Drug Discov Today. 2023 Sep 25:103790. doi: 10.1016/j.drudis.2023.103790. Online ahead of print.

ABSTRACT

Because drug response is multifactorial, graph models are uniquely powerful for comprehending its genetic architecture. We deconstruct drug response into many different and interdependent sub-traits, with each sub-trait controlled by multiple genes that act and interact in a complicated manner. The outcome of drug response is the consequence of multileveled intertwined interactions between pleiotropic effects and epistatic effects. Here, we propose a general statistical physics framework to chart the 3D geometric network that codes how epistasis pleiotropically influences a complete set of sub-traits to shape body-drug interactions. This model can dissect the topological architecture of epistatically induced pleiotropic networks (EiPN) and pleiotropically influenced epistatic networks (PiEN). We analyze and interpret the practical implications of the pleiotropic-epistatic entanglement model for pharmacogenomic studies.

PMID:37758020 | DOI:10.1016/j.drudis.2023.103790

J Pain Symptom Manage. 2023 Sep 25:S0885-3924(23)00687-5. doi: 10.1016/j.jpainsymman.2023.09.017. Online ahead of print.

ABSTRACT

CONTEXT: μ-opioid receptor gene (OPRM1) A118G polymorphism (rs1799971) causes loss of N-glycosylation sites at the extracellular domain of μ-opioid receptors. G-allele carriers show a limited response to morphine; however, studies investigating the impact of A118G polymorphism on the efficacy of opioids other than morphine are limited.

OBJECTIVE: To compare the effects of A118G polymorphism on the efficacy of various opioids.

METHODS: This prospective cohort study enrolled 222 in-patients administered one of the following opioid therapies for cancer pain as part of an opioid introduction or rotation strategy: tapentadol extended-release tablets, methadone tablets, hydromorphone controlled-release tablets, oxycodone controlled-release tablets, or transdermal fentanyl patches. The impact of A118G polymorphism on the difference in the Brief Pain Inventory-Short Form score on days 3, 7, and 14 from baseline was compared among the groups.

RESULTS: Overall, 81, 74, and 67 patients had the AA, AG, and GG genotypes, respectively, with an OPRM1 A118G G-allele variant frequency of 0.47. The reduction in the Brief Pain Inventory-Short Form score after opioid therapy initiation did not differ significantly among the patients with the three A118G genotypes treated with tapentadol (p = 0.84) or methadone (p = 0.97), whereas it was significantly smaller in G-allele carriers than that in AA homozygous patients treated with hydromorphone (p < 0.001), oxycodone (p = 0.031), or fentanyl (p < 0.001).

CONCLUSION: Tapentadol and methadone may be more suitable than hydromorphone, oxycodone, and fentanyl for G-allele carriers due to their dual mechanism of action and low susceptibility to OPRM1 A118G polymorphism.

PMID:37757956 | DOI:10.1016/j.jpainsymman.2023.09.017

Am J Hum Genet. 2023 Sep 20:S0002-9297(23)00314-2. doi: 10.1016/j.ajhg.2023.09.001. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) is an integral part of precision medicine and contributes to the maximization of drug efficacy and reduction of adverse drug event risk. Accurate information on PGx allele frequencies improves the implementation of PGx. Nonetheless, curating such information from published allele data is time and resource intensive. The limited number of allelic variants in most studies leads to an underestimation of certain alleles. We applied the Pharmacogenomics Clinical Annotation Tool (PharmCAT) on an integrated 200K UK Biobank genetic dataset (N = 200,044). Based on PharmCAT results, we estimated PGx frequencies (alleles, diplotypes, phenotypes, and activity scores) for 17 pharmacogenes in five biogeographic groups: European, Central/South Asian, East Asian, Afro-Caribbean, and Sub-Saharan African. PGx frequencies were distinct for each biogeographic group. Even biogeographic groups with similar proportions of phenotypes were driven by different sets of dominant PGx alleles. PharmCAT also identified "no-function" alleles that were rare or seldom tested in certain groups by previous studies, e.g., SLCO1B1∗31 in the Afro-Caribbean (3.0%) and Sub-Saharan African (3.9%) groups. Estimated PGx frequencies are disseminated via the PharmGKB (The Pharmacogenomics Knowledgebase: www.pharmgkb.org). We demonstrate that genetic biobanks such as the UK Biobank are a robust resource for estimating PGx frequencies. Improving our understanding of PGx allele and phenotype frequencies provides guidance for future PGx studies and clinical genetic test panel design, and better serves individuals from wider biogeographic backgrounds.

PMID:37757824 | DOI:10.1016/j.ajhg.2023.09.001

J Water Health. 2023 Sep;21(9):1342-1356. doi: 10.2166/wh.2023.186.

ABSTRACT

The present study aims to identify the Acanthamoeba genotypes and their pathogenic potential in three recreational lakes in Malaysia. Thirty water samples were collected by purposive sampling between June and July 2022. Physical parameters of water quality were measured in situ while chemical and microbiological analyses were performed in the laboratory. The samples were vacuum filtered through nitrate filter, cultured onto non-nutrient agar and observed microscopically for amoebic growth. DNAs from positive samples were extracted and made to react with polymerase chain reaction using specific primers. Physiological tolerance tests were performed for all Acanthamoeba-positive samples. The presence of Acanthamoeba was found in 26 of 30 water samples by PCR. The highest rate in lake waters contaminated with amoeba was in Biru Lake (100%), followed by Titiwangsa Lake (80%) and Shah Alam Lake (80%). ORP, water temperature, pH and DO were found to be significantly correlated with the presence of Acanthamoeba. The most common genotype was T4. Temperature- and osmo-tolerance tests showed that 8 (30.8%) of the genotypes T4, T9 and T11 were highly pathogenic. The presence of genotype T4 in habitats related to human activities supports the relevance of this amoeba as a potential public health concern.

PMID:37756200 | DOI:10.2166/wh.2023.186

Neurol Int. 2023 Sep 5;15(3):1117-1128. doi: 10.3390/neurolint15030069.

ABSTRACT

Migraine is a common primary headache disorder with both environmental and genetic inputs. Cumulative evidence indicates an association between vitamin D and headache. Unravelling the precise role of vitamin D and its receptor in the pathophysiology of migraine can eventually contribute to more efficient prevention and management of this headache disorder. The aim of the study was to investigate the relation of the three most studied VDR variants, i.e., FokI (rs2228570), TaqI (rs731236) and BsmI (rs1544410), with migraine susceptibility and distinct clinical phenotypes in a Southeastern European case-control population residing in Greece. DNA was extracted from 191 unrelated patients diagnosed with migraine and 265 headache-free controls and genotyped using real-time PCR (LightSNiP assays) followed by melting curve analysis. Genotype frequency distribution analysis of the TaqI and BsmI variants showed a statistically significant difference between migraine cases and controls. In addition, subgroup analyses revealed a significant association between all three studied VDR variants, particularly with a migraine without aura subtype. Therefore, the current study provides supporting evidence for a possible association of VDR variants with migraines, particularly migraine without aura susceptibility in Southeastern Europeans residing in Greece, further reinforcing the emerging role of vitamin D and its receptor in migraines.

PMID:37755360 | DOI:10.3390/neurolint15030069

Future Sci OA. 2023 Aug 22;9(10):FSO895. doi: 10.2144/fsoa-2023-0113. eCollection 2023 Dec.

ABSTRACT

AIM: To investigate the association between beta1-adrenergic receptor (ADRB1) polymorphisms and response to bisoprolol treatment in beta-blocker naive patients with acute coronary syndrome (ACS).

PATIENTS & METHODS: Seventy-seven patients received bisoprolol for four weeks. Blood pressure and heart rate were measured at baseline and during treatment. TaqMan allelic discrimination method was utilized for ADRB1 Ser49Gly and Arg389Gly genotyping.

RESULTS: Arg389Arg carriers showed greater reductions in systolic and diastolic blood pressure (-8.5% ± 7.8% vs -0.76% ± 8.7%, p = 0.000218), and (-9.5% ± 9.7% vs -0.80% ± 11.5%, p = 0.000149), respectively, compared with Gly389 carriers. No statistical difference was found for study's outcomes based on codon 49.

CONCLUSION: Arg389Gly polymorphism is a promising bisoprolol response predictor in ACS patients.

PMID:37753361 | PMC:PMC10518825 | DOI:10.2144/fsoa-2023-0113

Malar J. 2023 Sep 26;22(1):283. doi: 10.1186/s12936-023-04716-x.

ABSTRACT

BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is an X-linked disorder affecting over 400 million people worldwide. Individuals with molecular variants associated with reduced enzymatic activity are susceptible to oxidative stress in red blood cells, thereby increasing the risk of pathophysiological conditions and toxicity to anti-malarial treatments. Globally, the prevalence of G6PDd varies among populations. Accordingly, this study aims to characterize G6PDd distribution within the Ecuadorian population and to describe the spatial distribution of reported malaria cases.

METHODS: Molecular variants associated with G6PDd were genotyped in 581 individuals from Afro-Ecuadorian, Indigenous, Mestizo, and Montubio ethnic groups. Additionally, spatial analysis was conducted to identify significant malaria clusters with high incidence rates across Ecuador, using data collected from 2010 to 2021.

RESULTS: The A- c.202G > A and A- c.968T > C variants underpin the genetic basis of G6PDd in the studied population. The overall prevalence of G6PDd was 4.6% in the entire population. However, this frequency increased to 19.2% among Afro-Ecuadorian people. Spatial analysis revealed 12 malaria clusters, primarily located in the north of the country and its Amazon region, with relative risks of infection of 2.02 to 87.88.

CONCLUSIONS: The findings of this study hold significant implications for public health interventions, treatment strategies, and targeted efforts to mitigate the burden of malaria in Ecuador. The high prevalence of G6PDd among Afro-Ecuadorian groups in the northern endemic areas necessitates the development of comprehensive malaria eradication strategies tailored to this geographical region.

PMID:37752491 | DOI:10.1186/s12936-023-04716-x

Drug Metab Dispos. 2023 Sep 26:DMD-AR-2023-001400. doi: 10.1124/dmd.123.001400. Online ahead of print.

ABSTRACT

Pharmaceutical companies subject all new molecular entities to a series of in vitro metabolic characterizations that guide the selection and/or design of compounds predicted to have favourable pharmacokinetic properties in humans. Current drug metabolism research is based on liver tissue predominantly obtained from people of European origin with limited access to tissue from people of African origin. Given the inter-individual and inter-population genomic variability in genes encoding drug metabolizing enzymes, efficacy and safety of some drugs are poorly predicted for African populations. To address this gap, we have established the first comprehensive liver tissue biorepository inclusive of people of African origin. The African Liver Tissue Biorepository (ALTBio) Consortium currently includes three institutions in South Africa and one in Zimbabwe with plans to expand to other African countries. The program has collected 67 liver samples as of July 2023. DNA from the donors was genotyped for 120 variants in 46 pharmacogenes and revealed variants that are uniquely found in African populations, including the low activity African specific CYP2C9*5 and *8 variants relevant to the metabolism of diclofenac. Larger liver tissue samples were used to isolate primary human hepatocytes. Viability of the hepatocytes and microsomal fractions was demonstrated by the activity of selected CYP450s. This resource will be used to ensure the safety and efficacy of existing and new drugs in African populations. This will be done by characterizing compounds for properties such as drug clearance, metabolite and enzyme identification, drug-drug and drug-gene interactions. Significance Statement Standard optimization of drug metabolism of new molecular entities in the pharmaceutical industry uses subcellular fractions such as microsomes and isolated primary hepatocytes being being done mainly with tissue from donors of European origin. Pharmacogenetics research has shown that variants in genes coding for drug metabolizing enzymes have interindividual and interpopulation differences. We established an African liver tissue biorepository, that will be useful in ensuring drug discovery and development research takes into account drug responses in people of African origin.

PMID:37751997 | DOI:10.1124/dmd.123.001400

J Med Virol. 2023 Sep;95(9):e29113. doi: 10.1002/jmv.29113.

ABSTRACT

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), astonished the world and led to millions of deaths. Due to viral new mutations and immune evasion, SARS-CoV-2 ranked first in transmission and influence. The binding affinity of human leukocyte antigen (HLA) polymorphisms to SARS-CoV-2 might be related to immune escape, but the mechanisms remained unclear. In this study, we obtained the binding affinity of SARS-CoV-2 strains with different HLA proteins and identified 31 risk alleles. Subsequent structural predictions identified 10 active binding sites in these HLA proteins that may promote immune evasion. Particularly, we also found that the weak binding ability with HLA class I polymorphisms could contribute to the immune evasion of Omicron. These findings suggest important implications for preventing the immune evasion of SARS-CoV-2 and providing new insights for the vaccine design.

PMID:37750416 | DOI:10.1002/jmv.29113

Pharmacol Res. 2023 Sep 23:106938. doi: 10.1016/j.phrs.2023.106938. Online ahead of print.

NO ABSTRACT

PMID:37748560 | DOI:10.1016/j.phrs.2023.106938

Forensic Sci Int. 2023 Sep 21;352:111835. doi: 10.1016/j.forsciint.2023.111835. Online ahead of print.

ABSTRACT

BACKGROUND: Driving under the influence of drugs (DUID) is a risk factor for traffic accidents. The testing of oral fluid by roadside immunochromatography and laboratory-confirmed chromatography coupled to mass spectrometry (LC-MS/MS) analysis to detect drug abuse has increased in France. The aim of this study was to describe the trends observed in drivers testing positive for illicit drugs in oral fluid and to investigate the concordance between the two analytical methods used.

METHODS: We received for confirmation 3051 oral fluid samples from drivers who had tested positive at the roadside with a Drugwipe-5S® device between 2018 and 2021 around Grenoble, France. Samples were collected with FLOQSwab® and analyzed by LC-MS/MS (THC, amphetamine, methamphetamine, MDMA and MDA, MDEA, cocaine and benzoylecgonine, morphine and 6-monoacetylmorphine) at Grenoble Alpes University Hospital, France. Binomial logistic regression was performed to evaluate consumption trends.

RESULTS: Most of the drivers were men (93.2%), with a median age of 26 years (range: 14-66 years). Cannabis (94.6%) cocaine (17.5%) and MDMA (2.5%) were the drugs most frequently detected. Poly-drug use was observed in 17.3% of drivers and involved cannabis and cocaine in 85.3% of these drivers. Poly-drug use was more frequent among drivers over the age of 32 years (OR, 3.48; 95% CI, 2.59-4.68; p ≤ .001), as was cocaine use (OR, 5.15; 95% CI, 3.75-7.08; p ≤ .001). The frequency of positive tests for amphetamines was higher in women than in men (OR, 2.53; 95% CI, 1.50-4.27; p ≤ .001). The positive predictive value of Drugwipe-5S was 98.2% for cannabis, 22.6% for amphetamines, 75.4% for cocaine and 17.3% for opiates. At least one discrepancy between Drugwipe-5S® and LC-MS/MS results was observed for 22.3% of the samples tested.

CONCLUSION: We report recent trends for drivers testing positive for illicit drugs in oral fluid in France. Cannabis was the most prevalent drug of abuse identified, suggesting that a general prevention program might be useful. Our results also highlight the need for LC-MS/MS confirmation when screening oral fluid for drugs of abuse.

PMID:37748427 | DOI:10.1016/j.forsciint.2023.111835

Nucleosides Nucleotides Nucleic Acids. 2023 Sep 25:1-21. doi: 10.1080/15257770.2023.2262519. Online ahead of print.

ABSTRACT

Genetic variations in the human cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily D member 6 (CYP2D6) genes may affect drug metabolism and lead to alterations in phenotypes. Genetic variations are associated with toxicity, adverse drug reactions, inefficient treatment. Various in silico tools were combined to investigate the deleterious effects of missense non-synonymous single nucleotide polymorphisms (nsSNPs) of the human CYP2C9 and CYP2D6. The structural and functional effects of the high-risk non-synonymous SNPs in the human CYP2C9 and CYP2D6 were predicted by numerous computational mutation analysis methods. Out of 24 pathogenic missense SNPs in the CYP2C9, 22 nsSNPs had a decreasing effect on protein stability and 13 SNPs were showed to be located at conserved positions. Out of 27 high-risk deleterious non-synonymous SNPs in the human CYP2D6, 21 SNPs decreased protein stability and 16 nsSNPs were predicted to be positioned at conserved regions. Our present study suggests that the identified functional SNPs may affect drug metabolism associated with CYP2C9 and CYP2D6 enzymes.

PMID:37747773 | DOI:10.1080/15257770.2023.2262519

Cureus. 2023 Aug 23;15(8):e43977. doi: 10.7759/cureus.43977. eCollection 2023 Aug.

ABSTRACT

The field of cardiovascular medicine is undergoing a transformative shift towards personalized medicinal therapy, particularly in the context of post stent implantation. This narrative review explores the significance, challenges, and future directions of individualized treatment strategies for patients with coronary stents. The review highlights the pivotal role of personalized approaches in optimizing treatment efficacy and minimizing adverse events. Real-world clinical studies and trials underscore the importance of tailoring antiplatelet therapy based on platelet function testing, genetic testing, and risk scoring. These studies reveal that personalized medicinal treatment improves clinical outcomes by balancing preventing thrombotic events and mitigating bleeding risks. Challenges, including cost, test availability, patient adherence, and ethical considerations, are discussed in depth, shedding light on the complexities of implementing personalized approaches. Technological advancements, including omics data integration, artificial intelligence, and big data analytics, shape the future of personalized medicinal therapy. These tools enable precise pharmacogenomic selection of medications and the development of integrated risk-scoring systems. Patient engagement and education are also central, with empowered patients and remote monitoring contributing to collaborative decision-making. In conclusion, the narrative review underscores that personalized medicinal therapy post stent implantation holds immense promise for revolutionizing cardiovascular care. By embracing a comprehensive approach that considers genetics, clinical factors, and patient preferences, healthcare providers can optimize treatment outcomes and improve patient quality of life. The evolving landscape of personalized medicine offers a glimpse into a future where tailored treatment strategies become the cornerstone of precision cardiovascular care.

PMID:37746355 | PMC:PMC10516147 | DOI:10.7759/cureus.43977

Front Oncol. 2023 Sep 7;13:1217847. doi: 10.3389/fonc.2023.1217847. eCollection 2023.

ABSTRACT

Phenobarbital (PB) is an archetypal substance used as a mouse hepatocellular carcinoma (HCC) promotor in established experimental protocols. Our previous results showed CAR is the essential factor for PB induced HCC promotion. Subsequent studies suggested Gadd45β, which is induced by PB through CAR activation, is collaborating with CAR to repress TNF-α induced cell death. Here, we used Gadd45β null mice (Gadd45β KO) treated with N-diethylnitrosamine (DEN) at 5 weeks of age and kept the mice with PB supplemented drinking water from 7 to 57 weeks old. Compared with wild type mice, Gadd45β KO mice developed no HCC in the PB treated group. Increases in liver weight were more prominent in wild type mice than KO mice. Microarray analysis of mRNA derived from mouse livers found multiple genes specifically up or down regulated in wild type mice but not null mice in DEN + PB groups. Further qPCR analysis confirmed two genes, Tgfbr2 and irisin/Fndc5, were up-regulated in PB treated wild type mice but no significant increase was observed in Gadd45β KO mice. We focused on these two genes because previous reports showed that hepatic Irisin/Fndc5 expression was significantly higher in HCC patients and that irisin binds to TGF-β receptor complex that includes TGFBR2 subunit. Our results revealed irisin peptide in cell culture media increased the growth rate of mouse hepatocyte-derived AML12 cells. Microarray analysis revealed that irisin-regulated genes in AML12 cells showed a significant association with the genes in the TGF-β pathway. Expression of irisin/Fndc5 and Tgfbr2 induced growth of human HCC cell line HepG2. Thus, Gadd45β plays an indispensable role in mouse HCC development regulating the irisin/Fndc5 and Tgfbr2 genes.

PMID:37746289 | PMC:PMC10516603 | DOI:10.3389/fonc.2023.1217847

Front Pharmacol. 2023 Sep 8;14:1257745. doi: 10.3389/fphar.2023.1257745. eCollection 2023.

ABSTRACT

Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. Conclusion: DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia.

PMID:37745065 | PMC:PMC10515725 | DOI:10.3389/fphar.2023.1257745

Front Immunol. 2023 Sep 6;14:1250488. doi: 10.3389/fimmu.2023.1250488. eCollection 2023.

ABSTRACT

Embryo implantation is a key moment in pregnancy. Abnormal production of pro- and anti-inflammatory cytokines, their receptors and other immune factors may result in embryo implantation failure and pregnancy loss. The aim of this study was to determine the profile of selected pro- and anti-inflammatory factors in the blood plasma of patients undergoing in vitro fertilization (IVF) and control women who achieved pregnancy after natural conception. The examined patients were administered steroid prednisone. We present results concern the plasma levels of IFN-ɣ, BDNF, LIF, VEGF-A, sTNFR1 and IL-10. We found that IVF patients receiving steroids differed significantly from patients who were not administered such treatment in terms of IFN-γ and IL-10 levels. Moreover, IVF patients differed in secretion of all tested factors with the fertile controls. Our results indicated that women who secrete at least 1409 pg/ml of sTNFR1 have a chance to become pregnant naturally and give birth to a child, while patients after IVF must achieve a concentration of 962.3 pg/ml sTNFR1 in blood plasma for successful pregnancy. In addition, IVF patients secreting VEGF-A above 43.28 pg/ml have a greater risk of miscarriage or a failed transfer in comparison to women secreting below this value. In conclusion, fertile women present a different profile of pro- and anti-inflammatory cytokines, and growth factors compared to patients with recurrent implantation failure (RIF).

PMID:37744353 | PMC:PMC10511889 | DOI:10.3389/fimmu.2023.1250488

Front Immunol. 2023 Sep 6;14:1237986. doi: 10.3389/fimmu.2023.1237986. eCollection 2023.

ABSTRACT

OBJECTIVE: To identify the key coding genes underlying the biomarkers and pathways associated with giant cell arteritis (GCA), we performed an in situ spatial profiling of molecules involved in the temporal arteries of GCA patients and controls. Furthermore, we performed pharmacogenomic network analysis to identify potential treatment targets.

METHODS: Using human formalin-fixed paraffin-embedded temporal artery biopsy samples (GCA, n = 9; controls, n = 7), we performed a whole transcriptome analysis using the NanoString GeoMx Digital Spatial Profiler. In total, 59 regions of interest were selected in the intima, media, adventitia, and perivascular adipose tissue (PVAT). Differentially expressed genes (DEGs) (fold-change > 2 or < -2, p-adjusted < 0.01) were compared across each layer to build a spatial and pharmacogenomic network and to explore the pathophysiological mechanisms of GCA.

RESULTS: Most of the transcriptome (12,076 genes) was upregulated in GCA arteries, compared to control arteries. Among the screened genes, 282, 227, 40, and 5 DEGs were identified in the intima, media, adventitia, and PVAT, respectively. Genes involved in the immune process and vascular remodeling were upregulated within GCA temporal arteries but differed across the arterial layers. The immune-related functions and vascular remodeling were limited to the intima and media.

CONCLUSION: This study is the first to perform an in situ spatial profiling characterization of the molecules involved in GCA. The pharmacogenomic network analysis identified potential target genes for approved and novel immunotherapies.

PMID:37744332 | PMC:PMC10512077 | DOI:10.3389/fimmu.2023.1237986

J Vet Intern Med. 2023 Sep 24. doi: 10.1111/jvim.16871. Online ahead of print.

ABSTRACT

BACKGROUND: A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs.

HYPOTHESIS: PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet-rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results.

ANIMALS: Fifty-two privately owned CKCS with no or preclinical MMVD.

METHODS: Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate-induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography.

RESULTS: Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 μM (P < .0001) and Vel at 0.03 μM (P < .001). PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response.

CONCLUSIONS AND CLINICAL IMPORTANCE: The PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment.

PMID:37743723 | DOI:10.1111/jvim.16871

Br J Clin Pharmacol. 2023 Sep 24. doi: 10.1111/bcp.15913. Online ahead of print.

ABSTRACT

Genome-wide association studies (GWAS) have identified genetic variations associated with adverse drug effects in pharmacogenomics (PGx) research. Yet, interpreting the biological implications of these associations remains a challenge. This review highlights two promising post-GWAS methods for PGx. First, we discuss the polygenic architecture of the PGx traits, especially for drug-induced liver injury (DILI). Their experimental modelling using multiple donors' human primary hepatocytes and human liver organoids demonstrated the polygenic architecture of DILI susceptibility and found biological vulnerability in genetically high-risk tissue donors. Second, we discuss the challenges of interpreting the roles of variants in non-coding regions. Beyond methods involving expression quantitative trait locus analysis and massively parallel reporter assays, we suggest the use of in silico mutagenesis through machine learning methods to understand the roles of variants in transcriptional regulation. This review underscores the importance of these post-GWAS methods in providing critical insights into PGx, potentially facilitating drug development and personalized treatment. (149 words).

PMID:37743713 | DOI:10.1111/bcp.15913

J Genet Couns. 2023 Sep 22. doi: 10.1002/jgc4.1796. Online ahead of print.

ABSTRACT

Rapid advancements in genetics care requires responsive genetic counseling (GC) training capable of integrating new discoveries and practice into their curricula. The utilization of shared or standardized educational resources may address this need. Recognizing the potential of shared resources, the Pharmacogenetics (PGx) Working Group of the NSGC Precision Medicine Special Interest Group (SIG) launched a standardized education module using a flipped-classroom format to provide all GC programs equal access to PGx expertise and alleviate the burden of curriculum development. Following the initial success of the program, we aimed to explore the utilization of shared and standardized education resources more broadly, and better understand the perspectives of GC program faculty regarding their use. Twenty-nine program faculty representing at least 14 programs responded to an online survey. The majority (n = 21) reported sharing educational materials with another GC program, and 90% of those reported the shared materials to be beneficial as they promote collaboration, efficiency, address a gap in content, and provide access to experts. Similar benefits were described when using a standardized curriculum, which was defined as standardized lectures and activities created about a particular topic and made available to all genetic counseling programs; 16 participants indicated they would be very likely or likely to use a standardized curriculum. A secondary aim of the survey was to assess the existing PGx module that utilizes a flipped-classroom format. Overall, the PGx module was well received, indicating that a standardized shared module is well-suited for instruction on emerging and specialty topics. All participants believed the flipped-classroom format to be very or somewhat beneficial. In summary, results indicate that shared educational materials, including standardized education modules, are a potential solution to challenges related to efficiency and access to content experts in GC education, and program leadership is receptive to using them.

PMID:37740462 | DOI:10.1002/jgc4.1796