Int J Mol Sci. 2023 Feb 3;24(3):3031. doi: 10.3390/ijms24033031.

ABSTRACT

As a scientific community we assumed that exome sequencing will elucidate the basis of most heritable diseases. However, it turned out it was not the case; therefore, attention has been increasingly focused on the non-coding sequences that encompass 98% of the genome and may play an important regulatory function. The first WGS-based datasets have already been released including underrepresented populations. Although many databases contain pooled data from several cohorts, recently the importance of local databases has been highlighted. Genomic databases are not only collecting data but may also contribute to better diagnostics and therapies. They may find applications in population studies, rare diseases, oncology, pharmacogenetics, and infectious and inflammatory diseases. Further data may be analysed with Al technologies and in the context of other omics data. To exemplify their utility, we put a highlight on the Polish genome database and its practical application.

PMID:36769353 | DOI:10.3390/ijms24033031

Int J Mol Sci. 2023 Jan 30;24(3):2602. doi: 10.3390/ijms24032602.

ABSTRACT

Environmental chemicals, which are known to impact offspring health, have become a public concern. Constitutive activated receptor (CAR) is activated by various environmental chemicals and participates in xenobiotic metabolism. Here, we described the effects of maternal exposure to the CAR-specific ligand 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP, TC) on offspring health outcomes. Maternal TC exposure exhibited a stronger inhibition of body weight in 3-week-old and 8-week-old first-generation (F1) offspring female mice compared to controls. Further, maternal TC exposure obtained a strong increase in hepatic drug-metabolizing enzyme expression in 3-week-old female mice that persisted into 8-week-old adulthood. Interestingly, we observed distorted intestinal morphological features in 8-week-old F1 female mice in the TC-exposed group. Moreover, maternal TC exposure triggered a loss of intestinal barrier integrity by reducing the expression of intestinal tight junction proteins. Accordingly, maternal exposure to TC down-regulated serum triglyceride levels as well as decreased the expression of intestinal lipid uptake and transport marker genes. Mechanistically, maternal TC exposure activated the intestinal inflammatory response and disrupted the antioxidant system in the offspring female mice, thereby impeding the intestinal absorption of nutrients and seriously threatening offspring health. Altogether, these findings highlight that the effects of maternal TC exposure on offspring toxicity could not be ignored.

PMID:36768963 | DOI:10.3390/ijms24032602

Int J Mol Sci. 2023 Jan 28;24(3):2535. doi: 10.3390/ijms24032535.

ABSTRACT

Epilepsy is one of the most frequent chronic neurologic disorders that affects nearly 1% of the population worldwide, especially in developing countries. Currently, several antiepileptic drugs (AEDs) are available for its therapy, and although the prognosis is good for most patients, 20%-30% amongst them do not reach seizure freedom. Numerous factors may explain AED-resistance such as sex, age, ethnicity, type of seizure, early epilepsy onset, suboptimal dosing, poor drug compliance, alcohol abuse, and in particular, genetic factors. Specifically, the interindividual differences in drug response can be caused by single nucleotide polymorphisms (SNPs) in genes encoding for drug efflux transporters, for the brain targets of AEDs, and for enzymes involved in drug metabolism. In this review, we used the PubMed database to retrieve studies that assessed the influence of SNPs on the pharmacokinetic (PK), pharmacodynamic (PD), and efficacy of new antiepileptic drugs. Our results showed that polymorphisms in the ABCB1, ABCC2, UGT1A4, UGT2B7, UGT2B15, CYP2C9, and CYP2C19 genes have an influence on the PK and efficacy of AEDs, suggesting that a genetic pre-evaluation of epileptic patients could help clinicians in prescribing a personalized treatment to improve the efficacy and the safety of the therapy.

PMID:36768858 | DOI:10.3390/ijms24032535

Int J Mol Sci. 2023 Jan 20;24(3):2093. doi: 10.3390/ijms24032093.

ABSTRACT

Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP), and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). A total of 57 (41%) eyes were under three or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. The mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg, respectively. Significant differences in tIOP were found between heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (p = 0.031). The MD values presented significant differences between wildtype rs3766355 (-2 ± 2.2 dB), HT (-3.87 ± 4 dB), and HM carriers (-9.37 ± 9.51 dB) (p = 0.009). Significant differences were also observed between the MD in wildtype rs3753380 (-6.1 ± 8.67 dB), HT (-9.02 ± 8.63 dB), and HM carriers (-9.51 ± 7.44 dB) (p = 0.017). Patients carrying the variant rs3766355 in HM or HT presented clinically-significantly higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, and the more alleles that were affected, the worse the MD value, meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles.

PMID:36768422 | DOI:10.3390/ijms24032093

Int J Mol Sci. 2023 Jan 19;24(3):2011. doi: 10.3390/ijms24032011.

ABSTRACT

Severe Uncontrolled Asthma (SUA) counts for more than 25% of cases of severe asthma. The main factors that impair the quality of life of these patients are high doses of oral corticosteroids, the presence of exacerbations, and reduced lung function. The objective of this study was to evaluate, in real life, the clinical improvement of patients with SUA treated with anti-interleukin 5 (IL5) therapies: mepolizumab and benralizumab, together with the search for biomarkers associated with the response. We conducted a retrospective observational cohort study that included patients with severe uncontrolled eosinophilic asthma in a tertiary hospital receiving biological therapies. Three types of response were evaluated: improvement in lung function, reduction in exacerbations, and decrease in the use of oral corticosteroids. After 12 months of treatment, significant reductions were found in the number of exacerbations, the use of oral corticosteroids, and blood eosinophil levels for both biological therapies (p < 0.001). Lung function improved, achieving a significant improvement in %FEV1 (p < 0.001), as well as asthma control, with a significant increase in asthma control test (ACT) scores in both therapies. The markers associated with the corticosteroid-saving effect were the low doses of oral corticosteroids and absence of exacerbations for mepolizumab, and higher blood eosinophilia, absence of chronic obstructive pulmonary disease (COPD), and reduction in oral corticosteroid cycles for benralizumab. The greatest improvement in lung function in both therapies was linked to lower previous FEV1 levels and absence of other respiratory diseases. The reduction in exacerbations was associated with absence of exacerbations the previous year for mepolizumab and never smokers for benralizumab. The results of this real-life study confirm the clinical benefit obtained after the introduction of an anti-IL5 biological therapy and the possible predictive biomarkers of response to treatment.

PMID:36768331 | DOI:10.3390/ijms24032011

Int J Mol Sci. 2023 Jan 18;24(3):1945. doi: 10.3390/ijms24031945.

ABSTRACT

The cryopreservation of spermatogonia stem cells (SSCs) has been widely used as an alternative treatment for infertility. However, cryopreservation itself induces cryoinjury due to oxidative and osmotic stress, leading to reduction in the survival rate and functionality of SSCs. Glial-derived neurotrophic factor family receptor alpha 1 (GFRα1) and promyelocytic leukemia zinc finger (PLZF) are expressed during the self-renewal and differentiation of SSCs, making them key tools for identifying the functionality of SSCs. To the best of our knowledge, the involvement of GFRα1 and PLZF in determining the functionality of SSCs after cryopreservation with therapeutic intervention is limited. Therefore, the purpose of this review is to determine the role of GFRα1 and PLZF as biomarkers for evaluating the functionality of SSCs in cryopreservation with therapeutic intervention. Therapeutic intervention, such as the use of antioxidants, and enhancement in cryopreservation protocols, such as cell encapsulation, cryoprotectant agents (CPA), and equilibrium of time and temperature increase the expression of GFRα1 and PLZF, resulting in maintaining the functionality of SSCs. In conclusion, GFRα1 and PLZF have the potential as biomarkers in cryopreservation with therapeutic intervention of SSCs to ensure the functionality of the stem cells.

PMID:36768269 | DOI:10.3390/ijms24031945

Cells. 2023 Feb 2;12(3):485. doi: 10.3390/cells12030485.

ABSTRACT

We wished to understand the metabolic reprogramming underlying liver fibrosis progression in mice. Administration to male C57BL/6J mice of the hepatotoxins carbon tetrachloride (CCl4), thioacetamide (TAA), or a 60% high-fat diet, choline-deficient, amino-acid-defined diet (HF-CDAA) was conducted using standard protocols. Livers collected at different times were analyzed by gas chromatography-mass spectrometry-based metabolomics. RNA was extracted from liver and assayed by qRT-PCR for mRNA expression of 11 genes potentially involved in the synthesis of ascorbic acid from hexoses, Gck, Adpgk, Hk1, Hk2, Ugp2, Ugdh, Ugt1a1, Akr1a4, Akr1b3, Rgn and Gulo. All hepatotoxins resulted in similar metabolic changes during active fibrogenesis, despite different etiology and resultant scarring pattern. Diminished hepatic glucose, galactose, fructose, pentose phosphate pathway intermediates, glucuronic acid and long-chain fatty acids were compensated by elevated ascorbate and the product of collagen prolyl 4-hydroxylase, succinate and its downstream metabolites fumarate and malate. Recovery from the HF-CDAA diet challenge (F2 stage fibrosis) after switching to normal chow was accompanied by increased glucose, galactose, fructose, ribulose 5-phosphate, glucuronic acid, the ascorbate metabolite threonate and diminished ascorbate. During the administration of CCl4, TAA and HF-CDAA, aldose reductase Akr1b3 transcription was induced six- to eightfold, indicating increased conversion of glucuronic acid to gulonic acid, a precursor of ascorbate synthesis. Triggering hepatic fibrosis by three independent mechanisms led to the hijacking of glucose and galactose metabolism towards ascorbate synthesis, to satisfy the increased demand for ascorbate as a cofactor for prolyl 4-hydroxylase for mature collagen production. This metabolic reprogramming and causal gene expression changes were reversible. The increased flux in this pathway was mediated predominantly by increased transcription of aldose reductase Akr1b3.

PMID:36766828 | DOI:10.3390/cells12030485

Pharmacotherapy. 2023 Feb 10. doi: 10.1002/phar.2779. Online ahead of print.

ABSTRACT

Methotrexate (MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance. We conducted a retrospective cohort study of pediatric patients with ALL who received 4000-5000 mg/m2 of MTX to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance. We performed germline genotyping to determine genetic ancestry and allele status for 49 single nucleotide polymorphisms (SNPs) identified from the literature as related to MTX disposition. Bayesian hierarchical ordinal regression models for creatinine increase and for prolonged MTX clearance were developed. Hispanic ethnicity, body mass index (BMI) < 3%, BMI between 85-95%, and Native American genetic ancestry were found to be associated with an increased risk for creatinine elevation. Older age, Black race, and use of the intensive monitoring protocol were associated with a decreased risk for creatinine elevation. Older age, B- compared to T-ALL, and the minor alleles of rs2838958/SLC19A1 and rs7317112/ABCC4 were associated with an increased risk for delayed clearance. Black race, MTX dose reduction, and the minor allele of rs2306283/SLCO1B1 were found to be associated with a decreased risk for delayed clearance. These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.

PMID:36764694 | DOI:10.1002/phar.2779

Adv Sci (Weinh). 2023 Feb 10:e2204113. doi: 10.1002/advs.202204113. Online ahead of print.

ABSTRACT

The single-cell RNA sequencing (scRNA-seq) quantifies the gene expression of individual cells, while the bulk RNA sequencing (bulk RNA-seq) characterizes the mixed transcriptome of cells. The inference of drug sensitivities for individual cells can provide new insights to understand the mechanism of anti-cancer response heterogeneity and drug resistance at the cellular resolution. However, pharmacogenomic information related to their corresponding scRNA-Seq is often limited. Therefore, a transfer learning model is proposed to infer the drug sensitivities at single-cell level. This framework learns bulk transcriptome profiles and pharmacogenomics information from population cell lines in a large public dataset and transfers the knowledge to infer drug efficacy of individual cells. The results suggest that it is suitable to learn knowledge from pre-clinical cell lines to infer pre-existing cell subpopulations with different drug sensitivities prior to drug exposure. In addition, the model offers a new perspective on drug combinations. It is observed that drug-resistant subpopulation can be sensitive to other drugs (e.g., a subset of JHU006 is Vorinostat-resistant while Gefitinib-sensitive); such finding corroborates the previously reported drug combination (Gefitinib + Vorinostat) strategy in several cancer types. The identified drug sensitivity biomarkers reveal insights into the tumor heterogeneity and treatment at cellular resolution.

PMID:36762572 | DOI:10.1002/advs.202204113

Clin Transl Sci. 2023 Feb 9. doi: 10.1111/cts.13479. Online ahead of print.

ABSTRACT

Although major advancements have been made in the therapeutics for people with cystic fibrosis (PwCF), many still require the use of multiple medications to manage acute exacerbations of disease and maintain health. Iterative trial and error processes of pharmacotherapeutic management can be optimized by assessing and incorporating pharmacogenetics. For 82 PwCF, we reviewed 2 years of medication use and response history and interrogated metabolizer status for common pharmacogenes, revealing 3336 medication exposure events (MEEs) to 286 unique medications. As expected, the more frequent MEEs were those commonly used to treat cystic fibrosis (CF), such as antibiotics and respiratory medications. Antibiotics also comprised 56.7% of the undesirable drug responses. The impact of gene variants on drug responses was assessed using Pharmacogenomics Knowledgebase (PharmGKB) and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Thirty-three (11.5%) medications have strong evidence of genetic influence on response as evidenced by gene-based dosing guidelines. 110 (38.5%) unique medications had at least one association with a very important pharmacogene, whereas 143 (50%) were associated with at least one clinical or variant annotation. Over 97% of participants had at least one actionable genotype. Eleven (13.4%) patients with an actionable genotype, taking the impacted medication, had an undesirable drug response described in the CPIC guidelines that could potentially have been mitigated with a priori knowledge of the genotype. PwCF take many medications for disease management, with frequent dose changes to elicit a desired clinical effect. As CF care evolves, implementing pharmacogenetics testing can improve efficiency and safety of prescribing practices using precision selection and dosing at medication initiation.

PMID:36760155 | DOI:10.1111/cts.13479

Psychopharmacology (Berl). 2023 Feb 9. doi: 10.1007/s00213-023-06331-9. Online ahead of print.

ABSTRACT

RATIONALE: Weight gain is a frequent side effect of treatment with SGAs (second-generation antipsychotics) and a leading cause for nonadherence. Several candidate genes have been identified that could influence the amount of AIWG (antipsychotic-induced weight gain). The polymorphism rs17782313 near the MC4R (human melanocortin 4 receptor gene) was strongly associated with obesity in a large scale GWAS (genome wide association study), yet previous studies investigating its impact on AIWG did not lead to a definite conclusion regarding its effect. In particular, they were all relatively short and had a naturalistic design.

OBJECTIVE: We therefore examined the influence of the rs17782313 polymorphism on SGA-related weight gain.

METHODS: Participants of a multicenter randomized, controlled, double-blind study comparing two treatment strategies in individuals with schizophrenia or schizoaffective disorder were genotyped using a rapid-cycle polymerase chain reaction. Up to 252 individuals completed the first 2 weeks (phase I), 212 the entire 8 weeks (hence 'completers'). Patients received either amisulpride or olanzapine or both consecutively. Thirty-seven had their first episode. Weight gain occurring in different genotypes was statistically compared and confounding factors were adjusted by stepwise multiple linear regression. A correction for multiple testing was included.

RESULTS: Within 212 'completers', carriers of the C allele had a higher absolute weight gain than those homozygous for the T allele (2.6 kg vs. 1.2 kg), though this observation was not significant (P = 0.063). In the amisulpride subpopulation, this association appeared stronger and reached significance (2.5 kg vs. 0.7 kg, P = 0.043), though failed to remain significant after correction for multiple testing. A stepwise multiple linear regression showed a significant association in both the whole study population (P < 0.001) and the amisulpride subpopulation (P < 0.001).

CONCLUSION: Our results indicate that the rs17782313 polymorphism might influence antipsychotic-induced weight gain and therefore confirm some of the earlier conclusions.

PMID:36757449 | DOI:10.1007/s00213-023-06331-9

J Oncol. 2023 Jan 24;2023:7925378. doi: 10.1155/2023/7925378. eCollection 2023.

ABSTRACT

P-glycoprotein, product of the ABCB1 (ATP binding cassette subfamily B member 1) gene, has been reported to play an important role in multiple drug resistance during cancer therapy. However, its influence on non-small cell lung cancer (NSCLC) risk has not been clearly defined. The aim of the present study was to examine the association between clinicopathological factors and SNPs T-129C, C1236T, G2677T/A, and C3435T, as well as its haplotype, and to investigate the role of ABCB1 polymorphisms in NSCLC development. The study included 80 patients who suffered from NSCLC and underwent surgery to remove the tumour and 96 healthy controls. The tissues were genotyped by PCR-RFLP and sequencing methods, and the haplotype frequencies in both groups were estimated. The SNP C3435T was identified as a NSCLC risk factor. The presence of mutated allelic variant T (p=0.0103) or homozygote TT (p=0.0099) was observed significantly more often in cancer patients than in healthy controls. The two groups also demonstrated a highly significant difference in common haplotype frequency (p=0.01). The T-129-T1236-T2677-T3435 haplotype was found to be most closely associated with NSCLC risk. Although the investigated polymorphisms were not related to demographic features, clinicopathological lung tumour characteristics, or blood morphology indices, marginally significant correlations were found with some variables: C1236T with age of disease onset (p=0.0410); C3435T with smoking status (p=0.0561). As the findings indicate, lung cancer and control groups demonstrate significantly different patterns of -129/1236/2677/3435 haplotype distribution; T-T-T-T haplotype contributes to NSCLC susceptibility, and this effect is probably mainly dependent on C3435T. So far, similar studies were published in other populations.

PMID:36755808 | PMC:PMC9902128 | DOI:10.1155/2023/7925378

Front Genet. 2023 Jan 23;14:1099541. doi: 10.3389/fgene.2023.1099541. eCollection 2023.

ABSTRACT

Pharmacogenomics has been at the forefront of precision medicine during the last few decades. Precision medicine carries the potential of improving health outcomes at both the individual as well as population levels. To harness the benefits of its initiatives, careful dissection of existing health disparities as they relate to precision medicine is of paramount importance. Attempting to address the existing disparities at the early stages of design and implementation of these efforts is the only guarantee of a successful just outcome. In this review, we glance at a few determinants of existing health disparities as they intersect with pharmacogenomics research and implementation. In our opinion, highlighting these disparities is imperative for the purpose of researching meaningful solutions. Failing to identify, and hence address, these disparities in the context of the current and future precision medicine initiatives would leave an already strained health system, even more inundated with inequality.

PMID:36755573 | PMC:PMC9900000 | DOI:10.3389/fgene.2023.1099541

Expert Opin Drug Metab Toxicol. 2023 Feb 8. doi: 10.1080/17425255.2023.2178895. Online ahead of print.

ABSTRACT

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 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.

PMID:36755439 | DOI:10.1080/17425255.2023.2178895

Gut. 2023 Feb 8:gutjnl-2022-329297. doi: 10.1136/gutjnl-2022-329297. Online ahead of print.

NO ABSTRACT

PMID:36754608 | DOI:10.1136/gutjnl-2022-329297

Biol Psychiatry Cogn Neurosci Neuroimaging. 2023 Feb;8(2):140-150. doi: 10.1016/j.bpsc.2022.09.017. Epub 2022 Oct 23.

ABSTRACT

BACKGROUND: The glutamatergic system is thought to play an important role in the pathophysiology of bipolar disorder (BD). While there has been an increase in proton magnetic resonance spectroscopy studies examining this neurotransmission system, the results are inconsistent. Possible reasons for the inconsistency, including clinical features such as mood state and childhood versus adulthood age, were not addressed in previous meta-analyses.

METHODS: This systematic review and meta-analysis of proton magnetic resonance spectroscopy studies of BD included 40 studies, with 1135 patients with BD and 964 healthy control (HC) subjects.

RESULTS: Glutamate plus glutamine and glutamine levels in the anterior cingulate cortex of patients with BD were significantly elevated compared with those of HC subjects (standardized mean difference = 0.42, 0.48, respectively). Subgroup analyses showed that adult BD patients had significantly higher levels of glutamate plus glutamine than adult HC subjects, but this was not the case in pediatric patients. For mood states, anterior cingulate cortex glutamate plus glutamine levels were higher in patients with bipolar depression than those in HC subjects.

CONCLUSIONS: Our results imply that glutamatergic dysfunction in the anterior cingulate cortex may be implicated in the pathophysiology of BD, which is most evident in adult BD patients and patients with bipolar depression.

PMID:36754485 | DOI:10.1016/j.bpsc.2022.09.017

J Affect Disord. 2023 Feb 6:S0165-0327(23)00170-2. doi: 10.1016/j.jad.2023.02.017. Online ahead of print.

ABSTRACT

BACKGROUND: The objectives of the study were: (1) to examine the overall distribution of baseline platelet serotonin (5-hydroxytryptamine, 5-HT) values in patients seeking treatment for depression and to define subgroups based on the apparent presence or absence of drug exposure; (2) to assess the bioeffect of 5-HT reuptake inhibitors (SRIs) at the platelet 5-HT transporter; and (3) to examine the relationships of demographic variables including population (ancestry), sex, age, and season of sampling to platelet 5-HT concentration.

METHODS: Platelet 5-HT levels were measured in a cross-sectional study of 1433 Veterans Administration (VA) patients participating in a pragmatic multi-site pharmacogenomic treatment study of depression. Patients were characterized medically and demographically using VA health records and self-report.

RESULTS: A clearly bimodal distribution was observed for platelet 5-HT levels with the lower mode associated with patients exposed to SRIs at baseline. Median transporter blockade bioeffects were similar across the various selective 5-HT reuptake inhibitors (SSRIs) and 5-HT/norepinephrine reuptake inhibitors (SNRIs). In a subset of patients apparently not exposed to an SRI, significant effects of population and sex were observed with group mean platelet 5-HT levels being 25 % greater (p < 0.001) in African-American (AA) individuals compared to European-Americans (EAs). The female group mean was 14 % (p < 0.001) greater than male group mean. An effect of age was observed (r = -0.11, p < 0.001) and no effect of season or month of sampling was seen.

CONCLUSIONS: Further research is warranted to understand the bases and clinical implications of the population and sex differences. The apparent similarity in bioeffect at the 5-HT transporter across SSRIs and when comparing SSRIs and SNRIs informs discussions about initiating, dose adjustment and switching of 5-HT reuptake inhibitors.

PMID:36754092 | DOI:10.1016/j.jad.2023.02.017

Trends Genet. 2023 Feb 4:S0168-9525(23)00017-3. doi: 10.1016/j.tig.2023.01.002. Online ahead of print.

ABSTRACT

Genome-wide association studies (GWAS) have now correlated hundreds of genetic variants with complex genetic diseases and drug efficacy. Functional characterization of these factors remains challenging, particularly because of the lack of human model systems. Molecular and nanotechnological advances, in particular the ability to generate patient-specific PSC lines, differentiate them into diverse cell types, and seed and combine them on microfluidic chips, have led to the establishment of organ-on-a-chip (OoC) platforms that recapitulate organ biology. OoC technology thus provides unique personalized platforms for studying the effects of host genetics and environmental factors on organ physiology. In this review we describe the technology and provide examples of how OoCs may be used for disease modeling and pharmacogenetic research.

PMID:36746737 | DOI:10.1016/j.tig.2023.01.002

Environ Sci Pollut Res Int. 2023 Feb 6. doi: 10.1007/s11356-023-25675-5. Online ahead of print.

ABSTRACT

The unfavorable effects of environmental pollutants are becoming increasingly evident. In recent years, Caenorhabditis elegans (C. elegans) has been used as a powerful terrestrial model organism for environmental toxicity studies owing to its various advantages, including ease of culture, short lifespan, small size, transparent body, and well-characterized genome. In vivo bioassays and field studies can analyze and evaluate various toxic effects of the toxicants on the model organism, while emerging technologies allow profound insights into molecular disturbances underlying the observed phenotypes. In this review, we discuss the applications of C. elegans as a model organism in environmental toxicity studies and delineate apical assays such as lifespan, growth rate, reproduction, and locomotion, which are widely used in toxicity evaluation. In addition to phenotype assays, a comprehensive understanding of the toxic mode of action and mechanism can be achieved through a highly sensitive multi-omics approach, including the expression levels of genes and endogenous metabolites. Recent studies on environmental toxicity using these approaches have been summarized. This review highlights the practicality and advantages of C. elegans in evaluating the toxicity of environmental pollutants and presents the findings of recent toxicity studies performed using this model organism. Finally, we propose crucial technical considerations to escalate the appropriate use of C. elegans in examining the toxic effects of environmental pollutants.

PMID:36745349 | DOI:10.1007/s11356-023-25675-5

Clin Pharmacol Ther. 2023 Feb 6. doi: 10.1002/cpt.2864. Online ahead of print.

ABSTRACT

Genetics are presumed to contribute 30% to 40% to opioid use disorder (OUD), allowing for the possibility that genetic markers could be used to identify personal risk for developing OUD. We aimed to test the potential association between 180 candidate single nucleotide polymorphisms (SNPs), 120 of which were related to the dopamine reward pathway and 60 related to pharmacokinetics. Participants were randomly recruited in 2020-2021 in a cross-sectional genetic association study. Self-reported health history including Diagnostic and Statistical Manual of Mental Disorders (DSM-5) OUD criteria and buccal swabs were collected. A total of 1,301 participants were included in the analyses for this study. Of included participants, 250 met the DSM-5 criteria for ever having OUD. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and DSM-5 criteria consistent with OUD. Six SNPs found in 4 genes were associated with OUD: increased odds with CYP3A5 (rs15524 and rs776746) and DRD3 (rs324029 and rs2654754), and decreased odds with CYP3A4 (rs2740574) and CYP1A2 (rs2069514). Homozygotic CYP3A5 (rs15524 and rs776746) had the highest adjusted odds ratio (OR) of 2.812 (95% CI [1.737, 4.798]) and 2.495 (95% CI [1.670, 3.835]), respectively. Variants within the dopamine reward and opioid metabolism pathways have significant positive (DRD3, CYP3A5) and negative (CYP3A4, CYP1A2) associations with OUD. Identification of these variants provides promising possibilities for genetic prognostic and therapeutic targets for future investigation.

PMID:36744646 | DOI:10.1002/cpt.2864