacokinetics, efficacy, and adverse drug reactions. Fixed- and random-effects model meta-analyses using the ratio of means (ROM) were performed. Results: Seven studies involving 367 participants were included in a meta-analysis. The results showed that subjects carrying the A allele (AG/AA) of ABCC2 rs2273697 had a 1.23-fold increase in deferasirox Cmax (ROM = 1.23; 95% confidence interval [CI]:1.06-1.43; p = 0.007) and a lower Vd (ROM = 0.48; 95% CI: 0.36-0.63; p < 0.00001), compared to those with GG. A significant attenuated area under the curve of deferasirox was observed in the subjects with UGT1A3 rs3806596 AG/GG by 1.28-fold (ROM = 0.78; 95% CI: 0.60-0.99; p = 0.04). In addition, two SNPs of CYP24A1 were also associated with the decreased Ctrough: rs2248359 CC (ROM = 0.50; 95% CI: 0.29-0.87; p = 0.01) and rs2585428 GG (ROM = 0.47; 95% CI: 0.35-0.63; p < 0.00001). Only rs2248359 CC was associated with decreased Cmin (ROM = 0.26; 95% CI: 0.08-0.93; p = 0.04), while rs2585428 GG was associated with a shorter half-life (ROM = 0.44; 95% CI: 0.23-0.83; p = 0.01). Conclusion: This research summarizes the current evidence supporting the influence of variations in genes involved with drug transporters, drug-metabolizing enzymes, and vitamin D metabolism on deferasirox responses.

PMID:37261288 | PMC:PMC10227503 | DOI:10.3389/fphar.2023.1069854

Pharmacogenomics. 2023 Jun 1. doi: 10.2217/pgs-2023-0028. Online ahead of print.

ABSTRACT

Aim: To assess knowledge, confidence and perceptions of healthcare professionals specializing in primary care and pain management at Brigham and Women's Hospital, related to clinical pharmacogenomics (PGx). Methods: A 25-question online survey was distributed to 328 Brigham and Women's Hospital clinicians for analysis. Results: Thirty-four clinicians completed the survey. Respondents had minimal experience with PGx and limited awareness of PGx resources. Although respondents expressed belief that PGx has utility to improve medication-related patient outcomes, many lack confidence to apply PGx results to their practice. For clinical drug-gene questions relevant to primary care and/or pain management, respondents scored poorly. Conclusion: More clinician education is needed for appropriate utilization of PGx in clinical practice as it pertains to primary care and pain management.

PMID:37259972 | DOI:10.2217/pgs-2023-0028

Pharmaceuticals (Basel). 2023 Feb 9;16(2):262. doi: 10.3390/ph16020262.

ABSTRACT

Vitamin D has recently been found to influence the renin-angiotensin system (RAS); it can reduce the effects of renin-angiotensin system inhibitors (RASI) by decreasing plasma renin. This study examines the effect of vitamin D supplements on cardiac fibrosis markers, echocardiographic parameters, and epigenetic markers in patients with established acute coronary syndrome (ACS). It also looks at the incidence of vitamin D receptor (VDR) gene polymorphisms Apa I (rs7975232), Bsm I (rs1544410), Taq I (rs731236), and Fok I (rs2228570) and its association with the development of secondary major acute cardiovascular events (MACE) and heart failure (HF). A randomized controlled trial in which patients were divided into two groups was performed. Group 1 comprised of 125 ACS patients who received ACS standard therapy alone, while Group 2 consisted of 125 ACS patients who received ACS standard therapy plus vitamin D according to their vitamin D levels. Patients were monitored for 24 months to find subsequent MACE and HF. Vitamin D therapy for ACS patients resulted in a substantial decline in end systolic and end diastolic volumes (p = 0.0075 and 0.002, respectively), procollagen type III N-terminal peptide (PIIINP) and soluble ST2 levels (p = 0.007 and 0.001, respectively), as well as in ejection fraction and vitamin D level (p = 0.0001 and 0.008, respectively). In addition, vitamin D treatment was linked to a significant decline in the levels of noncoding RNA, such as mir361, lncRNA MEG3, and lncRNA Chaer (p = 2.9 × 10-4, 2.2 × 10-6, and 1.2 × 10-5, respectively). Furthermore, patients who suffered MACE had significantly higher levels of the Bsm I CC and Fok I GG genotypes (p = 4.8 × 10-4 and 0.003, respectively), while patients with HF had significantly higher levels of the Taq I AA genotype (p = 4.2 × 10-7). Supplementing ACS patients with vitamin D has been demonstrated to limit cardiac fibrosis and echocardiographic parameters, as well as epigenetic markers. Additionally, MACE and HF among ACS patients may be related to genetic variations among VDR gene polymorphisms.

PMID:37259407 | DOI:10.3390/ph16020262

Pharmaceuticals (Basel). 2023 Feb 8;16(2):259. doi: 10.3390/ph16020259.

ABSTRACT

Immune checkpoint inhibitors (ICI) are the standard of care for various malignancies and have been associated with a wide spectrum of complications that are phenotypically akin to primary autoimmune diseases. While the literature on these toxicities is growing, there is a paucity of data regarding ICI-associated scleroderma which can carry significant morbidity and limit the ability to continue effective ICI therapy. Our review aimed to analyze the current literature on ICI-associated systemic scleroderma (ICI-SSc) and key scleroderma mimics. Cases of ICI-SSc had notable differences from primary SSc, such as fewer vascular features and less seropositivity (such as scleroderma-specific antibodies and antinuclear antibodies). We found that patients with a diagnosis of SSc prior to the start of ICI can also experience flares of pre-existing disease after ICI treatment used for their cancer. Regarding scleroderma mimics, several cases of ICI-eosinophilic fasciitis have also been described with variable clinical presentations and courses. We found no cases of scleroderma mimics: ICI-scleromyxedema or ICI-scleroedema. There is a critical need for multi-institutional efforts to collaborate on developing a patient database and conducting robust, prospective research on ICI-scleroderma. This will ultimately facilitate more effective clinical evaluations and management for ICI-scleroderma.

PMID:37259404 | DOI:10.3390/ph16020259

Pharmaceuticals (Basel). 2023 Feb 6;16(2):244. doi: 10.3390/ph16020244.

ABSTRACT

In a preliminary study, we synthesized a series of new PDK1/MEK dual inhibitors. Antitumor activity screening showed that Compound YZT exerts a strong inhibitory action in A549 cells. However, the specific mechanism of YZT against non-small cell lung cancer (NSCLC) is largely unknown. This work confirmed the anti-proliferation and pro-apoptosis effects of YZT in NSCLC cells. Furthermore, YZT promotes autophagy and provokes complete autophagic flux in NSCLC cells. Notably, compared with YZT alone, the combination of YZT with the autophagy inhibitor chloroquine (CQ) or 3-methyladenine (3-MA) markedly strengthened the anti-proliferative and pro-apoptotic actions, suggesting that YZT-induced autophagy is cytoprotective. We further found that YZT-induced autophagy may exert a cytoprotective function by preserving the integrity of mitochondria and decreasing mitochondrial apoptosis. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that PDK1 is an upstream protein of the Akt/mTOR axis and western blotting verified that YZT induces autophagy by the PDK1/Akt/mTOR signaling axis. Finally, YZT plus CQ significantly enhanced the anticancer activities compared to YZT alone in an animal study and immunohistochemistry showed that the level of LC3 was increased by YZT, which is in line with the in vitro results. In short, our study provides reliable experimental basis for developing Compound YZT as a new chemotherapeutic drug candidate and suggests that combined administration of YZT with CQ is a potential therapy against NSCLC.

PMID:37259393 | DOI:10.3390/ph16020244

Expert Opin Drug Metab Toxicol. 2023 Jun 2:1-4. doi: 10.1080/17425255.2023.2220961. Online ahead of print.

NO ABSTRACT

PMID:37254883 | DOI:10.1080/17425255.2023.2220961

Fitoterapia. 2023 May 29:105553. doi: 10.1016/j.fitote.2023.105553. Online ahead of print.

ABSTRACT

Three undescribed lignan glycosides, echiunines E-G (1-3), as well as eight known compounds (4-11) were isolated from Fritillaria verticillata Willd. Among them, compounds 1-3 were a series of lignan glycosides reported for the first time from genus Fritillaria. Their structures were elucidated by analyses of extensive spectroscopic data and comparison of the NMR data with those reported previously, the absolute configuration of compounds were further confirmed by calculated ECD method. The NO release inhibitory effects of compounds were evaluated in LPS-activated RAW264.7 macrophages. Compounds 7-8 showed inhibitory acitivities in a dose-dependent manner.

PMID:37257697 | DOI:10.1016/j.fitote.2023.105553

Life Sci. 2023 May 29:121822. doi: 10.1016/j.lfs.2023.121822. Online ahead of print.

ABSTRACT

AIMS: Understanding of the molecular mechanisms of anti-TNFα therapy non-response and reliable biomarkers are essential for personalized medicine in Crohn's disease (CD) patients. Using RNA-seq data adjusted for deconvoluted fractions of peripheral blood cells, we recently described MMD gene, coding for a monocyte to macrophage differentiation factor, as a biomarker of adalimumab (anti-TNFα) therapy response in CD. The results also suggest that cell subtype-specific biomarkers may be superior to those measured in bulk peripheral blood. Here, we used functional cell model to further investigate the role of the monocyte to macrophage differentiation in adalimumab treatment response and evaluate monocyte/macrophage specific expression of the inflammatory cytokines as potential biomarkers for (non)response to adalimumab in CD patients.

MAIN METHODS: The peripheral monocytes of CD patients responsive and non-responsive to adalimumab were isolated, differentiated into macrophages, and exposed to inflammation and concurrent adalimumab therapy in vitro. The results were correlated to the clinical response of the donor patients.

KEY FINDINGS: Correlation is shown of the expression of two macrophage differentiation related genes- CD68 and MMD, with the expression of the inflammatory cytokines TNF, IL1B, IL6 and CXCL8. Monocytes and in vitro differentiated macrophages of adalimumab non-responders express more inflammatory cytokines than those of responders. The biggest difference was in the IL1B expression. Additionally, IL1B expression in the in vitro differentiated macrophages of CD patients correlates negatively with their clinical response to adalimumab.

SIGNIFICANCE: We propose the IL1B expression in the macrophages as a possible biomarker for adalimumab response in CD patients.

PMID:37257580 | DOI:10.1016/j.lfs.2023.121822

Comput Biol Chem. 2023 Apr 7;105:107868. doi: 10.1016/j.compbiolchem.2023.107868. Online ahead of print.

ABSTRACT

The characterization of drug - metabolizing enzymes is a significant problem for customized therapy. It is important to choose the right drugs for cancer victims, and the ability to forecast how those drugs will react is usually based on the available information, genetic sequence, and structural properties. To the finest of our knowledge, this is the first study to evaluate optimization algorithms for selection of features and pharmacogenetics categorization using classification methods based on a successful evolutionary algorithm using datasets from the Cancer Cell Line Encyclopaedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC). The study proposes the uses of Firefly and Grey Wolf Optimization techniques for feature extraction, while comparing the traditional Machine Learning (ML), ensemble ML and Stacking Algorithm with the proposed Convolutional Temporal Deep Neural Network or CTDN. With the potential to increase efficiency from the suggested intelligible classifier model for a suggestive chemotherapeutic drugs response prediction, our study is important in particular for selecting an acceptable feature selection method. The comparison analysis demonstrates that the proposed model not only surpasses the prior state-of-the-art methods, but also uses Grey Wolf and Fire Fly Optimization to lessen multicollinearity and overfitting.

PMID:37257399 | DOI:10.1016/j.compbiolchem.2023.107868

Genet Test Mol Biomarkers. 2023 May;27(5):133-141. doi: 10.1089/gtmb.2022.0109.

ABSTRACT

Background: There is extensive interindividual variability in response and tolerance to anticancer drugs. This heterogeneity provides a major limitation to the "rational" use of cytotoxic drugs, and it becomes a major problem in oncology giving a narrow therapeutic window with a vital risk. Among these anticancer drugs, irinotecan can cause dose-limiting toxicities, commonly diarrhea and neutropenia. Interaction among pathways of activation/inactivation (UGT1A1) and hepatobiliary transport of irinotecan and its metabolites could, in part, explain its interindividual variability. The objective of this study was to perform an exploratory analysis to evaluate the correlation between the genetic polymorphisms of UGT1A1 and ABCC2 with the different toxicities associated with irinotecan treatment. Materials and Methods: Seventy-five patients with solid cancers were included, all were administered an irinotecan-based regimen in both Mission Bay Medical Center; and Zuckerberg San Francisco General Hospital from May 2016 to December 2016. The patients' genotyping was performed for both the UGT1A1*28 polymorphism, and the ABCC2 - 1549G>A, and ABCC2 - 1249G>A single nucleotide polymorphism. Comparisons among qualitative data were assessed using the χ2-test, and Fisher's exact test in the case of small group sizes. Results: Diarrhea was observed in 40 patients (53.3%), among them only 9 patients had high grades diarrhea (grades III and IV). Grades III/IV of nausea were more frequently associated with the ABCC2-1549 AA genotype (83.3% p = 0.004) in patients with colorectal cancer. In pancreatic cancer, a significant absence of diarrhea grades III-IV was noted in patients with the ABCC2 1249 GG genotype compared to the other ABCC2 1249 genotypes.

PMID:37257181 | DOI:10.1089/gtmb.2022.0109

Expert Rev Pharmacoecon Outcomes Res. 2023 May 31. doi: 10.1080/14737167.2023.2220966. Online ahead of print.

ABSTRACT

OBJECTIVES: To assess the cost-effectiveness of Arg16Gly ADRB2 pharmacogenomic testing compared with no Arg16Gly ADRB2 testing to guide the use of long-acting β2 receptor agonist (LABA) in asthma patients aged 1 to 5 years in China.

METHODS: This economic evaluation developed a Markov model with four health states (no exacerbation, mild exacerbation, moderate-to-severe exacerbation, and death). Transition probabilities were estimated from the rate of exacerbations, the case-fatality rate of patients hospitalized for exacerbations, and natural mortality. Costs included drug costs and exacerbation management costs. Cost inputs and utilities for each health state were gained from public databases and the literature. Costs and quality-adjusted life years (QALYs) were estimated for ten years. Deterministic and probabilistic sensitivity analyses were performed.

RESULTS: In the base case analysis, in contrast to the group without the genotype test, the incremental total cost was -¥334.7, and the incremental QALY was 0.001 in the Arg16Gly ADRB2 genotyping group. Therefore, the Arg16Gly ADRB2 test group was the dominant strategy for children with asthma in China. The sensitivity analyses showed that the model was relatively stable.

CONCLUSION: Arg16Gly ADRB2 testing before using LABA is a cost-effective approach compared with no gene testing for pediatric asthma.

PMID:37256257 | DOI:10.1080/14737167.2023.2220966

Front Pharmacol. 2023 May 15;14:1184523. doi: 10.3389/fphar.2023.1184523. eCollection 2023.

ABSTRACT

Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.

PMID:37256234 | PMC:PMC10226670 | DOI:10.3389/fphar.2023.1184523

Front Pharmacol. 2023 May 15;14:1199462. doi: 10.3389/fphar.2023.1199462. eCollection 2023.

ABSTRACT

Background: Awareness about the importance of implementing DPYD pharmacogenetics in clinical practice to prevent severe side effects related to the use of fluoropyrimidines has been raised over the years. Since 2012 at the National Cancer Institute, CRO-Aviano (Italy), a diagnostic DPYD genotyping service was set up. Purpose: This study aims to describe the evolution of DPYD diagnostic activity at our center over the last 10 years as a case example of a successful introduction of pharmacogenetic testing in clinical practice. Methods: Data related to the diagnostic activity of in-and out-patients referred to our service between January 2012 and December 2022 were retrieved from the hospital database. Results: DPYD diagnostic activity at our center has greatly evolved over the years, shifting gradually from a post-toxicity to a pre-treatment approach. Development of pharmacogenetic guidelines by national and international consortia, genotyping, and IT technology evolution have impacted DPYD testing uptake in the clinics. Our participation in a large prospective implementation study (Ubiquitous Pharmacogenomics) increased health practitioners' and patients' awareness of pharmacogenetic matters and provided additional standardized infrastructures for genotyping and reporting. Nationwide test reimbursement together with recommendations by regulatory agencies in Europe and Italy in 2020 definitely changed the clinical practice guidelines of fluoropyrimidines prescription. A dramatic increase in the number of pre-treatment DPYD genotyping and in the coverage of new fluoropyrimidine prescriptions was noticed by the last year of observation (2022). Conclusion: The long path to a successful DPYD testing implementation in the clinical practice of a National Cancer Center in Italy demonstrated that the development of pharmacogenetic guidelines and genotyping infrastructure standardization as well as capillary training and education activity for all the potential stakeholders are fundamental. However, only national health politics of test reimbursement and clear recommendations by drug regulatory agencies will definitely move the field forward.

PMID:37256229 | PMC:PMC10225682 | DOI:10.3389/fphar.2023.1199462

BMC Cardiovasc Disord. 2023 May 31;23(1):279. doi: 10.1186/s12872-023-03321-9.

ABSTRACT

AIM: The anticoagulation effect of warfarin is usually evaluated by percentage of time in therapeutic range (PTTR), which is negatively correlated with the risk of warfarin adverse reactions. This study aimed to explore the effects of genetic and nongenetic factors on anticoagulation efficacy of warfarin during different therapeutic range.

METHODS: We conducted an observational retrospective study aiming at evaluating the impact of clinical and genetic factors on PTTR from initial to more than six months treatment. This analysis included patients with heart valve replace (HVR) surgery who underwent long-term or life-long time treatment with standard-dose warfarin for anticoagulation control in Second Xiangya Hospital. All patients were followed for at least 6 months. We genotyped single nucleotide polymorphisms in VKORC1 and CYP2C9 associated with altered warfarin dose requirements and tested their associations with PTTR.

RESULTS: A total of 629 patients with intact clinical data and available genotype data were enrolled in this study, and only 38.63% patients achieved good anticoagulation control (PTTR > 0.6). Clinical factors, including male gender, older age, overweight, AVR surgery and stroke history, were associated with higher PTTR. Patients with VKORC1 -1639AA genotype had significantly higher PTTR level compared with GA/GG genotype carriers only in the first month of treatment. Patients with CYP2C9*3 allele had higher PTTR compared with CYP2C9*1*1 carriers. Moreover, compared with VKORC1 -1639 AG/GG carriers, INR > 4 was more likely to be present in patients with AA genotype. The frequency of CYP2C9*1*3 in patients with INR > 4 was significantly higher than these without INR > 4.

CONCLUSION: We confirmed the relevant factors of warfarin anticoagulation control, including genetic factors (VKORC1 -1639G > A and CYP2C9*3 polymorphisms) and clinical factors (male gender, older age, overweight, AVR surgery and stroke history), which could be helpful to individualize warfarin dosage and improve warfarin anticoagulation control during different treatment period.

PMID:37254053 | DOI:10.1186/s12872-023-03321-9

Eur Heart J Cardiovasc Pharmacother. 2023 May 30:pvad040. doi: 10.1093/ehjcvp/pvad040. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentration of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping. In this study we aimed to develop an easy, clinically implementable functional gene risk score (GRS) of common variants in SLCO1B1 to identify patients at risk of statin intolerance.

METHODS AND RESULTS: A GRS was developed from four common variants in SLCO1B1. In statin users from Tayside Scotland, UK, those with a high-risk GRS had increased odds across three phenotypes of statin intolerance (general statin intolerance: ORGSI 2.42[95%CI:1.29, 4.31], p = 0.003; statin-related myopathy ORSRM 2.51[95%CI:1.28, 4.53], p = 0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85[95%CI:1.03, 6.65], p = 0.02). In contrast, using the Val174Ala genotype alone or the recommended OATP1B1 functional phenotypes produced weaker and less reliable results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99 [95%CI:1.01, 3.95], p = 0.048; ORGRS 1.76 [95%CI:1.16, 2.69], p = 0.008). For those requiring high-dose statin therapy, the high-risk GRS was more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared to Val174Ala (general statin intolerance: HRVal174Ala 2.49 [95%CI:1.09, 5.68], p = 0.03; HRGRS 2.44 [95%CI:1.46, 4.08], p < 0.001). Finally, sequence kernel association testing (SKAT) confirmed rare variants in SLCO1B1 are associated with the risk of intolerance (p = 0.02).

CONCLUSIONS: We provide evidence that a gene risk score based on four common SLCO1B1 variants provides an easily implemented genetic tool that is more reliable than the current recommended practice in estimating the risk and predicting early onset statin intolerance.

PMID:37253618 | DOI:10.1093/ehjcvp/pvad040

Front Pharmacol. 2023 May 9;14:1159307. doi: 10.3389/fphar.2023.1159307. eCollection 2023.

ABSTRACT

Introduction: Genetic variation in the thiopurine S-methyltransferase (TPMT) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in TPMT still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously. Objective: The aim of this study was to evaluate the effect of genetic variants in ITPA, TPMT, NUDT15, XDH, and ABCB1 on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia. Methods: Genotyping of ITPA, and XDH was performed using KASP genotyping assay, while that of TPMT, NUDT15, and ABCB1 with TaqMan® SNP genotyping assays. Clinical profile of the patients was collected for the first 6 months of the maintenance phase treatment. The primary outcome was the incidence of grade 4 neutropenia. Bivariable followed by multivariable cox regression analysis was performed to identify genetic variants associated with the development of grade 4 neutropenia within the first 6 months of maintenance treatment. Results: In this study, genetic variants in XDH and ITPA were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for XDH rs2281547 were 2.956 times (AHR 2.956, 95% CI = 1.494-5.849, p = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype. Conclusion: In conclusion, in this cohort, XDH rs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other than TPMT involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

PMID:37251339 | PMC:PMC10214954 | DOI:10.3389/fphar.2023.1159307

Front Pharmacol. 2023 May 11;14:1175737. doi: 10.3389/fphar.2023.1175737. eCollection 2023.

ABSTRACT

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region's continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the "need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics". Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%-99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC.

PMID:37251329 | PMC:PMC10213898 | DOI:10.3389/fphar.2023.1175737

Pharmacogenomics. 2023 May 30. doi: 10.2217/pgs-2023-0045. Online ahead of print.

ABSTRACT

Background: Pain is a common cause of hospitalization in sickle cell disease (SCD) patients. Failure to effectively control pain remains a challenge in patient care. Materials & methods: The authors conducted a cross-sectional study to determine the effect of CYP2D6 and UGT2B7 polymorphisms on pain management in 106 Zimbabwean SCD patients. Participant information was collected on a questionnaire. Genotyping was conducted using the GenoPharm® pharmacogenomics open array panel containing CYP2D6 and UGT genetic variants implicated in opioid response. Results: The reduced function alleles CYP2D6*17 and *29 had high frequencies of 15.9% and 12.9%, respectively. UGT2B7 rs73823859 showed a statistically significant correlation with pain levels (p = 0.0454). Conclusion: This study demonstrated the role of UGT2B7 polymorphism in SCD patient pain management.

PMID:37248824 | DOI:10.2217/pgs-2023-0045

Transfusion. 2023 May 29. doi: 10.1111/trf.17447. Online ahead of print.

ABSTRACT

BACKGROUND: Transfusion-associated circulatory overload (TACO) is a severe adverse reaction (AR) contributing to the leading cause of mortality associated with transfusions. As strategies to mitigate TACO have been increasingly adopted, an update of prevalence rates and risk factors associated with TACO using the growing sources of electronic health record (EHR) data can help understand transfusion safety.

STUDY DESIGN AND METHODS: This retrospective study aimed to provide a timely and reproducible assessment of prevalence rates and risk factors associated with TACO. Novel natural language processing methods, now made publicly available on GitHub, were developed to extract ARs from 3178 transfusion reaction reports. Other patient-level data were extracted computationally from UCSF EHR between 2012 and 2022. The odds ratio estimates of risk factors were calculated using a multivariate logistic regression analysis with case-to-control matched on sex and age at a ratio of 1:5.

RESULTS: A total of 56,208 patients received transfusions (total 573,533 units) at UCSF during the study period and 102 patients developed TACO. The prevalence of TACO was estimated to be 0.2% per patient (102/total 56,208). Patients with a history of coagulopathy (OR, 1.36; 95% CI, 1.04-1.79) and transplant (OR, 1.99; 95% CI, 1.48-2.68) were associated with increased odds of TACO.

DISCUSSION: While TACO is a serious AR, events remained rare, even in populations enriched with high-risk patients. Novel computational methods can be used to find and continually surveil for transfusion ARs. Results suggest that patients with history or presence of coagulopathy and organ transplant should be carefully monitored to mitigate potential risks of TACO.

PMID:37248741 | DOI:10.1111/trf.17447