Search Results (18)

Background/Objectives: Aneuploidy is near-ubiquitous in cancer and can decrease chemotherapy efficacy while also sensitizing cells to other drugs. Methods: To systematically identify treatment strategies that target aneuploid cancers, data were integrated from The Cancer Genome Atlas (TCGA; 10,967 samples, 16,948 aneuploidy events) and the Broad Institute’s Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) screen of 578 cancer cell lines and 4518 compounds. Results: Our analyses uncovered 37,720 significant positive and negative associations linking specific aneuploidies and treatments with patient prognosis or cell viability. Within TCGA data, 22 treatments correlated with improved 5-year survival for specific aneuploid cancers, whereas 46 were linked to worse outcomes. A complementary analysis of PRISM identified 17,946 compound–aneuploidy associations and 16,189 mechanism of action (MOA)–aneuploidy associations. Pathway-altering compounds that selectively reduce viability in cells with aneuploidy profiles were discovered, including an unexpectedly prominent number of glucocorticoid receptor agonists. Conclusions: This integrated dataset provides a resource for designing therapeutic decision hypotheses, identifying drug-repurposing opportunities, and informing future studies aimed at targeting aneuploidy-induced vulnerabilities in cancer. Full article

Background/Objectives: Pharmacogenomic screening plays a crucial role in optimizing chemotherapy outcomes and minimizing toxicity. Characterizing the baseline distribution of genetic variants in specific populations is essential to inform the prioritization of drug–gene combinations for clinical implementation. The objective of this study was to investigate the distribution of pharmacogenetic variants in 36 genes related to the fluoropyrimidine (FP) pathway among healthy Omani individuals, forming a foundation for future studies in cancer patients receiving FP-based chemotherapy. Methods: Ninety-eight healthy Omani participants aged ≥18 years were recruited at the Sultan Qaboos Comprehensive Cancer Care and Research Center. Whole-blood samples were collected, and genomic DNA was extracted. Targeted next-generation sequencing was performed using a custom Ion AmpliSeq panel covering coding exons and splice-site regions of 36 genes involved in FP metabolism and response. Results: A total of 999 variants were detected across the 36 genes, with 63.3% being heterozygous. The ABCC4 gene had the highest mutation frequency (76 mutations), while DHFR and SMUG1 had the lowest (<10 mutations). In DPYD, four functionally significant variants were found at frequencies ranging from 1 to 8.2% of the population. Missense mutations were also observed in MTHFR and UGT1A1. Three actionable variants in DPYD and MTHFR, associated with 5-fluorouracil and/or capecitabine response, were identified. Additionally, 27 novel single-nucleotide polymorphisms of unknown clinical significance were detected. Conclusions: This study reveals key pharmacogenetic variants in the Omani population, underscoring the importance of integrating pharmacogenomic testing into routine care to support safer, more personalized chemotherapy in the region. Full article

A variable number tandem repeat polymorphism has been described in the CYP2C9 promoter (pVNTR) with three types of fragments: short (pVNTR-S), medium (pVNTR-M), and long (pVNTR-L). The pVNTR-S allele appears in strong linkage disequilibrium (LD) with the non-functional CYP2C9*3 allele in populations of European ancestry, but independently of this, it also appears to reduce the level of CYP2C9 expression in human liver by up to 34%. Objectives: This study, in a Dominican population with varying amounts of Western European, African, and Native American ancestry, aims primarily to determine the frequency of CYP2C9 pVNTR, and the degree of LD of pVNTR-S with CYP2C9*3. Secondarily, it explores if the frequency of the pVNTR-S allele is over- or under-represented in those with a greater component of African ancestry. Methods: A total of 193 healthy volunteers from the Dominican Republic participated in the study. The promoter region of CYP2C9 was amplified and analyzed by capillary electrophoresis. Analyses of CYP2C9 genotypes (*2, *3, *5, *6, and *8) and genetic ancestry, estimated in 176 Dominican individuals by genotyping 90 ancestry informative markers, were previously performed in this population. Results: The frequencies of CYP2C9 pVNTR-L, M, and S variants are 0.065, 0.896, and 0.039, respectively. LD between pVNTR-S and CYP2C9*3 was found (D’ = 0.756, r² = 0.702) to be weaker than in European populations. Conclusions: Populations with a greater African ancestry component appear to present a lower-than-expected frequency of pVNTR-S, as well as a lower tendency for this and CYP2C9*3 alleles to be inherited together, as is common in Europeans. The present exploratory results warrant further research in vivo about the effects of pVNTR-S in predicting CYP2C9 activity. Its inclusion in CYP2C9 testing panels for personalized drug therapy could be relevant in populations such as the Dominican, where the LD between pVNTR-S and CYP2C9*3 is low. Full article

Background/Objectives: This review examines the role of pharmacogenomics in individual responses to the pharmacotherapy of various drugs of abuse, including alcohol, cocaine, and opioids, to identify genetic variants that contribute to variability in substance use disorder treatment outcomes. In addition, it explores the pharmacomicrobiomic aspects of substance use, highlighting the impact of the gut microbiome on bioavailability, drug metabolism, pharmacodynamics, and pharmacokinetics. Results: Research on pharmacogenetics has identified several promising genetic variants that may contribute to the individual variability in responses to existing pharmacotherapies for substance addiction. However, the interpretation of these findings remains limited. It is estimated that genetic factors may account for 20–95% of the variability in individual drug responses. Therefore, genetic factors alone cannot fully explain the differences in drug responses, and factors such as gut microbiome diversity may also play a significant role. Drug microbial biotransformation is produced by microbial exoenzymes that convert low molecular weight organic compounds into analogous compounds by oxidation, reduction, hydrolysis, condensation, isomerization, unsaturation, or by the introduction of heteroatoms. Despite significant advances in pharmacomicrobiomics, challenges persist including the lack of standardized methodologies, inter-individual variability, limited understanding of drug biotransformation mechanisms, and the need for large-scale validation studies to develop microbiota-based biomarkers for clinical use. Conclusions: Progress in the pharmacogenomics of substance use disorders has provided biological insights into the pharmacological needs associated with common genetic variants in drug-metabolizing enzymes. The gut microbiome and its metabolites play a pivotal role in various stages of drug addiction including seeking, reward, and biotransformation. Therefore, integrating pharmacogenomics with pharmacomicrobiomics will form a crucial foundation for significant advances in precision and personalized medicine. Full article

Chronic Obstructive Pulmonary Disease (COPD) manifests as a genetically diverse and intricate lung condition with various subtypes. The development of the disease and response to treatment are influenced by the interplay between genetic and environmental factors. The predominant therapeutic approaches include bronchodilator therapy and corticosteroid treatment. Studies in COPD pharmacogenetics involve genome-wide association (GWA) studies, gene profiling, whole-genome sequencing, and other omics-based investigations. Many of these investigations have focused on the association between genetic variations and the response to β2 agonist treatment. Additionally, several studies have explored the impact of gene variations on the response to inhaled corticosteroid (ICS) treatment, with a specific focus on polymorphisms in the glucocorticoid receptor (GR) signaling pathway. However, a significant challenge lies in the inconclusive or inconsistent results of these pharmacogenetic studies, underscoring the research community’s struggle to provide sufficient evidence for the clinical implementation of COPD pharmacogenetics. To address these challenges, further research and larger genome-wide studies are essential. These efforts aim to uncover additional COPD subtypes, identify predictors of treatment response, and discover novel genetic markers for COPD. The integration of genomics, detailed evaluations such as chest CT scans, spirometry tests, and blood analyses, along with DNA collection in clinical research, is critical for translating COPD pharmacogenetics into clinical practice. Furthermore, advancing our understanding of the complex interactions between genetics, phenotypes, and environmental factors will be pivotal for improving individualized prognostic assessments and enhancing treatment outcomes in COPD. Full article

A recently discovered haplotype—CYP2C:TG—determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the CYP2C:TG haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (n = 283) treated with clopidogrel over 3–6 months were classified by CYP2C19 phenotype based on the CYP2C19*2*17 genotype, and based on the CYP2C19/CYP2C cluster genotype, and regarding carriage of the CYP2:TG haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2–14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6–20.5%). The incidence of ischemic events was similar in CYP2C:TG carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the CYP2C19/CYP2C cluster genotype or CYP2C:TG haplotype on the clinical efficacy/safety of clopidogrel. Full article

The nomenclature of star alleles has been widely used in pharmacogenomics to enhance treatment outcomes, predict drug response variability, and reduce adverse reactions. However, the discovery of numerous rare functional variants through genome sequencing introduces complexities into the star-allele system. This study aimed to assess the nature and impact of the rapid discovery of numerous rare functional variants in the traditional haplotype-based star-allele system. We developed a new method to construct haplogroups, representing a common ancestry structure, by iteratively excluding rare and functional variants of the 25 representative pharmacogenes using the 2504 genomes from the 1000 Genomes Project. In total, 192 haplogroups and 288 star alleles were identified, with an average of 7.68 ± 4.2 cross-ethnic haplogroups per gene. Most of the haplogroups (70.8%, 136/192) were highly aligned with their corresponding classical star alleles (VI = 1.86 ± 0.78), exhibiting higher genetic diversity than the star alleles. Approximately 41.3% (N = 119) of the star alleles in the 2504 genomes did not belong to any of the haplogroups, and most of them (91.3%, 105/116) were determined by a single variant according to the allele-definition table provided by CPIC. These functional single variants had low allele frequency (MAF < 1%), high evolutionary conservation, and variant deleteriousness, which suggests significant negative selection. It is suggested that the traditional haplotype-based naming system for pharmacogenetic star alleles now needs to be adjusted by balancing both traditional haplotyping and newly emerging variant-sequencing approaches to reduce naming complexity. Full article

Multidrug resistance (MDR) commonly leads to cancer treatment failure because cancer cells often expel chemotherapeutic drugs using ATP-binding cassette (ABC) transporters, which reduce drug levels within the cells. This study investigated the clinical characteristics and single nucleotide variant (SNV) in ABCB1, ABCC1, ABCC2, ABCC4, and ABCG2, and their association with mortality in pediatric patients with central nervous system tumors (CNST). Using TaqMan probes, a real-time polymerase chain reaction genotyped 15 SNPs in 111 samples. Patients were followed up until death or the last follow-up day using the Cox proportional hazards model. An association was found between the rs1045642 (ABCB1) in the recessive model (HR = 2.433, 95% CI 1.098–5.392, p = 0.029), and the ICE scheme in the codominant model (HR = 9.810, 95% CI 2.74–35.06, p ≤ 0.001), dominant model (HR = 6.807, 95% CI 2.87–16.103, p ≤ 0.001), and recessive model (HR = 6.903, 95% CI 2.915–16.544, p = 0.038) significantly increased mortality in this cohort of patients. An association was also observed between the variant rs3114020 (ABCG2) and mortality in the codominant model (HR = 5.35, 95% CI 1.83–15.39, p = 0.002) and the dominant model (HR = 4.421, 95% CI 1.747–11.185, p = 0.002). A significant association between the ICE treatment schedule and increased mortality risk in the codominant model (HR = 6.351, 95% CI 1.831–22.02, p = 0.004, HR = 9.571, 95% CI 2.856–32.07, p ≤ 0.001), dominant model (HR = 6.592, 95% CI 2.669–16.280, p ≤ 0.001), and recessive model (HR = 5.798, 95% CI 2.411–13.940, p ≤ 0.001). The genetic variants rs3114020 in the ABCG2 gene and rs1045642 in the ABCB1 gene and the ICE chemotherapy schedule were associated with an increased mortality risk in this cohort of pediatric patients with CNST. Full article

Crohn’s disease (CD), rheumatoid arthritis, psoriatic arthritis and other inflammatory diseases comprise a group of chronic diseases with immune-mediated pathogenesis which share common pathological pathways, as well as treatment strategies including anti-TNF biologic therapy. However, the response rate to anti-TNF therapy among those diseases varies, and approximately one third of patients do not respond. Since pharmacogenetic studies for anti-TNF therapy have been more frequent for other related diseases and are rare in CD, the aim of our study was to further explore markers associated with anti-TNF response in other inflammatory diseases in Slovenian CD patients treated with the anti-TNF drug adalimumab (ADA). We enrolled 102 CD patients on ADA, for which the response was defined after 4, 12, 20 and 30 weeks of treatment, using an IBDQ questionnaire and blood CRP value. We genotyped 41 SNPs significantly associated with response to anti-TNF treatment in other diseases. We found novel pharmacogenetic association between SNP rs755622 in the gene MIF (macrophage migration inhibitory factor) and SNP rs3740691 in the gene ARFGAP2 in CD patients treated with ADA. The strongest and most consistent association with treatment response was found for the variant rs2275913 in gene IL17A (p = 9.73 × 10⁻³). Full article

Caffeine is the most consumed drug in the world, and it is commonly used by children. Despite being considered relatively safe, caffeine can have marked effects on sleep. Studies in adults suggest that genetic variants in the adenosine A2A receptor (ADORA2A, rs5751876) and cytochrome P450 1A (CYP1A, rs2472297, rs762551) loci are correlated with caffeine-associated sleep disturbances and caffeine intake (dose), but these associations have not been assessed in children. We examined the independent and interaction effects of daily caffeine dose and candidate variants in ADORA2A and CYP1A on the sleep quality and duration in 6112 children aged 9–10 years who used caffeine and were enrolled in the Adolescent Brain Cognitive Development (ABCD) study. We found that children with higher daily caffeine doses had lower odds of reporting > 9 h of sleep per night (OR = 0.81, 95% CI = 0.74–0.88, and p = 1.2 × 10⁻⁶). For every mg/kg/day of caffeine consumed, there was a 19% (95% CI = 12–26%) decrease in the odds of children reporting > 9 h of sleep. However, neither ADORA2A nor CYP1A genetic variants were associated with sleep quality, duration, or caffeine dose. Likewise, genotype by caffeine dose interactions were not detected. Our findings suggest that a daily caffeine dose has a clear negative correlation with sleep duration in children, but this association is not moderated by the ADORA2A or CYP1A genetic variation. Full article

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. Methods: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. Results: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1–12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8–12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5–21.1) and severe CIPN. Conclusions: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice. Full article

Background: Methotrexate (MTX) is considered the first choice among disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) treatment. However, response to it varies as approximately 40% of the patients do not respond and would lose the most effective period of treatment time. Therefore, having a predictive biomarker before starting MTX treatment is of utmost importance. Methylation of long interspersed nucleotide element-1 (LINE-1) is generally considered a surrogate marker for global genomic methylation, which has been reported to associate with disease activity after MTX therapy. Methods: We performed a prospective study on 273 naïve early RA (ERA) patients who were treated with MTX, followed up to 12 months, and classified according to their therapy response. The baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMC) of cases were assessed by bisulfite pyrosequencing. Results: Baseline LINE-1 methylation level per se turned out not to predict the response to the therapy, nor did age, sex, body mass index, or smoking status. However, if cases were stratified according to positivity to rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) or seronegativity, we observed an opposite association between baseline LINE-1 methylation levels and optimal response to MTX therapy among responders. The best response to MTX therapy was associated with hypermethylated LINE-1 among double-positive ERA cases (p-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (p-value: 0.01). Conclusion: The LINE-1 methylation level in PBMCs of naïve ERA cases associates with the degree of response to MTX therapy in an opposite way depending on the presence of RF and ACPA antibodies. Our results suggest LINE-1 methylation level as a new epigenetic biomarker for predicting the degree of response to MTX in both double-positive and seronegative ERA patients. Full article

The altered activity of drug metabolism enzymes (DMEs) is a hallmark of chemotherapy resistance. Cytochrome P450s (CYPs), mainly CYP3A4, and several oxidoreductases are responsible for Phase I metabolism of doxorubicin (DOX), an anthracycline widely used in breast cancer (BC) treatment. This study aimed to investigate the role of Phase I DMEs involved in the first stages of acquisition of DOX-resistance in BC cells. For this purpose, the expression of 92 DME genes and specific CYP-complex enzymes activities were assessed in either sensitive (MCF-7 parental cells; MCF-7/DOX^S) or DOX-resistant (MCF-7/DOX^R) cells. The DMEs genes detected to be significantly differentially expressed in MCF-7/DOX^R cells (12 CYPs and eight oxidoreductases) were indicated previously to be involved in tumor progression and/or chemotherapy response. The analysis of CYP-mediated activities suggests a putative enhanced CYP3A4-dependent metabolism in MCF-7/DOX^R cells. A discrepancy was observed between CYP-enzyme activities and their corresponding levels of mRNA transcripts. This is indicative that the phenotype of DMEs is not linearly correlated with transcription induction responses, confirming the multifactorial complexity of this mechanism. Our results pinpoint the potential role of specific CYPs and oxidoreductases involved in the metabolism of drugs, retinoic and arachidonic acids, in the mechanisms of chemo-resistance to DOX and carcinogenesis of BC. Full article

Retinal diseases are major causes of irreversible vision loss and blindness. Despite extensive research into their pathophysiology and etiology, pharmacotherapy effectiveness and surgical outcomes remain poor. Based largely on numerous preclinical studies, administration of mesenchymal stem cells (MSCs) as a therapeutic strategy for retinal diseases holds great promise, and various approaches have been applied to the therapies. However, hindered by the retinal barriers, the initial vision for the stem cell replacement strategy fails to achieve the anticipated effect and has now been questioned. Accumulating evidence now suggests that the paracrine effect may play a dominant role in MSC-based treatment, and MSC-derived extracellular vesicles emerge as a novel compelling alternative for cell-free therapy. This review summarizes the therapeutic potential and current strategies of this fascinating class of cells in retinal degeneration and other retinal dysfunctions. Full article

Background: The increase in the medical use of cannabis has revealed a number of beneficial effects, a variety of adverse side effects and great inter-individual variability. Association studies connecting consumption, addiction and side effects related to recreational cannabis use have led to the identification of several polymorphic genes that may play a role in the pharmacodynamics and pharmacokinetics of cannabis. Method: In total, 600 patients treated with cannabis were genotyped for several candidate polymorphic genes (single-nucleotide polymorphism; SNP), encoding receptors CNR1 and TRPV1; for the ABCB1 transporter; for biotransformation, bioactivation and biosynthesis; and CYP3A4, COMT and UGT2B7 conjugation. Results: Three polymorphic genes (ABCB1, TRPV1 and UGT2B7) were identified as being significantly associated with decline in pain after treatment with cannabis. Patients simultaneously carrying the most favourable allele combinations showed a greater reduction (polygenic effect) in pain compared to those with a less favourable combination. Considering genotype combinations, we could group patients into good responders, intermediate responders and poor or non-responders. Results suggest that genetic makeup is, at the moment, a significant predictive factor of the variability in response to cannabis. Conclusions: This study proves, for the first time, that certain polymorphic candidate genes may be associated with cannabis effects, both in terms of pain management and side effects, including therapy dropout. Significance: Our attention to pharmacogenetics began in 2008, with the publication of a first study on the association between genetic polymorphisms and morphine action in pain relief. The study we are presenting is the first observational study conducted on a large number of patients involving several polymorphic candidate genes. The data obtained suggest that genetic makeup can be a predictive factor in the response to cannabis therapy and that more extensive and planned studies are needed for the opening of new scenarios for the personalization of cannabis therapy. Full article