Pharmacogenomics

Clinical implementation of drug metabolizing gene-based therapeutic interventions worldwide

Sat, 2021-10-02 06:00

Hum Genet. 2021 Oct 1. doi: 10.1007/s00439-021-02369-x. Online ahead of print.

ABSTRACT

Over the last few years, the field of pharmacogenomics has gained considerable momentum. The advances of new genomics and bioinformatics technologies propelled pharmacogenomics towards its implementation in the clinical setting. Since 2007, and especially the last-5 years, many studies have focused on the clinical implementation of pharmacogenomics while identifying obstacles and proposed strategies and approaches for overcoming them in the real world of primary care as well as outpatients and inpatients clinics. Here, we outline the recent pharmacogenomics clinical implementation projects and provide details of the study designs, including the most predominant and innovative, as well as clinical studies worldwide that focus on outpatients and inpatient clinics, and primary care. According to these studies, pharmacogenomics holds promise for improving patients' health in terms of efficacy and toxicity, as well as in their overall quality of life, while simultaneously can contribute to the minimization of healthcare expenditure.

PMID:34599365 | DOI:10.1007/s00439-021-02369-x

Categories: Literature Watch

Suppressor of variegation 3-9 homologue 1 impairment and neutrophil-skewed systemic inflammation are associated with comorbidities in COPD

Sat, 2021-10-02 06:00

BMC Pulm Med. 2021 Oct 2;21(1):276. doi: 10.1186/s12890-021-01628-x.

ABSTRACT

BACKGROUND: Systemic manifestations and comorbidities are characteristics of chronic obstructive pulmonary disease (COPD) and are probably due to systemic inflammation. The histone methyltransferase SUV39H1 controls the Th1/Th2 balance. We previously reported that reduced SUV39H1 expression contributed to abnormal inflammation in COPD. Here, we aimed to determine whether impaired SUV39H1 expression in COPD patients associated with neutrophilic/eosinophilic inflammation responses and comorbidities.

METHODS: A total of 213 COPD patients and 13 healthy controls were recruited from the Shuang Ho Hospital, Taipei Medical University. SUV39H1 levels in peripheral blood mononuclear cells (PBMCs) from 13 healthy and 30 COPD participants were measured by immunoblotting. We classified the patients into two groups based on low (fold change, FC < 0.5) and high SUV39H1 expression (FC ≥ 0.5) compared to normal controls. Clinical outcomes including neutrophil or eosinophil counts associated with SUV39H1-related inflammation were evaluated by Chi square analyses or Mann-Whitney U test. The correlations between the percentage of neutrophils and number of COPD comorbidities or Charlson Comorbidity Index (CCI) scores were performed by Spearman's rank analysis.

RESULTS: Low SUV39H1 expression group had high neutrophil counts relative to high SUV39H1expression group. In the COPD cohort, the high comorbidity group (≥ 2 comorbidities) had higher counts of whole white blood cell (WBC) and neutrophil, and lower proportion of eosinophil and eosinophil/neutrophil, as compared with low comorbidity group (0 and 1 comorbidities). The quantity of neutrophils was associated with COPD comorbidities (Spearman's r = 0.388, p < 0.001), but not with CCI scores. We also found that the high comorbidity group had more exacerbations per year compared with low comorbidity group (1.5 vs. 0.9 average exacerbations, p = 0.005). However, there were no significant differences between groups with these non-frequent (0-1 exacerbation) and frequent exacerbations per year (> 1 exacerbation) in numbers of WBC and proportion of neutrophils, eosinophils or eosinophil/neutrophil. Finally, patients with high comorbidities had lower SUV39H1 levels in their PBMCs than did those with low comorbidities.

CONCLUSION: Blood neutrophil counts are associated with comorbidities in COPD patients. Impaired SUV39H1 expression in PBMCs from COPD patients are correlated with neutrophilic inflammation and comorbidities.

PMID:34598691 | DOI:10.1186/s12890-021-01628-x

Categories: Literature Watch

Tricyclic antidepressants for major depressive disorder: a comprehensive evaluation of current practice in the Netherlands

Sat, 2021-10-02 06:00

BMC Psychiatry. 2021 Oct 1;21(1):481. doi: 10.1186/s12888-021-03490-x.

ABSTRACT

BACKGROUND: Traditionally tricyclic antidepressants (TCAs) have an important place in treatment of major depressive disorder (MDD). Today, often other antidepressant medications are considered as first step in the pharmacological treatment of MDD, mainly because they are associated with less adverse effects, whereby the position of TCAs appears unclear. In this study we aimed to examine the current practice of TCAs in treatment of unipolar MDD.

METHODS: A mixed methods approach was applied. First, a selection of leading international and national guidelines was reviewed. Second, actual TCA prescription was examined by analyzing health records of 75 MDD patients treated with the TCAs nortriptyline, clomipramine or imipramine in different centers in the Netherlands. Third, promotors and barriers influencing the choice for TCAs and dosing strategies were explored using semi-structured interviews with 24 Dutch psychiatrists.

RESULTS: Clinical practice guidelines were sometimes indirective and inconsistent with each other. Health records revealed that most patients (71%) attained therapeutic plasma concentrations within two months of TCA use. Patients who achieved therapeutic plasma concentrations reached them on average after 19.6 days (SD 10.9). Both health records and interviews indicated that therapeutic nortriptyline concentrations were attained faster compared to other TCAs. Various factors were identified influencing the choice for TCAs and dosing by psychiatrists.

CONCLUSIONS: Guideline recommendations and clinical practice regarding TCA prescription for MDD vary. To increase consistency in clinical practice we recommend development of an up-to-date guideline integrating selection and dosing of TCAs, including the roles of therapeutic drug monitoring and pharmacogenetics. Such a guideline is currently lacking and would contribute to optimal TCA treatment, whereby efficacy and tolerability may be increased.

PMID:34598683 | DOI:10.1186/s12888-021-03490-x

Categories: Literature Watch

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

Fri, 2021-10-01 06:00

J Clin Invest. 2021 Oct 1:e152386. doi: 10.1172/JCI152386. Online ahead of print.

ABSTRACT

BACKGROUND: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition.

METHODS: We combined individual level data from 13,888 COVID-19 patients (N=7,185 hospitalized) from 17 cohorts in nine countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications and laboratory values. We next performed meta-analyses using FinnGen and the Columbia University COVID-19 Biobank.

RESULTS: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR 1.4, 95%CI 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR 2.1, 95%CI 1.6-2.6), venous thromboembolism (OR 1.7, 95%CI 1.2-2.4), and hepatic injury (OR 1.5, 95%CI 1.2-2.0). Risk allele carriers ≤60 years had higher odds of death or severe respiratory failure (OR 2.7, 95%CI 1.8-3.9) compared to those >60 years (OR 1.5, 95%CI 1.2-1.8, interaction-p=0.038). Amongst individuals ≤60 years who died or experienced severe respiratory failure, 32.3% were risk variant carriers, compared to 13.9% of those not experiencing these outcomes. The genetic risk improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.

CONCLUSIONS: The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced amongst individuals ≤60 years. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.

PMID:34597274 | DOI:10.1172/JCI152386

Categories: Literature Watch

Pharmacogenetics: Knowledge assessment amongst Syrian pharmacists and physicians

Fri, 2021-10-01 06:00

BMC Health Serv Res. 2021 Oct 1;21(1):1031. doi: 10.1186/s12913-021-07040-9.

ABSTRACT

BACKGROUND: Pharmacogenetics targets genetic variations that influence drug response. It is relatively a new science that has not been vastly employed in most developing countries including Syria. Therefore we aimed at evaluating the depth of knowledge in pharmacogenetics and the attitude towards it amongst Syrian pharmacists and physicians.

METHODS: We carried out an internet-based questionnaire consisted of 26 questions, sent through specialized websites and private groups with a large number of pharmacists and physicians members. The survey was available online for a period of 1 month.

RESULTS: The total number of respondents was 154, mostly female pharmacists. Our statistical analysis showed a strong positive association between profession (in favour of pharmacists) and pharmacogenetics knowledge p = 0.049; however, no correlation with experience p = 0.811 was found. A significant difference was reported between the knowledge of pharmacists and physicians p = 0.001 concerning drugs that need pharmacogenetics testing before being prescribed. The majority of respondents had no information about applying genetic tests in Syria before prescribing medications nor did they possess the knowledge regarding drugs that show differential responses in patients according to their unique genotypes. In our study, the percentage knowledge assessment score was low in general (mean ± Standard deviation, SD) (46% ± 13.9%). The majority of the respondents agreed that pharmacists should provide counselling to patients on the subject of pharmacogenetics. Respondents' opinions varied concerning making pharmacogenetics learning a priority.

CONCLUSION: Lack of pharmacogenetics knowledge was found amongst respondents in general. Our findings raise concerns about the lack of awareness amongst physicians, which may hinder the implementation of this crucial field in Syria. We suggest an emphasis on the role of education, training, and conducting genotyping research on the Syrian population.

PMID:34592972 | DOI:10.1186/s12913-021-07040-9

Categories: Literature Watch

Growth hormone secretagogue peptide-6 enhances Oreochromicins transcription and antimicrobial activity in tilapia (Oreochromis sp.)

Thu, 2021-09-30 06:00

Fish Shellfish Immunol. 2021 Sep 27:S1050-4648(21)00233-3. doi: 10.1016/j.fsi.2021.08.011. Online ahead of print.

ABSTRACT

Growth Hormone-Releasing Peptide 6 (GHRP-6) (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH2) is an agonist of the growth hormone secretagogue receptor. GHRP-6 mimics the effect of ghrelin. The present study focuses on the immunomodulatory effects of GHRP-6 in tilapia with and without the presence of Pseudomonas aeruginosa infection. GHRP-6 up-regulated the transcription levels of three piscidin-like antimicrobial peptides (Oreochromicins I, II, and III) and granzyme in a tissue-dependent manner. Antimicrobial activity stimulation in serum (lysozyme and anti-protease activity) was also confirmed. Besides, GHRP-6 enhanced the in vitro antimicrobial activity against P. aeruginosa in tilapia gills mucus and serum samples and decreased the bacterial load in vivo after infection with this Gram-negative bacterium. Our results evidenced, for the first time, a direct link between a growth hormone secretagogue ghrelin mimetic in fish and the enhancement of antimicrobial peptides transcription, which suggests that this secretagogue is capable to lead the activation of microbicidal activity in tilapia. Thus, these results open new possibilities for GHRP-6 application in aquaculture to stimulate the teleost immune system as an alternative treatment against opportunistic bacteria.

PMID:34592474 | DOI:10.1016/j.fsi.2021.08.011

Categories: Literature Watch

Regeneration Roadmap: database resources for regenerative biology

Thu, 2021-09-30 06:00

Nucleic Acids Res. 2021 Sep 30:gkab870. doi: 10.1093/nar/gkab870. Online ahead of print.

ABSTRACT

Regeneration plays an instrumental role in biological development and damage repair by constructing and replacing cells, tissues, and organs. Since regenerative capacity declines with age, promoting regeneration is heralded as a potential strategy for delaying aging. On this premise, mechanisms that regulate regeneration have been extensively studied across species and in different tissues. However, an open and comprehensive database collecting and standardizing the abundant data generated in regeneration research, such as high-throughput sequencing data, remains to be developed. In this work, we constructed Regeneration Roadmap to systematically and comprehensively collect such information over 2.38 million data entries across 11 species and 36 tissues, including regeneration-related genes, bulk and single-cell transcriptomics, epigenomics, and pharmacogenomics data. In this database, users can explore regulatory and expression changes of regeneration-associated genes in different species and tissues. Regeneration Roadmap provides the research community with a long-awaited and valuable data resource featuring convenient computing and visualizing tools, which is publicly available at https://ngdc.cncb.ac.cn/regeneration/index.

PMID:34591960 | DOI:10.1093/nar/gkab870

Categories: Literature Watch

Remdesivir, Sinus Bradycardia and Therapeutic Drug Monitoring in Children With Severe COVID-19

Thu, 2021-09-30 06:00

Pediatr Infect Dis J. 2021 Aug 24. doi: 10.1097/INF.0000000000003309. Online ahead of print.

NO ABSTRACT

PMID:34591799 | DOI:10.1097/INF.0000000000003309

Categories: Literature Watch

Heavy Metal Concentrations in Malaysian Adults' Hair and Associated Variables in Bukit Mertajam, Penang, Malaysia

Thu, 2021-09-30 06:00

Biol Trace Elem Res. 2021 Sep 30. doi: 10.1007/s12011-021-02942-5. Online ahead of print.

ABSTRACT

The presence of heavy metals in human hair is being tracked to predict health risk, forensics, and environmental monitoring. Heavy metals are typically non-biodegradable and have a lengthy half-life, allowing them to linger in humans and the environment for many years. Heavy metal exposure in hair has been attributed to multiple sources from the environment and food intake. In this study, copper (Cu), nickel (Ni), zinc (Zn), chromium (Cr), manganese (Mn), lead (Pb), and cadmium (Cd) levels were measured in the scalp hair of 50 individuals in Bukit Mertajam, Penang, Malaysia. In conjunction with sampling, subjects' age, gender, lifestyle, diet, and working environment were also obtained through the questionnaire. The Atomic Absorption Spectrometry (AAS) method was used to extract all the metals in the hair samples. The mean concentrations of heavy metals were found to be in the following order (unit of mg/kg): Cr > Zn > Pb > Ni > Cd > Cu. Manganese was detected below the limit of quantitation among the elements (< LOQ). All elements except Mn were higher and comparable to the previous studies' international limit values. Cadmium prevalence was substantially associated with age, smoking habit, dyed hair, and working environment in Pearson's correlation analysis (p ≤ 0.05). Zinc was also found to be related to the working environment. Some elements were observed to be statistically related between heavy metals, Cd/Zn, Cd/Ni, Cr/Ni, and Pb/Ni, whereas smoking habit/dyed hair and dyed hair/working environment were the associated factors for metal distribution that were statistically correlated (p ≤ 0.05). To recapitulate, this study found that the distribution of heavy metals in hair was influenced by associated factors and between heavy metals. It has been indicated that heavy metal exposure to humans is influenced by factors such as geographical location, lifestyle, and working environment.

PMID:34591221 | DOI:10.1007/s12011-021-02942-5

Categories: Literature Watch

Homicidal poisoning series in a nursing home: retrospective toxicological investigations in bone marrow and hair

Thu, 2021-09-30 06:00

Int J Legal Med. 2021 Sep 30. doi: 10.1007/s00414-021-02703-y. Online ahead of print.

ABSTRACT

Homicidal poisonings remain rare and can be difficult to detect, especially in the elderly or in medical settings. In this atypical poisoning series, a young nursing assistant purposely poisoned thirteen residents of a nursing home and killed ten of them. The medications used were a mix of psychotropic medications (cyamemazine, loxapine, tiapride, risperidone, and mirtazapine), under liquid formulation, which were inducing malaise and coma. The forensic investigation included analysis of blood, urine, hair, and bone marrow and exhumations of seven corpses up to 3 years after the inhumation. Hair collected from a hairbrush of a cremated victim have been analyzed. Bone marrow sample preparation was based on a liquid/liquid triple extraction. Hair were incubated after decontamination overnight at 55 °C in methanol. Segmentation was possible for seven samples, except for delayed exhumation samples (n = 4) and hairbrush hair sample (n = 1). The extracts were then analyzed using gas chromatography coupled with mass spectrometry (GC-MS) for unknown screening and using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for a targeted screening and quantification. Screenings revealed the presence of the same mix of psychotropic medications. Cyamemazine, mirtazapine, loxapine, tiapride, and risperidone hair concentrations were 6-17,458 pg/mg, 74-1271 pg/mg, 9-1346 pg/mg, 13-148 pg/mg, and 3-5 pg/mg, respectively. Cyamemazine bone marrow concentrations were 229 and 681 ng/g and 152-717 ng/mL in blood. Patients' medications were also identified and quantified. This poisoning series provide analytical data that could support subsequent toxicological result interpretation in similar forensic cases.

PMID:34591183 | DOI:10.1007/s00414-021-02703-y

Categories: Literature Watch

Effects of genetic polymorphisms of ABCB1 on the efficacy of anesthetic and analgesic agents: a systematic review

Thu, 2021-09-30 06:00

Pharmacogenomics. 2021 Sep 30. doi: 10.2217/pgs-2021-0079. Online ahead of print.

ABSTRACT

Aim: To perform a systematic review to determine the effect of ABCB1 (1236C>T, 2677G>T/A and 3435C>T) variants on the effects of anesthetic and analgesic agents in various surgical procedures. Materials & methods: Literature was obtained from established databases and reference tracking. The main outcome measures were efficacy of anesthetic and analgesic agents intraoperative or within 48 h post surgery of human population. Results: Seventeen studies were included for data extraction from 1127 screened studies. The influences of ABCB1 gene polymorphisms on analgesic effects showed conflicting results. The mutational homozygous TT genotypes of 1236C>T and 3435C>T polymorphisms demonstrated significant association with the anesthetic effects. Conclusion: The mutational homozygous TT genotype in both ABCB1 1236C>T and 3435C>T is associated with weaker anesthetic effect but there are no clearly demonstrated analgesic effects.

PMID:34590490 | DOI:10.2217/pgs-2021-0079

Categories: Literature Watch

The Janus-like Association Between Proton Pump Inhibitors and Dementia

Thu, 2021-09-30 06:00

Curr Alzheimer Res. 2021 Sep 29. doi: 10.2174/1567205018666210929144740. Online ahead of print.

ABSTRACT

Early pharmacoepidemiological studies suggested that Proton Pump Inhibitors (PPIs) might increase the risk of Alzheimer's Disease (AD) and non-AD related dementias. These findings were supported by preclinical studies, specifically stressing the proamyloidogenic and indirect anticholinergic effects of PPIs. However, further large-scale pharmacoepidemiological studies showed inconsistent results on the association between PPIs and dementia. Pharmacodynamically, these findings might be related to the LXR/RXR-mediated amyloid clearance effect and anti-inflammatory action of PPIs. Further aspects that influence PPI effects on AD are related to patient-specific pharmacokinetic and pharmacogenomic characteristics. In conclusion, a personalized (individualized) medicinal approach is necessary to model and predict the potential harmful or beneficial effects of PPIs in AD and non-AD-related dementias in the future.

PMID:34587884 | DOI:10.2174/1567205018666210929144740

Categories: Literature Watch

New psychoactive and classic substances in pooled urine samples collected at the Ultra Europe festival in Split, Croatia

Wed, 2021-09-29 06:00

Arh Hig Rada Toksikol. 2021 Sep 28;72(3):198-204. doi: 10.2478/aiht-2021-72-3509.

ABSTRACT

We believe that analysing pooled urine samples for recreational drugs used at mass events can provide useful information about trends in drug use. An opportunity arose with the Ultra Europe music festival, which is attended by more than 150,000 people from over 150 countries every year. We analysed 30 pooled urine samples collected from portable chemical toilets located at or close to the Ultra Europe music festival venue in Split, Croatia in 2016-2018 to detect the presence of classic and new psychoactive substances (NPS). Four urine samples collected in 2016 were from a toilet without added chemicals (otherwise used to kill the smell) while the remaining samples were collected from toilets with added chemicals. Samples were qualitatively analysed with gas chromatography-mass spectrometry (GC/MS) using the full-scan mode. Data were compared with the Wiley mass spectral library of designer drugs and our in-house library containing about 1000 compounds and metabolites. We identified forty-six different substances and metabolites, 26 of which were classic substances/metabolites, mostly from the stimulants group, while 20 were NPS. In the NPS group, most of them were phenethylamines and cathinones. The variety of substances was the highest on the first day of the festival regardless of the year, but 2018 showed a significant drop compared to the previous two years. The results of our study revealed a stable trend of classic drug consumption, while NPS trend changed from one year to another.

PMID:34587666 | DOI:10.2478/aiht-2021-72-3509

Categories: Literature Watch

Associations of <em>NLRP3</em> and <em>CARD8</em> gene polymorphisms with alcohol dependence and commonly related psychiatric disorders: a preliminary study

Wed, 2021-09-29 06:00

Arh Hig Rada Toksikol. 2021 Sep 28;72(3):191-197. doi: 10.2478/aiht-2021-72-3432.

ABSTRACT

We investigated two functional polymorphisms in NLRP3 inflammasome genes (NLRP3 rs35829419 and CARD8 rs2043211) and their association with alcohol dependence and related anxiety, depression, obsession-compulsion, or aggression in 88 hospitalised alcohol-dependent patients, 99 abstinent alcohol-dependent participants, and 94 controls, all male Caucasian. Alcohol dependence-related psychiatric disorders were assessed with the Zung Depression and Anxiety scale, Buss-Durkee Hostility Inventory, Alcohol Use Disorders Identification Test, Brief Social Phobia Scale, Obsessive Compulsive Drinking Scale, and Yale-Brown Obsessive-Compulsive Scale. For genotyping we used the allele-specific quantitative polymerase chain reaction-based methods. The three groups differed significantly in CARD8 rs2043211 distribution (P=0.049; chi-squared=9.557; df=4). The NLPR3 rs35829419 polymorphism was not significantly associated with alcohol dependence. In hospitalised alcohol-dependent patients the investigated polymorphisms were not associated with scores indicating alcohol consumption or comorbid symptoms. In abstinent alcohol-dependent subjects homozygotes for the polymorphic CARD8 allele presented with the highest scores on the Zung Anxiety Scale (p=0.048; df=2; F=3.140). Among controls, CARD8 genotype was associated with high scores on the Obsessive Compulsive Drinking Scale (P=0.027; df=2; F=3.744). In conclusion, our results reveal that CARD8 rs2043211 may play some role in susceptibility to alcohol dependence, expression of anxiety symptoms in abstinent alcohol-dependent subjects, and in obsessive compulsive drinking in healthy controls. However, further studies with larger cohorts are required to confirm these preliminary findings.

PMID:34587665 | DOI:10.2478/aiht-2021-72-3432

Categories: Literature Watch

Retrospective Assessment of Clonality of a Legacy Cell Line by Analytical Subcloning of the Master Cell Bank

Wed, 2021-09-29 06:00

Biotechnol Prog. 2021 Sep 29:e3215. doi: 10.1002/btpr.3215. Online ahead of print.

ABSTRACT

In recent years assurance of clonality of the production cell line has been emphasized by health authorities during review of regulatory submissions. When insufficient assurance of clonality is provided, augmented control strategies may be required for a commercial production process. In this study, we conducted a retrospective assessment of clonality of a legacy cell line through analysis of subclones from the master cell bank (MCB). Twenty-four subclones were randomly selected based on a predetermined acceptance sampling plan. All these subclones share a conserved integration junction, thus providing a high level of assurance that the cell population in the MCB was derived from a single progenitor cell. However, Southern blot analysis indicates that at least four subpopulations possibly exist in the MCB. Additional characterization of these four subpopulations demonstrated that the resulting changes in product quality attributes of some subclones are not related to the genetic heterogeneity observed in Southern blot hybridization. Furthermore, process consistency, process comparability, and analytical comparability have been demonstrated in batches produced across varying manufacturing processes, scales, facilities, cell banks and cell ages. Finally, process and product consistency together with a high level of assurance of clonal origin of the MCB helped clear the hurdle for regulatory approval without requirement of additional control strategies. This article is protected by copyright. All rights reserved.

PMID:34586757 | DOI:10.1002/btpr.3215

Categories: Literature Watch

Pharmacogenomics of celiprolol - evidence for a role of P-glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics

Wed, 2021-09-29 06:00

Clin Transl Sci. 2021 Sep 29. doi: 10.1111/cts.13159. Online ahead of print.

ABSTRACT

The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single-dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure. The candidate gene analysis showed that the ABCB1 c.3435T>C and c.2677T/G>A, and the SLCO1A2 c.516A>C variants were associated with reduced celiprolol area under the plasma concentration-time curve (AUC0-∞ ). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC0-∞ . A genotype scoring system was developed based on these variants and applied to stratify the participants to low and high celiprolol exposure genotype groups. The mean AUC0-∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC0-∞ in the high exposure group (p = 1.08 × 10-11 ). In addition, the results showed gene-gene interactions in the effects of SLCO1A2 and ABCB1 variants on celiprolol AUC0-∞ (p < 5 × 10-6 ) suggesting an interplay between organic anion transporting polypeptide 1A2 and P-glycoprotein in celiprolol absorption. Taken together, these data indicate that P-glycoprotein and organic anion transporting polypeptide 1A2 play a role in celiprolol pharmacokinetics. Furthermore, patients with ABCB1 and SLCO1A2 genotypes associated with low celiprolol exposure may have an increased risk of poor blood-pressure lowering response to celiprolol.

PMID:34585840 | DOI:10.1111/cts.13159

Categories: Literature Watch

Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of <sup>1</sup>H-magnetic resonance spectroscopy studies

Wed, 2021-09-29 06:00

Mol Psychiatry. 2021 Sep 28. doi: 10.1038/s41380-021-01297-6. Online ahead of print.

ABSTRACT

BACKGROUND: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels.

METHODS: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength.

RESULTS: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18-0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21-0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05-0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = -0.40; 95% CIs: -0.62 to -0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38-1.01; Glu: g = 0.63; 95% CIs: 0.31-0.94) while MCC Glu levels were decreased in the patient group except TRS (g = -0.17; 95% CIs: -0.33 to -0.01).

CONCLUSIONS: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.

PMID:34584230 | DOI:10.1038/s41380-021-01297-6

Categories: Literature Watch

Genetic landscape of 125 pharmacogenes in Chinese from the Chinese Millionome Database

Wed, 2021-09-29 06:00

Sci Rep. 2021 Sep 28;11(1):19222. doi: 10.1038/s41598-021-98877-x.

ABSTRACT

Inter-individual differences of drug responses could be attributed to genetic variants of pharmacogenes such as cytochrome P450 (CYP), phase 2 enzymes, and transporters. In contrast to extensive studies on the genetic polymorphisms of CYP gene, genetic mutation spectrum of other pharmacogenes was under-representative in the pharmacogenetics investigations. Here we studied the genetic variations of 125 pharmacogenes including drug transporters, non-CYP phase 1 enzymes, phase 2 enzymes, nuclear receptors and others in Chinese from the Chinese Millionome Database (CMDB), of which 38,188 variants were identified. Computational analyses of the 2554 exonic variants found 617 deleterious missense variants, 91.1% of which were rare, and of the 54 loss-of-function (splice acceptor, splice donor, start lost, and stop gained) variants, 53 (98.1%) were rare. These results suggested an enrichment of rare variants in functional ones for pharmacogenes. Certain common functional variants including NUDT15 13:48611934 G/A (rs186364861), UGT1A1 2:234676872 C/T (rs34946978), and ALDH2 12:112241766 G/A (rs671) were population-specific for CMDB Chinese because they were absent (with a zero of variant allele frequency) or very rare in other gnomAD populations. These findings might be useful for the further pharmacogenomics research and clinical application in Chinese.

PMID:34584183 | DOI:10.1038/s41598-021-98877-x

Categories: Literature Watch

Impact of pharmacogenetics on intravenous tacrolimus exposure and conversions to oral therapy

Tue, 2021-09-28 06:00

Transplant Cell Ther. 2021 Sep 25:S2666-6367(21)01253-7. doi: 10.1016/j.jtct.2021.09.011. Online ahead of print.

ABSTRACT

BACKGROUND: CYP3A5 and CYP3A4 are the predominant enzymes responsible for tacrolimus metabolism, however only a proportion of the population expresses CYP3A5 secondary to genetic variation. CYP3A5 is expressed in both the intestine and the liver and has been shown to impact both oral tacrolimus bioavailability and metabolism. It is recommended to increase the initial tacrolimus dose by 50-100% in patients who are known CYP3A5 expressers, however it is currently unknown whether this dose adjustment is appropriate for intravenous (IV) tacrolimus administration.

OBJECTIVE: The objective of this study was to evaluate the impact of CYP3A5 genotype as well as other pharmacogenes on IV tacrolimus exposure to determine whether the current genotype-guided dosing recommendations are appropriate for this formulation. Additionally, this study aimed to investigate dose conversion requirements among CYP3A5 genotypes when converting from IV to PO tacrolimus.

STUDY DESIGN: This study was a retrospective chart review of all patients who underwent allogeneic stem cell transplant at Michigan Medicine between 6/1/2014 to 3/1/2018 who received IV tacrolimus at the time of their transplant. Secondary use samples were obtained for genotyping CYP3A5, CYP3A4 and ABCB1. Patient demographic information, tacrolimus dosing and troughs, and concomitant medications at the time of tacrolimus trough were retrospectively collected from the patient medical record. The IV dose-controlled concentration (C/D) and the IV:PO exposure ratio was calculated for all tacrolimus doses and patients, respectively. The impact of CYP3A5, CYP3A4, and ABCB1 genotypes on the IV C/D were evaluated with linear mixed modeling. The impact of CYP3A5 genotype on the IV:PO ratio was evaluated while controlling for age and concomitant azole inhibitor.

RESULTS: CYP3A5 and CYP3A4 genotypes were significantly associated with the IV C/D with CYP3A5 expressers having 20% lower and CYP3A4 rapid metabolizers having 20% lower tacrolimus exposure. Neither genotype remained significant in the multivariable model although age, hematocrit, and concomitant strong azole inhibitors were associated with increased IV C/D. When controlling for patient age and sex, CYP3A5 expressers had significantly higher IV/PO ratios than CYP3A5 non-expressers (3.42 vs 2.78, p=0.04). Post-hoc analysis identified the IV/PO ratio may differ among different CYP3A5 genotypes and azole inhibitor combinations.

CONCLUSIONS: This study has demonstrated that the current genotype-guided tacrolimus dose adjustment recommendations are inappropriate for CYP3A5 expressers receiving IV tacrolimus. Although CYP3A5 genotype is likely a minor contributor to IV tacrolimus exposure, genotype, in addition to capturing concomitant CYP3A inhibitors would likely improve IV:PO dose conversion selection.

PMID:34583027 | DOI:10.1016/j.jtct.2021.09.011

Categories: Literature Watch

High-risk HPV genotypes in Zimbabwean women with cervical cancer: Comparative analyses between HIV-negative and HIV-positive women

Tue, 2021-09-28 06:00

PLoS One. 2021 Sep 28;16(9):e0257324. doi: 10.1371/journal.pone.0257324. eCollection 2021.

ABSTRACT

BACKGROUND: High-risk human papillomavirus HPV (HR-HPV) modifies cervical cancer risk in people living with HIV, yet African populations are under-represented. We aimed to compare the frequency, multiplicity and consanguinity of HR-HPVs in HIV-negative and HIV-positive Zimbabwean women.

METHODS: This was a cross-sectional study consisting of women with histologically confirmed cervical cancer attending Parirenyatwa Group of Hospitals in Harare, Zimbabwe. Information on HIV status was also collected for comparative analysis. Genomic DNA was extracted from 258 formalin fixed paraffin embedded tumour tissue samples, and analysed for 14 HR-HPV genotypes. Data was analysed using Graphpad Prism and STATA.

RESULTS: Forty-five percent of the cohort was HIV-positive, with a median age of 51 (IQR = 42-62) years. HR-HPV positivity was detected in 96% of biospecimens analysed. HPV16 (48%), was the most prevalent genotype, followed by HPV35 (26%), HPV18 (25%), HPV58 (11%) and HPV33 (10%), irrespective of HIV status. One third of the cohort harboured a single HPV infection, and HPV16 (41%), HPV18 (21%) and HPV35 (21%) were the most prevalent. HIV status did not influence the prevalence and rate of multiple HPV infections (p>0.05). We reported significant (p<0.05) consanguinity of HPV16/18 (OR = 0.3; 95% CI = 0.1-0.9), HPV16/33 (OR = 0.3; 95% CI = 0.1-1.0), HPV16/35 (OR = 3.3; 95% CI = 2.0-6.0), HPV35/51 (OR = 6.0; 95%CI = 1.8-15.0); HPV39/51 (OR = 6.4; 95% CI = 1.8-15), HPV31/52 (OR = 6.2; 95% CI = 1.8-15), HPV39/56 (OR = 11 95% CI = 8-12), HPV59/68 (OR = 8.2; 95% CI = 5.3-12.4), HPV66/68 (OR = 7; 95% CI = 2.4-13.5), independent of age and HIV status.

CONCLUSION: We found that HIV does not influence the frequency, multiplicity and consanguinity of HR-HPV in cervical cancer. For the first time, we report high prevalence of HPV35 among women with confirmed cervical cancer in Zimbabwe, providing additional evidence of HPV diversity in sub-Saharan Africa. The data obtained here probes the need for larger prospective studies to further elucidate HPV diversity and possibility of selective pressure on genotypes.

PMID:34582476 | DOI:10.1371/journal.pone.0257324

Categories: Literature Watch

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