PLoS One. 2023 Apr 20;18(4):e0284386. doi: 10.1371/journal.pone.0284386. eCollection 2023.

ABSTRACT

The genetic basis of variability in drug response is at the core of pharmacogenomics (PGx) studies, aiming at reducing adverse drug reaction (ADR), which have interethnic variability. This study used the Kardiovize Brno 2030 random urban Czech sample population to analyze polymorphisms in a wide spectrum of genes coding for liver enzymes involved in drug metabolism. We aimed at correlating real life drug consumption with pharmacogenomic profile, and at comparing these data with the SUPER-Finland Finnish PGx database. A total of 250 individuals representative of the Kardiovize Brno 2030 cohort were included in an observational study. Blood DNA was extracted and 59 single nucleotide polymorphisms within 13 genes (BCHE, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5, F2, F5, IFNL3, SLCO1B1, TPMT, UGT1A1, VKORC1), associated to different drug metabolizing rates, were characterized by genotyping using a genome wide commercial array. Widely used drugs such as anti-coagulant warfarin and lipid lowering agent atorvastatin were associated to an alarmingly high percentage of users with intermediate/poor metabolism for them. Significant differences in the frequency of normal/intermediate/poor/ultrarapid/rapid metabolizers were observed for CYPD26 (p<0.001), CYP2C19 (p<0.001) and UGT1A1 (p<0.001) between the Czech and the Finnish study populations. Our study demonstrated that administration of some popular drugs to a Czech random sample population is associated with different drug metabolizing rates and therefore exposing to risk for ADRs. We also highlight interethnic differentiation of some common pharmacogenetics variants between Central (Czech) and North European (Finnish) population studies, suggesting the utility of PGx-informed prescription based on variant genotyping.

PMID:37079615 | DOI:10.1371/journal.pone.0284386

Clin Pharmacol Ther. 2023 Apr 20. doi: 10.1002/cpt.2912. Online ahead of print.

ABSTRACT

The antiretroviral drug efavirenz remains widely used in children and mothers during breastfeeding in tuberculosis-endemic areas. Evaluating the safety of efavirenz during breastfeeding requires an understanding of its pharmacokinetics in breast milk, its exposure in the breastfed infant and the potential influence of polymorphisms in drug disposition genes. The interplay of these factors between the mother and the nursing infant is a complex scenario that can be readily investigated using physiologically based pharmacokinetic (PBPK) modelling. A verified PBPK model for efavirenz describing the CYP3A4- and CYP2B6-mediated auto-induction during multiple dosing was reported previously and was applied in this study to predict the exposure of efavirenz in vulnerable populations, including children (down to the age of 3 months), mothers and breastfeeding infants, accounting for the various CYP2B6 genotypes. Predicted pharmacokinetic parameters for mothers, breastfeeding infants and children aged ≥3 months were reasonably consistent with observed data, irrespective of CYP2B6 genotype. The clinically significant trend towards higher infant efavirenz exposure from GG/GG to TT/TT composite maternal/infant CYP2B6 genotypes was captured reasonably well by the PBPK model. Thereafter, simulations were performed to determine the adequacy of the current WHO (≥3 years) and FDA (≥3 months) weight-based dosing regimens for efavirenz in children according to CYP2B6 genotype. The findings of this study indicate that PBPK models can be used in designing studies in vulnerable populations and providing guidance on optimal doses based on developmental physiology and pharmacogenetics.

PMID:37078251 | DOI:10.1002/cpt.2912

J Thromb Haemost. 2023 Apr 19:S1538-7836(23)00332-X. doi: 10.1016/j.jtha.2023.04.014. Online ahead of print.

ABSTRACT

Quantitative abnormalities in factor VIII (FVIII) and its binding partner, von Willebrand factor (VWF), are associated with an increased risk for bleeding or thrombosis and pathways that regulate the clearance of VWF-FVIII can strongly influence their plasma levels. In 2010, the CHARGE genome-wide association study (GWAS) meta-analysis identified variants in the genes for the sinusoidal endothelial receptors CLEC4M, stabilin-2, and SCARA5 as being associated with plasma levels of VWF and/or FVIII in normal individuals. The ability of these receptors to bind, internalize, and clear the VWF-FVIII complex from the circulation has now been reported in a series of studies utilizing in vitro and in vivo models. The receptor stabilin-2 has also been shown to modulate the immune response to infused VWF-FVIII concentrates in a murine model. In addition, the influence of genetic variants in CLEC4M, STAB2, and SCARA5 on type 1 VWD/low VWF phenotype, FVIII pharmacokinetics, and the risk for venous thromboembolism have been described in a number of patient-based studies. Understanding the role of these receptors in the regulation of VWF-FVIII clearance has led to significant insights into the genomic architecture that modulates plasma VWF and FVIII levels, improving the understanding of pathways that regulate VWF-FVIII clearance and the mechanistic basis of quantitative VWF-FVIII pathologies.

PMID:37085036 | DOI:10.1016/j.jtha.2023.04.014

Ned Tijdschr Geneeskd. 2023 Apr 19;167:D7584.

ABSTRACT

Pharmacogenetics holds the promise of personalized medicine, resulting in higher effectiveness and fewer adverse effects. Yet, the clinical benefit of a pre-emptive pharmacogenetic test has not been demonstrated rigorously. Recently an open-label real-world implementation study has been published, in which patients were randomized to either genotype-informed treatment (based on a 12-gene pharmacogenetic panel) or standard treatment. The study shows that genotype-informed prescription of different types of medication, i.e., opioids, anticoagulants and antidepressants, leads to a 30% reduction of clinically relevant adverse effects. This result is promising and indicates that genotype-informed treatment improves medication safety. Unfortunately, the influence of genotype-informed treatment on the balance between effectiveness and adverse effects could not be assessed and cost-effectiveness data are pending. Hence, a pharmacogenetic panel and a DNA medication pass for everyone are on the horizon, but not yet there.

PMID:37078568

Drug Metab Pers Ther. 2023 Apr 19. doi: 10.1515/dmpt-2022-0189. Online ahead of print.

ABSTRACT

OBJECTIVES: A study was conducted to develop and validate the warfarin pharmacogenetic dose optimization algorithm considering the clinical pharmacogenetic implementation consortium (CPIC) recommendations for the Asian ethnicity population.

METHODS: The present prospective observational study recruited warfarin-receiving patients. We collected a three ml blood sample for VKORC1, CYP2C9*2, CYP2C9*3, and CYP4F2 polymorphism assessment during the follow-up visits. Clinical history, sociodemographic and warfarin dose details were noted.

RESULTS: The study recruited 300 patients (250 in derivation and 50 in validation timed cohort) receiving warfarin therapy. The baseline characteristics were similar in both cohorts. BMI, presence of comorbidity, VKORC1, CYP2C9*2, and CYP2C9*3 were identified as covariates significantly affecting the warfarin weekly maintenance dose (p<0.001 for all) and the same were included in warfarin pharmacogenetic dose optimization algorithm building. The algorithm built-in the present study showed a good correlation with Gage (r=0.57, p<0.0001), and IWPC (r=0.51, p<0.0001) algorithms, widely accepted in western side of the globe. The receiver operating characteristic curve analysis showed a sensitivity of 73 %, a positive predictive value of 96 %, and a specificity of 89 %. The algorithm correctly identified the validation cohort's warfarin-sensitive, intermediate reacting, and resistant patient populations.

CONCLUSIONS: Validation and comparisons of the warfarin pharmacogenetic dose optimization algorithm have made it ready for the clinical trial assessment.

PMID:37075481 | DOI:10.1515/dmpt-2022-0189

Chem Res Toxicol. 2023 Apr 19. doi: 10.1021/acs.chemrestox.2c00414. Online ahead of print.

ABSTRACT

Carbamazepine (CBZ) is an aromatic anticonvulsant known to cause drug hypersensitivity reactions, which range in severity from relatively mild maculopapular exanthema to potentially fatal Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). These reactions are known to be associated with human leukocyte antigen (HLA) class I alleles, and CBZ interacts preferentially with the related HLA proteins to activate CD8+ T-cells. This study aimed to evaluate the contribution of HLA class II in the effector mechanism(s) of CBZ hypersensitivity. CBZ-specific T-cells clones were generated from two healthy donors and two hypersensitive patients with high-risk HLA class I markers. Phenotype, function, HLA allele restriction, response pathways, and cross-reactivity of CBZ-specific T-cells were assessed using flow cytometry, proliferation analysis, enzyme-linked immunosorbent spot, and enzyme-linked immunosorbent assay. The association between HLA class II allele restriction and CBZ hypersensitivity was reviewed using Allele Frequency Net Database. Forty-four polyclonal CD4+ CBZ-specific T-cell clones were generated and found to be restricted to HLA-DR, particularly HLA-DRB1*07:01. This CD4+-mediated response proceeded through a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the CD8+ response, CBZ-stimulated CD4+ clones secreted granulysin, a key mediator of SJS-TEN. Our database review revealed an association between HLA-DRB1*07:01 and CBZ-induced SJS-TEN. These findings implicate HLA class II antigen presentation as an additional pathogenic factor for CBZ hypersensitivity reactions. Both HLA class II molecules and drug-responsive CD4+ T-cells should be evaluated further to gain better insights into the pathogenesis of drug hypersensitivity reactions.

PMID:37074725 | DOI:10.1021/acs.chemrestox.2c00414

Expert Opin Drug Metab Toxicol. 2023 Apr 18. doi: 10.1080/17425255.2023.2202813. Online ahead of print.

ABSTRACT

INTRODUCTION: Membrane transporters are now widely recognized for their role in the absorption, distribution, clearance and elimination of drugs. The organic cation transporters (OCTs, SLC22A) are expressed in the intestine, liver and kidneys and are of importance in determining systemic pharmacokinetics and tissue-specific exposure of drugs and metabolites.

AREAS COVERED: An overview of the role of OCTs in drug disposition is presented. Genetic variation in OCTs and the effects on pharmacokinetics and drug response were discussed.

EXPERT OPINION: Clinical studies demonstrated significance of OCT1 and OCT2 in the hepatic uptake and renal secretion of drug, respectively. These mechanisms are important in determining the systemic pharmacokinetics and tissue exposure and thus pharmacodynamics of several drug (e.g. metformin, morphine, sumatriptan). Emerging pharmacogenomic data also suggest multidrug and toxin extrusion pump (MATE1, SLC47A1) contribute to pharmacokinetics and response of drugs like metformin and cisplatin. Considerations to genotyping of functional and common variants of OCTs should be given, particularly for cationic drugs with hepatic elimination or renal secretion being major clearance pathways, in the clinical development. While the current evidence indicate that pharmacokinetic variability associated with known genotypes of OCTs/MATEs is relatively small, they may be of relevance in the tissue-specific effects and for drugs with low therapeutic index.

PMID:37070463 | DOI:10.1080/17425255.2023.2202813

Nat Med. 2023 Apr 17. doi: 10.1038/s41591-023-02268-w. Online ahead of print.

ABSTRACT

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

PMID:37069360 | DOI:10.1038/s41591-023-02268-w

Pharmacogenet Genomics. 2023 Apr 10. doi: 10.1097/FPC.0000000000000497. Online ahead of print.

ABSTRACT

With the scarcity of pharmacological otoprotective agents against cisplatin-induced ototoxicity (CIO), researchers find themselves compelled to look at and navigate all possible strategies to identify ways to prevent CIO. One of these promising strategies is pharmacogenomic implementation. This strategy aims for identifying and detecting high-risk genetic variants to tailor cisplatin therapy to reach the best survival outcomes with the least risk of ototoxicity.

PMID:37068004 | DOI:10.1097/FPC.0000000000000497

JAMA Netw Open. 2023 Apr 3;6(4):e238585. doi: 10.1001/jamanetworkopen.2023.8585.

ABSTRACT

IMPORTANCE: A platelet ADP P2Y12 receptor (P2Y12) inhibitor plus aspirin is standard therapy for patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Compared with clopidogrel, prasugrel and ticagrelor are associated with superior antiatherothrombotic effects but increased bleeding risk; with recent guideline updates, it is important to describe current treatment patterns and the role of bleeding risk in treatment choice.

OBJECTIVE: To describe secular trends and determinants of initial P2Y12 inhibitor choice and switching, including deescalation (switch from prasugrel or ticagrelor to clopidogrel).

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used MarketScan Commercial Claims Data from 2010 to 2019 for patients aged 18 years or older who underwent PCI for ACS, had no P2Y12 inhibitor use in the past year, and filled a P2Y12 inhibitor prescription within 30 days after PCI hospitalization discharge. Data were analyzed from February to May 2022.

EXPOSURES: Clopidogrel, prasugrel, and ticagrelor, with determinants including bleeding risk measured using Academic Research Consortium for High Bleeding Risk criteria, sociodemographic characteristics, P2Y12 inhibitor copays, and bleeding events during follow-up.

MAIN OUTCOMES AND MEASURES: The prevalence of each P2Y12 inhibitor among patients who initiated the drugs and the prevalence of switching within 12 months after PCI were evaluated. The association between baseline bleeding risk and bleeding manifestations during follow-up and initial treatment and deescalation were calculated using multivariable logistic and Cox proportional hazards regression models.

RESULTS: Between 2010 and 2019, 62 423 patients were identified who initiated P2Y12 inhibitors (females, 22.4%; males, 77.6%; mean [SD] age, 54.32 [7.13] years). The prevalence of clopidogrel as initial therapy decreased from 77.5% in 2010 to 29.6% in 2019, while initial use of prasugrel or ticagrelor increased from 22.5% to 60.4%. Within 1 year after PCI, 11.0% of patients switched therapy, mostly for deescalation. Deescalation prevalence increased from 1.8% in 2010 to 12.6% in 2018. Between 2016 and 2018, 8588 of 22 886 (37.5%) patients had major baseline bleeding risk, which decreased the selection of prasugrel or ticagrelor as initial therapy (adjusted odds ratio, 0.78; 95% CI, 0.74-0.84). Among 11 285 patients who initiated prasugrel or ticagrelor, major bleeding risk at baseline (adjusted hazard ratio, 1.11; 95% CI, 1.00-1.23) and the occurrence of bleeding during follow-up (adjusted hazard ratio, 4.42; 95% CI, 3.62-5.93) were associated with deescalation.

CONCLUSIONS AND RELEVANCE: A strong shift in preference for prasugrel and ticagrelor as initial therapy following PCI for ACS was observed. Deescalation increased over the study period. Major bleeding risk at baseline was moderately associated with initial treatment choice but had a limited association with deescalation. The increasing use of more potent P2Y12 inhibitors emphasizes opportunities to enhance preemptive patient-centered treatment strategies to maintain optimal antiplatelet activity while reducing bleeding risk during the subacute period following PCI for ACS.

PMID:37067798 | DOI:10.1001/jamanetworkopen.2023.8585

Front Genet. 2023 Mar 30;14:1114774. doi: 10.3389/fgene.2023.1114774. eCollection 2023.

ABSTRACT

Dyslipidemias are risk factors in diseases of significant importance to public health, such as atherosclerosis, a condition that contributes to the development of cardiovascular disease. Unhealthy lifestyles, the pre-existence of diseases, and the accumulation of genetic variants in some loci contribute to the development of dyslipidemia. The genetic causality behind these diseases has been studied primarily on populations with extensive European ancestry. Only some studies have explored this topic in Costa Rica, and none have focused on identifying variants that can alter blood lipid levels and quantifying their frequency. To fill this gap, this study focused on identifying variants in 69 genes involved in lipid metabolism using genomes from two studies in Costa Rica. We contrasted the allelic frequencies with those of groups reported in the 1000 Genomes Project and gnomAD and identified potential variants that could influence the development of dyslipidemias. In total, we detected 2,600 variants in the evaluated regions. However, after various filtering steps, we obtained 18 variants that have the potential to alter the function of 16 genes, nine variants have pharmacogenomic or protective implications, eight have high risk in Variant Effect Predictor, and eight were found in other Latin American genetic studies of lipid alterations and the development of dyslipidemia. Some of these variants have been linked to changes in blood lipid levels in other global studies and databases. In future studies, we propose to confirm at least 40 variants of interest from 23 genes in a larger cohort from Costa Rica and Latin American populations to determine their relevance regarding the genetic burden for dyslipidemia. Additionally, more complex studies should arise that include diverse clinical, environmental, and genetic data from patients and controls and functional validation of the variants.

PMID:37065472 | PMC:PMC10098023 | DOI:10.3389/fgene.2023.1114774

Future Virol. 2023 Mar. doi: 10.2217/fvl-2022-0187. Epub 2023 Apr 11.

ABSTRACT

Aim: This study aimed to analyze the phylogenetic relationships between the ACE2 of humans and other animals and investigate the potential interaction between SARS-CoV-2 RBD and ACE2 of different species. Materials & methods: The phylogenetic construction and molecular interactions were assessed using computational models. Results & conclusion: Despite the evolutionary distance, 11 species had a perfect fit for the interaction between their ACE2 and SARS-CoV-2 RBD (Chinchilla lanigera, Neovison vison, Rhinolophus sinicus, Emballonura alecto, Saccopteryx bilineata, Numida meleagris). Among them, the avian N. meleagris was reported for the first time in this study as a probable SARS-CoV-2 host due to the strong molecular interactions. Therefore, predicting potential hosts for SARS-CoV-2 for understanding the epidemiological cycle and proposal of surveillance strategies.

PMID:37064326 | PMC:PMC10096339 | DOI:10.2217/fvl-2022-0187

Health Sci Rep. 2023 Apr 11;6(4):e1210. doi: 10.1002/hsr2.1210. eCollection 2023 Apr.

ABSTRACT

BACKGROUND AND AIMS: The dengue virus is widespread throughout Bangladesh and significantly contributes to morbidity and mortality. One effective method for preventing further dengue epidemics is to reduce mosquito breeding at the most opportune period each year. This study aims to determine dengue prevalence in 2022 by comparing previous years' data and estimating the period of this disease's most significant incidence.

METHODS: From the beginning of 2008-December 15, 2022, we looked at the monthly reports of cases made to the Bangladesh Institute of Epidemiology, Disease Control, and Research.

RESULTS: According to our findings, there were 61089 confirmed dengue cases in 2022, with 269 fatalities - the highest annual death toll for this disease since 2000. Almost one-third (32.14%) of all dengue deaths in Bangladesh occurred in 2022 (1 January-15 December), highlighting the severity of the threat posed by this disease in the coming year. Furthermore, we observe that the months in the second half of any year in Bangladesh are the most at risk for dengue transmission. In 2022, Dhaka city and Chittagong are hit the hardest (incidence: 63.07% vs. 14.42%; morality: 63.34% vs. 24.16%), showing the relevance of population density in spreading this fatal disease.

CONCLUSION: Statistics show an increase in dengue cases every day, and the year 2022 will be marked as the peak of the disease's death prevalence. Both the individuals and the government of Bangladesh need to take action to reduce the dissemination of this epidemic. If not, the country will soon be in great peril.

PMID:37064322 | PMC:PMC10090488 | DOI:10.1002/hsr2.1210

Front Pharmacol. 2023 Mar 29;14:1180487. doi: 10.3389/fphar.2023.1180487. eCollection 2023.

NO ABSTRACT

PMID:37063283 | PMC:PMC10090656 | DOI:10.3389/fphar.2023.1180487

Tuberculosis (Edinb). 2023 Apr 16;140:102343. doi: 10.1016/j.tube.2023.102343. Online ahead of print.

ABSTRACT

Multidrug-resistant (MDR) or extensively drug-resistant (XDR) Tuberculosis (TB) is a major challenge to global TB control. Therefore, accurate tracing of in-country MDR-TB transmission are crucial for the development of optimal TB management strategies. This study aimed to investigate the diversity of MTBC in Nigeria. The lineage and drug-resistance patterns of the clinical MTBC isolates of TB patients in Southwestern region of Nigeria were determined using the WGS approach. The phenotypic DST of the isolates was determined for nine anti-TB drugs. The sequencing achieved average genome coverage of 65.99X. The most represented lineages were L4 (n = 52, 83%), L1 (n = 8, 12%), L2 (n = 2, 3%) and L5 (n = 1, 2%), suggesting a diversified MTB population. In term of detection of M/XDR-TB, while mutations in katG and rpoB genes are the strong predictors for the presence of M/XDR-TB, the current study also found the lack of good genetic markers for drug resistance amongst the MTBC in Nigeria which may pose greater problems on local tuberculosis management efforts. This high-resolution molecular epidemiological data provides valuable insights into the mechanistic for M/XDR TB in Lagos, Nigeria.

PMID:37080082 | DOI:10.1016/j.tube.2023.102343

Biochimie. 2023 Apr 14:S0300-9084(23)00086-X. doi: 10.1016/j.biochi.2023.04.009. Online ahead of print.

ABSTRACT

Type 2 diabetes mellitus (DM) poses a major burden for the treatment and control of tuberculosis (TB). Characterization of the underlying metabolic perturbations in DM patients with TB infection would yield insights into the pathophysiology of TB-DM, thus potentially leading to improvements in TB treatment. In this study, a multimodal metabolomics and lipidomics workflow was applied to investigate plasma metabolic profiles of patients with TB and TB-DM. Significantly different biological processes and biomarkers in TB-DM vs. TB were identified using a data-driven, knowledge-based framework. Changes in metabolic and signaling pathways related to carbohydrate and amino acid metabolism were mainly captured by amide HILIC column metabolomics analysis, while perturbations in lipid metabolism were identified by the C18 metabolomics and lipidomics analysis. Compared to TB, TB-DM exhibited elevated levels of bile acids and molecules related to carbohydrate metabolism, as well as the depletion of glutamine, retinol, lysophosphatidylcholine, and phosphatidylcholine. Moreover, arachidonic acid metabolism was determined as a potential important factor in the interaction between TB and DM pathophysiology. In a correlation network of the significantly altered molecules, among the central nodes, chenodeoxycholic acid was robustly associated with TB and DM. Fatty acid (22:4) was a component of all significant modules. In conclusion, the integration of multimodal metabolomics and lipidomics provides a thorough picture of the metabolic changes associated with TB-DM. The results obtained from this comprehensive profiling of TB patients with DM advance the current understanding of DM comorbidity in TB infection and contribute to the development of more effective treatment.

PMID:37062470 | DOI:10.1016/j.biochi.2023.04.009

J Sci Med Sport. 2023 Mar;26(3):181-182. doi: 10.1016/j.jsams.2023.02.007. Epub 2023 Mar 6.

NO ABSTRACT

PMID:37061291 | DOI:10.1016/j.jsams.2023.02.007

Clin Gastroenterol Hepatol. 2023 Apr 13:S1542-3565(23)00270-7. doi: 10.1016/j.cgh.2023.03.044. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor-(TNF)α antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1*05 genotype and risk of immunogenicity with TNFα antagonists.

METHODS: Through a systematic review till 14 July, 2022, we identified studies in patients with IMIDs treated with TNFα antagonists, which reported the risk of immunogenicity and/or secondary loss of response in patients with HLA-DQA1*05 variants. Primary outcome was risk of immunogenicity. We performed random effects meta-analysis and used GRADE to appraise certainty of evidence.

RESULTS: On meta-analysis of 13 studies (3,756 patients, median follow-up, 12m; 41% with variants), HLA-DQA1*05 variants were associated with 75% higher risk of immunogenicity compared to wild type [relative risk (RR), 1.75 (95% CI, 1.37-2.25)] with considerable heterogeneity (I2=62%) (low certainty evidence). Positive and negative predictive value of HLA-DQA1*05 variants for predicting immunogenicity was 30% and 80%, respectively. Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs- and TNFα antagonist-type, modified this association. Patients with HLA-DQA1*05 variants experienced 2.2-fold higher risk of secondary loss of response [six cohorts; RR, 2.24 (1.67-3.00), I2=0%] (moderate certainty evidence).

CONCLUSION: Variants in HLA-DQA1*05 are associated with an increased risk in immunogenicity and secondary loss of response in patients with IMIDs treated with TNFα antagonists. However, the positive and negative predictive value is moderate, and decisions on concomitant use of IMMs to prevent immunogenicity should be individualized based on all factors that influence drug clearance.

PMID:37061107 | DOI:10.1016/j.cgh.2023.03.044

Expert Rev Clin Pharmacol. 2023 Apr 15. doi: 10.1080/17512433.2023.2203381. Online ahead of print.

NO ABSTRACT

PMID:37060346 | DOI:10.1080/17512433.2023.2203381

Redox Biol. 2023 Apr 5;62:102696. doi: 10.1016/j.redox.2023.102696. Online ahead of print.

ABSTRACT

As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE-/- mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.

PMID:37058999 | DOI:10.1016/j.redox.2023.102696