Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus.

BACKGROUND: The prevalence of metabolic-associated fatty liver disease (MAFLD) is a growing public health issue in people living with human immunodeficiency virus (PLWH). However, the pathophysiology of MAFLD is still unknown, and the role of genetic variables is only now becoming evident. AIM: To evaluate the associations of gene-polymorphism-related MAFLD in PLWH. METHODS: The study employed transient elastography with a controlled attenuation parameter ≥ 248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand. Candidate single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan® MGB probe 5' nuclease assays for seven MAFLD-related genes. Statistical analyses included SNP frequency analysis, Fisher's Exact and Chi-square tests, odds ratio calculations, and multivariable logistic regression. RESULTS: The G-allele carriers of PNPLA3 (rs738409) exhibited a two-fold rise in MAFLD, increasing by 2.5 times in MAFLD with human immunodeficiency virus infection. The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times (P = 0.001) more significant chance of developing aberrant triglyceride among PLWH. CONCLUSION: The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

The association of CYP2C19 LoF alleles with adverse clinical outcomes in stroke patients taking clopidogrel: An updated meta-analysis.

The aggregated risk of recurrent stroke in stroke/transient ischemic attack (TIA) patients carrying CYP2C19 LoF alleles who take clopidogrel has not been investigated recently, and the available research is limited. This study aimed to perform an updated meta-analysis to assess the association between CYP2C19 LoF alleles and the risk of recurrent stroke in patients taking clopidogrel. Databases were searched for the literature on eligible studies. The end points were recurrent stroke, composite vascular events, and bleeding events. Odds ratios (ORs) were calculated using RevMan software, where p < 0.05 was considered statistically significant. Patients carrying CYP2C19 LoF alleles who were treated with clopidogrel had a significantly increased risk of recurrent ischemic stroke compared with non-carriers (OR 2.18, 96% CI 1.80-2.63; p < 0.00001). The risk of recurrent stroke was only significantly different in Asian patients (OR 2.29, 96% CI 1.88-2.80; p < 0.00001) but not in patients of other ethnicities; however, there were a limited number of studies in other ethnic groups. Both observational studies (OR 2.83, 96% CI 2.20-3.65; p < 0.00001) and RCTs (OR 1.48, 96% CI 1.10-1.98; p = 0.009) found associations with a significantly increased risk of recurrent ischemic stroke. Asian stroke patients or TIA patients carrying CYP2C19 LoF alleles and taking clopidogrel were at a significantly higher risk of recurrent ischemic stroke than non-carriers. Significantly increased risk of recurrent ischemic stroke was found in both observational studies and RCTs.

Influence of pharmacogenomic polymorphisms on allopurinol-induced cutaneous adverse drug reactions in Thai patients.

BACKGROUND: Allopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. METHODS: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls. RESULTS: Out of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2-266.8; P = 1.9 × 10- 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3-670.5 and p-value = 1.7 × 10- 27). CONCLUSIONS: Thus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.

Pharmacogenomics of Preeclampsia therapies: Current evidence and future challenges for clinical implementation.

Preeclampsia is a pregnancy-specific disorder, and it is a leading cause of maternal and perinatal morbidity and mortality. The application of pharmacogenetics to antihypertensive agents and dose selection in women with preeclampsia is still in its infancy. No current prescribing guidelines from the clinical pharmacogenetics implementation consortium (CPIC) exist for preeclampsia. Although more studies on pharmacogenomics are underway, there is some evidence for the pharmacogenomics of preeclampsia therapies, considering both the pharmacokinetic (PK) and pharmacodynamic (PD) properties of drugs used in preeclampsia. It has been revealed that the CYP2D6*10 variant is significantly higher in women with preeclampsia who are non-responsive to labetalol compared to those who are in the responsive group. Various genetic variants of PD targets, i.e., NOS3, MMP9, MMP2, TIMP1, TIMP3, VEGF, and NAMPT, have been investigated to assess the responsiveness of antihypertensive therapies in preeclampsia management, and they indicated that certain genetic variants of MMP9, TIMP1, and NAMPT are more frequently observed in those who are non-responsive to anti-hypertensive therapies compared to those who are responsive. Further, gene-gene interactions have revealed that NAMPT, TIMP1, and MMP2 genotypes are associated with an increased risk of preeclampsia, and they are more frequently observed in the non-responsive subgroup of women with preeclampsia. The current evidence is not rigorous enough for clinical implementation; however, an institutional or regional-based retrospective analysis of audited data may help close the knowledge gap during the transitional period from a traditional approach (a "one-size-fits-all" strategy) to the pharmacogenomics of preeclampsia therapies.

Pharmacogenomics of chloroquine and hydroxychloroquine: current evidence and future implications.

As substrates of CYP2C8, CYP3A4/5 and CYP2D6, chloroquine's (CQ) and hydroxychloroquine's (HCQ) efficacy and safety may be affected by variants in the genes encoding these enzymes. This paper aims to assimilate the current evidence on the pharmacogenomics of CQ/HCQ and to identify risk phenotypes affecting the safety or efficacy of these drugs. It has been found that some CYP3A5, CYP2D6 and CYP2C8 genetic variants may affect the safety or effectiveness of CQ/HCQ. The phenotypes predictively representing ultra-rapid and poor metabolizers have been considered high-risk phenotypes. After considering these high-risk phenotypes in different ethnic groups, it is predicted that a considerable proportion of patients taking CQ/HCQ may be at risk of either therapeutic failure or severe toxicities.

Association between Q192R PON1 genetic polymorphism and major adverse cardiovascular events in patients treated with clopidogrel: an updated meta-analysis.

BACKGROUND: Clopidogrel's responsiveness may be affected by the paraoxonase-1 (PON1) enzyme encoded by the Q192R PON1 genetic variant. We aimed to determine the aggregated risk of MACEs associated with carrying Q192R PON1 genetic variant in patients taking clopidogrel. RESEARCH DESIGN AND METHODS: Different databases were searched systematically for eligible studies, and risk ratio (RR) was measured using RevMan software where P <0.05 was set statistically significant. RESULTS: Nineteen studies were included consisting of 17,815 patients. It was found that patients carrying either homozygous or a combination of heterozygous and homozygous variants were not significantly associated with increased risk of MACEs compared to the non-carriers (QQ vs. RR: RR=0.99, 95% CI 0.69-1.42, P=0.96; QQ+QR vs RR; RR=1.05, 95% CI 0.82-1.35, P=0.70). The risk of MACEs was also not significantly different in other genetic model (QQ vs QR+RR) (RR=1.09, 95% CI 0.93-1.27, P=0.30). Further, bleeding events were not significantly different in different genetic models (QQ vs RR; RR=1.13, 95% CI 0.58-2.21, P=0.71; QQ+QR vs RR; RR=1.09, 95% CI 0.66-1.81, P=0.73; QQ vs QR+RR; RR=1.08, 95% CI 0.76-1.55, P=0.66). CONCLUSIONS: The results suggest that the Q192R PON1 genetic polymorphism has no significant impact on the risk of MACEs or bleeding events in patients treated with clopidogrel.

Azole antifungals and inter-individual differences in drug metabolism: the role of pharmacogenomics and precision medicine.

INTRODUCTION: Azole antifungal drugs are commonly prescribed to treat invasive fungal infections in various disease conditions. However, these drugs are substrates and inhibitors of cytochrome P450 (CYP) enzymes, UGT1A4, and P-gp. The genetic variants of CYP3A4/5, CYP2C9, CYP2C19, ABCB1, or UGT1A4 can modify the safety or effectiveness of azole antifungals. AREAS COVERED: This review has collated the recent advances in the pharmacogenomics of azole antifungals pertaining to their metabolism and the safety or effectiveness of their use. A literature search was performed in PubMed from inception to the 5th of December 2022 to retrieve articles focusing on pharmacogenomics of azole antifungals. EXPERT OPINION: Optimizing the safety or effectiveness of most azole antifungals, excluding voriconazole, through pharmacogenomics remains largely theoretical, pending laboratory assessment in future studies. However, the ample evidence of the clinically significant pharmacogenetic impacts of voriconazole, due to the CYP2C19 genetic variability, favors clinical implementation. The inconsistencies of the pharmacogenomics-based dosing guidelines for voriconazole, from different international pharmacogenomics working groups, may hinder clinicians in assimilating and applying such pharmacogenetic information into clinical practice. Consideration of drug-drug interactions along with the pharmacogenetic effects may advance the precision medicine of azole antifungals and allow greater effectiveness in clinical practice.

Pharmacogenomics in Asians: Differences and similarities with other human populations.

INTRODUCTION: Various pharmacogenomic (PGx) variants differ widely in different ethnicities. and clinical outcomes associated with these variants may also be substantially varied. Literature was searched in different databases, i.e. PubMed, ScienceDirect, Web of Science, and PharmGKB, from inception to 30 June 2022 for this review. AREAS COVERED: Certain PGx variants were distinctly varied in Asian populations compared to the other human populations, e.g. CYP2C19*2,*3,*17; CYP2C9*2,*3; CYP2D6*4,*5,*10,*41; UGT1A1*6,*28; HLA-B*15:02, HLA-B*15:21, HLA-B*58:01, and HLA-A*31:01. However, certain other variants do not vary greatly between Asian and other ethnicities, e.g. CYP3A5*3; ABCB1, and SLCO1B1*5. As evident in this review, the risk of major adverse cardiovascular events (MACE) was much stronger in Asian patients taking clopidogrel and who inherited the CYP2C19 loss-of-function alleles, e.g. CYP2C19*2 and*3, when compared to the western/Caucasian patients. Additionally, the risk of carbamazepine-induced severe cutaneous adverse drug reactions (SCARs) for the patients inheriting HLA-B*15:02 and HLA-B*15:21 alleles varied significantly between Asian and other ethnicities. In contrast, both Caucasian and Asian patients inheriting the SLCO1B1*5 variant possessed a similar magnitude of muscle toxicity, i.e. myopathy. EXPERT OPINION: Asian countries should take measures toward expanding PGx research, as well as initiatives for the purposes of obtaining clinical benefits from this newly evolving and economically viable treatment model.

Pharmacogenomics and non-genetic factors affecting drug response in autism spectrum disorder in Thai and other populations: current evidence and future implications.

Autism spectrum disorder (ASD) may affect family and social life profoundly. Although there is no selective pharmacotherapy for ASD, the Food and Drug Administration (FDA) has recommended risperidone/aripiprazole to treat the associated symptoms of ASD, such as agitation/irritability. Strong associations of some pharmacokinetic/pharmacodynamic gene variants, e.g., CYP2D6 and DRD2, with risperidone-induced hyperprolactinemia have been found in children with ASD, but such strong genetic associations have not been found directly for aripiprazole in ASD. In addition to pharmacogenomic (PGx) factors, drug-drug interactions (DDIs) and possibly cumulative effects of DDIs and PGx may affect the safety or effectiveness of risperidone/aripiprazole, which should be assessed in future clinical studies in children with ASD. Reimbursement, knowledge, and education of healthcare professionals are the key obstacles preventing the successful implementation of ASD pharmacogenomics into routine clinical practice. The preparation of national and international PGx-based dosing guidelines for risperidone/aripiprazole based on robust evidence may advance precision medicine for ASD.

Potential factors influencing COVID-19 vaccine acceptance and hesitancy among university students in Bangladesh: a cross-sectional comparative study.

This study investigated Coronavirus disease 2019 (COVID-19) vaccine acceptance, and compared the potential factors influencing vaccine acceptance and hesitancy between public university (PuU) and private university (PrU) students in Bangladesh. An anonymous, self-administered questionnaire was sent to 640 PuU and 660 PrU students in Google Form between 25th September and 22nd November 2021, which resulted in the participation of 1034 (461 PuU vs. 573 PrU) respondents (response rate: 72.03% vs. 86.81%). The pooled vaccine acceptance rates among PuU and PrU students were almost similar (88.1%, 95% confidence interval (CI) 85.1-91.1 vs. 87.6%, 95% CI 84.6-90.6). Employing binary logistic regression to assess the association between various potential factors and vaccine acceptance, the study revealed that out of 10 predictors, 'safety' and 'efficacy' had highly significant positive associations with vaccine acceptance in both cohorts (P = 0.000, P = 0.005). 'Political roles' was found to have varied effects- a significant (P = 0.02) negative and a significant positive (P = 0.002) association with vaccine acceptance in PuU and PrU students, respectively. Additionally, 'communication' (P = 0.003) and 'trust' (P = 0.01) were found to have significant positive associations in PrU students while 'rumours' (P = 0.03) had negative association in PuU students. The odds of accepting the COVID-19 vaccine were 1.5 vs. 0.9 in PuU and PrU students. Although chi-square analysis did not show any significant association between gender and vaccine acceptance, discrepancies were found in the factors that potentially affect vaccine uptake decision between PuU and PrU students. COVID-19 vaccine uptake may be improved if vaccine-related information becomes available and is communicated to large numbers of people effectively. The implementation of multidisciplinary interventional educational programmes may also be considered as a preferred approach to improve student's engagement in pandemic awareness and vaccine readiness.

Implementation of HLA-B*15:02 Genotyping as Standard-of-Care for Reducing Carbamazepine/Oxcarbazepine Induced Cutaneous Adverse Drug Reactions in Thailand.

Objective: This study aimed to investigate the clinical impact of HLA-B*15:02 pharmacogenomics (PGx) testing before carbamazepine (CBZ)/oxcarbazepine (OXC) prescriptions and to determine whether this PGx testing was associated with the reduction of CBZ/OXC-induced cutaneous adverse drug reactions (CADRs) in Thailand. Methods: This retrospective observational cohort study was conducted by obtaining relevant HLA-B*15:02 PGx-testing and clinical data from electronic medical records during 2011-2020. 384 patient data were included in this study to investigate the clinical decision on CBZ/OXC usage before and after the HLA-B*15:02 PGx testing, and 1,539 patient data were included in this study to demonstrate the incidence of CBZ/OXC-induced SCARs and SJS between HLA-B*15:02 tested and non-tested patients. To analyze and summarize the results, descriptive statistics were employed, and Fisher exact test was used to compare the clinical difference between the HLA-B*15:02 positive and negative groups and to compare the differences of SCARs incidence. Results: 384 patients were included in this study as per the inclusion criteria. Of these, 70 patients carried HLA-B*15:02, of which 63 and 65 patients were not prescribed with CBZ/OXC before and after the availability of genotyping results, respectively. In the remaining HLA-B*15:02 non-carriers, 48, and 189 patients were prescribed CBZ/OXC before and after genotyping results were available, respectively. The findings of this study showed that the incidence of SCARs of CBZ/OXC was significantly lower (p < 0.001) in the HLA-B*15:02 screening arm than in the non-screening arm. Conclusion: HLA-B pharmacogenetics testing influenced the selection of appropriate AEDs. The presence of mild rash in the HLA-B*15:02 negative group indicates that other genetic biomarker (HLA-A*31:01) and/or non-genetic variables are involved in CBZ/OXC-induced CADRs, emphasizing that CBZ/OXC prescriptions necessitate CADR monitoring. The hospital policy and clinical decision support (CDS) alert system is essential to overcome the barriers associated with the utilization of PGx guidelines into clinical practice.

Association of UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic polymorphisms with irinotecan-induced toxicity in Asian cancer patients: Meta-analysis.

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. The aim was 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. A PubMed literature search for eligible studies was conducted. Odds ratios (ORs) were measured using RevMan software where p values <0.05 were statistically significant. Patients that 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 carrying 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 those with heterozygous variants. However, patients carrying the ABCC2 c.3972C>T genetic variant were not significantly associated with neutropenia (OR 1.67; 95% CI 0.98-2.84; p = 0.06) and were significantly associated with a reduction in irinotecan-induced diarrhea (OR 0.31; 95% CI 0.11-0.81; p = 0.02). Asian cancer patients should undergo screening for both UGT1A1*6 and UGT1A1*28 genetic variants to reduce substantially irinotecan-induced severe toxicities.

Associations of HLA genetic variants with carbamazepine-induced cutaneous adverse drug reactions: An updated meta-analysis.

Aggregated risk of carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) with different HLA variants are unclear and limited in terms of the power of studies. This study aimed to assess the aggregated risk of CBZ-induced cADRs associated with carrying the following HLA variants: HLA-B*15:02, HLA-B*15:11, HLA-B*15:21, HLA-B*38:02, HLA-B*40:01, HLA-B*46:01, HLA-B*58:01, HLA-A*24:02, and HLA-A*31:01. Literature was searched in different databases following PRISMA guidelines. The outcomes were measured as odds ratio (OR) using RevMan software by a random/fixed effects model, where p < 0.05 was set as statistical significance. In total, 46 case-control studies met the inclusion criteria and were included in this analysis consisting of 1817 cases and 6614 controls. It was found that case-patients who carried the HLA-B*15:02 allele were associated with a significantly increased risk of CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) compared to controls (OR 26.01; 95% CI 15.88-42.60; p < 0.00001). The aggregated risk of cADRs was slightly higher in Asian compared to Caucasian patients (Asians: OR 14.84; 95% CI 8.95-24.61; p < 0.00001; Caucasians: OR 11.65; 95% CI 1.68-80.70; p = 0.01). Further, HLA-B*15:11, HLA-B*15:21, or HLA-A*31:01 allele was also associated with significantly increased risk of CBZ-induced cADRs (HLA-B*15:11: OR 6.08; 95% CI 2.28-16.23; p = 0.0003; HLA-B*15:21: OR 5.37; 95% CI 2.02-14.28; p = 0.0008; HLA-A*31:01: OR 5.92; 95% CI 4.35-8.05; p < 0.00001). Other HLA variants were not found to have any significant associations with CBZ-induced cADRs. Strong associations between the HLA-B*15:02, HLA-B*15:11, HLA-B*15:21, or HLA-A*31:01 allele with CBZ-induced cADRs have been established in this analysis. Pharmacogenetic testing of particular HLA alleles before initiation of CBZ therapy may be beneficial to patients and may help to eradicate cADRs substantially.

Evolution of HLA-B Pharmacogenomics and the Importance of PGx Data Integration in Health Care System: A 10 Years Retrospective Study in Thailand.

Background: The HLA-B is the most polymorphic gene, play a crucial role in drug-induced hypersensitivity reactions. There is a lot of evidence associating several risk alleles to life-threatening adverse drug reactions, and a few of them have been approved as valid biomarkers for predicting life-threatening hypersensitivity reactions. Objectives: The objective of this present study is to present the progression of HLA-B pharmacogenomics (PGx) testing in the Thai population during a 10-year period, from 2011 to 2020. Methods: This was a retrospective observational cohort study conducted at the Faculty of Medicine Ramathibodi Hospital. Overall, 13,985 eligible patients who were tested for HLA-B risk alleles between periods of 2011-2020 at the study site were included in this study. Results: The HLA PGx testing has been increasing year by year tremendously, 94 HLA-B testing was done in 2011; this has been raised to 2,880 in 2020. Carbamazepine (n = 4,069, 33%), allopurinol (n = 4,675, 38%), and abacavir (n = 3,246, 26%) were the most common drugs for which the HLA-B genotyping was performed. HLA-B*13:01, HLA-B*15:02 and HLA-B*58:01 are highly frequent, HLA-B*51:01 and HLA-B*57:01 are moderately frequent alleles that are being associated with drug induced hypersensitivity. HLA-B*59:01 and HLA-B*38:01 theses alleles are rare but has been reported with drug induced toxicity. Most of the samples were from state hospital (50%), 36% from private clinical laboratories and 14% from private hospitals. Conclusion: According to this study, HLA-B PGx testing is increasing substantially in Thailand year after year. The advancement of research in this field, increased physician awareness of PGx, and government and insurance scheme reimbursement assistance could all be factors. Incorporating PGx data, along with other clinical and non-clinical data, into clinical decision support systems (CDS) and national formularies, on the other hand, would assist prescribers in prioritizing therapy for their patients. This will also aid in the prediction and prevention of serious adverse drug reactions.

Pharmacogenomics in clinical practice to prevent risperidone-induced hyperprolactinemia in autism spectrum disorder.

Autism spectrum disorder (ASD) is a global challenge that may disrupts family and social life significantly. There is robust evidence for the association of a pharmacokinetic gene variant (e.g., CYP2D6) with risperidone-induced hyperprolactinemia in ASD. Association of a pharmacodynamic gene variant (e.g., DRD2) with risperidone-induced hyperprolactinemia in ASD is also evident from multiple studies. In addition to genetic factors, dose, duration and drug-drug interactions of risperidone might also increase the serum prolactin level. There are several difficulties, such as reimbursement, knowledge and education of healthcare providers, in implementing risperidone pharmacogenomics into clinical practice. However, preparation of national and international pharmacogenomics-based dosing guidelines of risperidone may advance precision medicine of ASD.

Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies.

Many drugs are being administered to tackle coronavirus disease 2019 (COVID-19) pandemic situations without establishing clinical effectiveness or tailoring safety. A repurposing strategy might be more effective and successful if pharmacogenetic interventions are being considered in future clinical studies/trials. Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, however, from inferring the pharmacokinetic (PK)/pharmacodynamic(PD) properties and some pharmacogenetic evidence in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs. We strongly mandate to undertake a pharmacogenetic assessment for at least these drug-gene pairs (atazanavir-UGT1A1, ABCB1, SLCO1B1, APOA5; efavirenz-CYP2B6; nevirapine-HLA, CYP2B6, ABCB1; lopinavir-SLCO1B3, ABCC2; ribavirin-SLC28A2; tocilizumab-FCGR3A; ivermectin-ABCB1; oseltamivir-CES1, ABCB1; clopidogrel-CYP2C19, ABCB1, warfarin-CYP2C9, VKORC1; non-steroidal anti-inflammatory drugs (NSAIDs)-CYP2C9) in COVID-19 patients for advancing precision medicine. Molecular docking and computational studies are promising to achieve new therapeutics against SARS-CoV-2 infection. The current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although natural occurring compounds from different herbs against SARS-CoV-2 infection are favorable, however, accurate experimental investigation of these compounds is warranted to provide insightful information. Moreover, clinical considerations of drug-drug interactions (DDIs) and drug-herb interactions (DHIs) of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6) and herbogenetic (e.g., andrographolide and CYP2C9) interventions, collectively called multifactorial drug-gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.

Potential factors influencing COVID-19 vaccine acceptance and hesitancy: A systematic review.

BACKGROUND AND AIMS: Although vaccines are considered the most effective and fundamental therapeutic tools for consistently preventing the COVID-19 disease, worldwide vaccine hesitancy has become a widespread public health issue for successful immunization. The aim of this review was to identify an up-to-date and concise assessment of potential factors influencing COVID-19 vaccine acceptance and refusal intention, and to outline the key message in order to organize these factors according to country count. METHODS: A systematic search of the peer-reviewed literature articles indexed in reputable databases, mainly Pub Med (MEDLINE), Elsevier, Science Direct, and Scopus, was performed between21stJune 2021 and10th July 2021. After obtaining the results via careful screening using a PRISMA flow diagram, 47 peer-reviewed articles met the inclusion criteria and formed the basic structure of the review. RESULTS: In total, 11 potential factors were identified, of which the greatest number of articles (n = 28) reported "safety" (34.46%; 95% CI 25.05─43.87) as the overarching consideration, while "side effects" (38.73%; 95% CI 28.14─49.32) was reported by 22 articles, which was the next common factor. Other potential factors such as "effectiveness" were identified in 19 articles (29.98%; 95% CI 17.09─41.67), followed by "trust" (n = 15 studies; 27.91%; 95% CI 17.1─38.73),"information sufficiency"(n = 12; 34.46%; 95% CI 35.87─63.07),"efficacy"(n = 8; 28.73%; 95% CI 9.72─47.74), "conspiracy beliefs" (n = 8; 14.30%; 95% CI 7.97─20.63),"social influence" (n = 6; 42.11%; 95% CI 14.01─70.21), "political roles" (n = 4; 16.75%; 95% CI 5.34─28.16), "vaccine mandated" (n = 4; 51.20%; 95% CI 20.25─82.15), and "fear and anxiety" (n = 3; 8.73%; 95% CI 0.59─18.05). The findings for country-specific influential vaccination factors revealed that, "safety" was recognized mostly (n = 14) in Asian continents (32.45%; 95% CI 19.60─45.31), followed by the United States (n = 6; 33.33%; 95% CI12.68─53.98). "Side effects" was identified from studies in Asia and Europe (n = 6; 35.78%; 95% CI 16.79─54.77 and 16.93%; 95% CI 4.70─28.08, respectively), followed by Africa (n = 4; 74.60%, 95% CI 58.08─91.11); however, public response to "effectiveness" was found in the greatest (n = 7) number of studies in Asian countries (44.84%; 95% CI 25─64.68), followed by the United States (n = 6; 16.68%, 95% CI 8.47─24.89). In Europe, "trust" (n = 5) appeared as a critical predictor (24.94%; 95% CI 2.32─47.56). "Information sufficiency" was identified mostly (n = 4) in articles from the United States (51.53%; 95% CI = 14.12─88.74), followed by Asia (n = 3; 40%; 95% CI 27.01─52.99). More concerns was observed relating to "efficacy" and "conspiracy beliefs" in Asian countries (n = 3; 27.03%; 95% CI 10.35─43.71 and 18.55%; 95% CI 8.67─28.43, respectively). The impact of "social influence" on making a rapid vaccination decision was high in Europe (n = 3; 23.85%, 95% CI -18.48─66.18), followed by the United States (n = 2; 74.85%). Finally, "political roles" and "vaccine-mandated" were important concerns in the United States. CONCLUSIONS: The prevailing factors responsible for COVID-19 vaccine acceptance and hesitancy varied globally; however, the global COVID-19 vaccine acceptance relies on several common factors related to psychological and, societal aspect, and the vaccine itself. People would connect with informative and effective messaging that clarifies the safety, side effects, and effectiveness of prospective COVID-19 vaccines, which would foster vaccine confidence and encourage people to be vaccinated willingly.

Effect of GSTA1 Variants on Busulfan-Based Conditioning Regimen Prior to Allogenic Hematopoietic Stem-Cell Transplantation in Pediatric Asians.

Busulfan is widely used as a chemotherapy treatment before hematopoietic stem-cell transplantation (HSCT). However, the response of busulfan is highly variable and unpredictable, whereby the pharmacogenetic interference of glutathione S-transferase (GST) has strong evidence in Caucasians and some adult Asians but not in pediatric Asian patients. This study was aimed at investigating the associations of GST genetic polymorphisms with variations in the pharmacokinetic (PK) properties of busulfan in pediatric Asian patients. This retrospective cohort study recruited 92 pediatric patients. The polymorphism of GSTA1 was genotyped by Sanger sequencing, and GSTM1 and GSTP1 were genotyped by real-time PCR. Drug concentration and PK estimation were identified using an LC-MS/MS method and a noncompartmental model. Statistical analysis was performed by R software. Out of 92 patients, 48 (53%) were males, the mean age was 8.4 ± 5.12 years old, and the average weight was 26.52 ± 14.75 kg. The allele frequencies of GSTA1*B and of GSTM1 and GSTP1* deletions were 16.9%, 68.5%, and 21.2%, respectively. Patients with GSTA1*B had a statistically significant impact on the PK of busulfan, whereas those with GSTM1 and GSTP1 did not (p > 0.05). The carriers of GSTA1*B showed a significant difference compared to noncarriers in terms of t1/2 (for first dose: 161.9 vs. 134.3 min, p = 0.0016; for second dose: 156.1 vs. 129.8, p = 0.012), CL (88.74 vs. 124.23 mL/min, p = 0.0089), Cmax (4232.6 vs. 3675.5 ng/mL, p = 0.0021), and AUC (5310.6 vs. 4177.1 µM/min, p = 0.00033). The augmentation of AUC was around 27.1% in patients carrying the GSTA1*B variant. The GSTA1 polymorphism was significantly associated with variations of the pharmacokinetic properties of busulfan treatment in pediatric Asian patients.

Effects of the CYP2C19 LoF allele on major adverse cardiovascular events associated with clopidogrel in acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis.

The aggregated risk of major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients inheriting CYP2C19 loss-of function (LoF) alleles who underwent percutaneous coronary intervention (PCI) and were treated with clopidogrel is controversial. In the current study, we searched the literature in different databases for eligible studies. The risk ratio (RR) was measured where p<0.05 was statistically significant. The ACS patients with either one or two CYP2C19 LoF alleles who underwent PCI, treated with clopidogrel were correlated with a significantly escalated risk of MACE compared with noncarriers (RR: 1.53, 95% CI: 1.39-1.69, p < 0.00001), driven by CV death (RR: 1.88, 95% CI: 1.18-3.01, p = 0.008), MI (RR: 1.67, 95% CI: 1.21-2.31, p = 0.002) and ST (RR: 1.90, 95% CI: 1.27-2.84, p = 0.002). Patients with two CYP2C19 LoF alleles were correlated with significantly greater risk of MACE compared with noncarriers (RR: 3.91, 95% CI: 2.78-5.50, p < 0.00001). Further analysis revealed that the risk of MACE was markedly significant in Asian patients (RR: 2.02, 95% CI: 1.67-2.44, p < 0.00001) and was comparatively low significance in western patients (RR: 1.35, 95% CI: 1.20-1.52, p < 0.00001). There was no significantly different bleeding events in patients with CYP2C19 LoF alleles compared with noncarriers (RR: 0.99, 95% CI: 0.85-1.15, p = 0.87). The ACS patients inheriting CYP2C19 LoF alleles, who underwent PCI and were treated with clopidogrel were correlated with significantly increased risk of MACE compared with noncarriers.