Genes (Basel). 2021 Aug 18;12(8):1259. doi: 10.3390/genes12081259.

ABSTRACT

Several pharmacogenetic-based decision support tools for psychoactive medication selection are available. However, the scientific evidence of the gene-drug pairs analyzed is mainly based on pharmacogenetic studies in patients with major depression or schizophrenia, and their clinical utility is mostly assessed in major depression. This study aimed at evaluating the impact of individual genes, with pharmacogenetic relevance in other psychiatric conditions, in the response to treatment in bipolar depression. Seventy-six patients diagnosed with bipolar disorder and an index major depressive episode were included in an observational retrospective study. Sociodemographic and clinical data were collected, and all patients were genotyped using a commercial multigene pharmacogenomic-based tool (Neuropharmagen®, AB-Biotics S.A., Barcelona, Spain). Multiple linear regression was used to identify pharmacogenetic and clinical predictors of efficacy and tolerability of medications. The pharmacogenetic variables response to serotonin-norepinephrine reuptake inhibitors (SNRIs) (ABCB1) and reduced metabolism of quetiapine (CYP3A4) predicted patient response to these medications, respectively. ABCB1 was also linked to the tolerability of SNRIs. An mTOR-related multigenic predictor was also associated with a lower number of adverse effects when including switch and autolytical ideation. Our results suggest that the predictors identified could be useful to guide the pharmacological treatment in bipolar disorder. Additional clinical studies are necessary to confirm these findings.

PMID:34440433 | DOI:10.3390/genes12081259

Genes (Basel). 2021 Jul 30;12(8):1192. doi: 10.3390/genes12081192.

ABSTRACT

Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from <50 kb to >9 Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8 Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS.

PMID:34440366 | DOI:10.3390/genes12081192

Genes (Basel). 2021 Jul 29;12(8):1179. doi: 10.3390/genes12081179.

ABSTRACT

Uterine leiomyomas are tumors, which are hormone driven and originate from the smooth muscle layer of the uterine wall. In addition to known genes in leiomyoma pathogenesis, recent approaches also highlight epigenetic malfunctions as an important mechanism of gene dysregulation. RNA sequencing raw data from pair-matched normal myometrium and fibroid tumors from two independent studies were used as discovery and validation sets and reanalyzed. RNA extracted from normal myometrium and fibroid tumors from 58 Slovenian patients was used as independent confirmation of most significant differentially expressed genes. Subsequently, GWA data from leiomyoma patients were used in order to identify genetic variants at epigenetic marks. Gene Ontology analysis of the overlap of two independent RNA-seq analyses showed that NPTX1, NPTX2, CHRM2, DRD2 and CACNA1A were listed as significant for several enriched GO terms. All five genes were subsequently confirmed in the independent Slovenian cohort. Additional integration and functional analysis showed that genetic variants in these five gene regions are listed at a chromatin structure and state, predicting promoters, enhancers, DNase hypersensitivity and altered transcription factor binding sites. We identified a unique subgroup of dysregulated synaptic signaling genes involved in the biology and pathogenesis of leiomyomas, adding to the complexity of tumor biology.

PMID:34440356 | DOI:10.3390/genes12081179

Genes (Basel). 2021 Jul 29;12(8):1168. doi: 10.3390/genes12081168.

ABSTRACT

The genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the government was terminated in 2014, the approach had proven its effectiveness and had built the foundation for the development of more sophisticated diagnostic tools, clinical collaborations, and new molecular-based treatments for FH patients. As such, the community was driven to continue the program, insurance companies were convinced to collaborate, and multiple approaches were launched to find new index cases with FH. Additionally, the screening was extended, now also including other heritable dyslipidemias. For this purpose, a diagnostic next-generation sequencing (NGS) panel was developed, which not only comprised the culprit LDLR, APOB, and PCSK9 genes, but also 24 other genes that are causally associated with genetic dyslipidemias. Moreover, the NGS technique enabled further optimization by including pharmacogenomic genes in the panel. Using such a panel, more patients that are prone to cardiovascular diseases are being identified nowadays and receive more personalized treatment. Moreover, the NGS output teaches us more and more about the dyslipidemic landscape that is less straightforward than we originally thought. Still, continuous progress is being made that underlines the strength of genetics in dyslipidemia, such as discovery of alternative genomic pathogenic mechanisms of disease development and polygenic contribution.

PMID:34440342 | DOI:10.3390/genes12081168

Biomedicines. 2021 Jul 24;9(8):882. doi: 10.3390/biomedicines9080882.

ABSTRACT

5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a standard of care to treat colorectal cancers (CRCs). As an antimetabolite, 5-FU inhibits thymidylate synthase to disrupt the synthesis and repair of DNA and RNA. However, only a small proportion of patients benefit from 5-FU treatment due to the development of drug resistance. This study applied pharmacogenomic analysis using two public resources, the Genomics of Drug Sensitivity in Cancer (GDSC) and the Connectivity Map, to predict agents overcoming 5-FU resistance in CRC cells based on their genetic background or gene expression profile. Based on the genetic status of adenomatous polyposis coli (APC), the most frequent mutated gene found in CRC, we found that combining a MEK inhibitor with 5-FU exhibited synergism effects on CRC cells with APC truncations. While considering the gene expression in 5-FU resistant cells, we demonstrated that targeting ROCK is a potential avenue to restore 5-FU response to resistant cells with wild-type APC background. Our results reveal MEK signaling plays a pivotal role in loss-of-function, APC-mediated 5-FU resistance, and ROCK activation serves as a signature in APC-independent 5-FU resistance. Through the use of these available database resources, we highlight possible approaches to predict potential drugs for combinatorial therapy for patients developing resistance to 5-FU treatment.

PMID:34440086 | DOI:10.3390/biomedicines9080882

Biomedicines. 2021 Jul 23;9(8):875. doi: 10.3390/biomedicines9080875.

ABSTRACT

The gut microbiota is constituted by more than 40,000 bacterial species involved in key processes including high order brain functions. Altered composition of gut microbiota has been implicated in psychiatric disorders and in modulating the efficacy and safety of psychotropic medications. In this work we characterized the composition of the gut microbiota in 38 patients with schizophrenia (SCZ) and 20 healthy controls (HC), and tested if SCZ patients with different response to antipsychotics (18 patients with treatment resistant schizophrenia (TRS), and 20 responders (R)) had specific patterns of gut microbiota composition associated with different response to antipsychotics. Moreover, we also tested if patients treated with typical antipsychotics (n = 20) presented significant differences when compared to patients treated with atypical antipsychotics (n = 31). Our findings showed the presence of distinct composition of gut microbiota in SCZ versus HC, with several bacteria at the different taxonomic levels only present in either one group or the other. Similar findings were observed also depending on treatment response and exposure to diverse classes of antipsychotics. Our results suggest that composition of gut microbiota could constitute a biosignatures of SCZ and TRS.

PMID:34440078 | DOI:10.3390/biomedicines9080875

Biomolecules. 2021 Aug 2;11(8):1142. doi: 10.3390/biom11081142.

ABSTRACT

Pregnane X Receptor (PXR) belongs to the nuclear receptors' superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR's regulation. Antineoplastic agents are of particular interest since cancer patients are characterized by significant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may alter the function of the protein and are linked with significant effects on the pharmacokinetics of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. It is also expected that this review will highlight the importance of PXR polymorphisms in selection of chemotherapy, prediction of adverse effects and personalized medicine.

PMID:34439808 | DOI:10.3390/biom11081142

ESMO Open. 2021 Aug 23;6(5):100236. doi: 10.1016/j.esmoop.2021.100236. Online ahead of print.

ABSTRACT

BACKGROUND: In this study, we evaluated the association between genetic polymorphisms of 23 genes associated with gemcitabine metabolism and the clinical efficacy of gemcitabine in breast cancer patients.

PATIENTS AND METHODS: This prospective, pharmacogenetic study was conducted in cooperation with a phase II clinical trial. A total of 103 genetic polymorphisms of the 23 genes involved in gemcitabine transport and metabolism were selected for genotyping. The associations of genetic polymorphisms with overall survival, progression-free survival (PFS), and 6-month PFS were analyzed.

RESULTS: A total of 91 breast cancer patients were enrolled in this study. In terms of 6-month PFS, rs1044457 in CMPK1 was the most significant genetic polymorphism [55.9% for CT and TT and 78.9% for CC, P < 0.001, hazard ratio (HR): 4.444, 95% confidence interval (CI): 1.905-10.363]. For the rs693955 in SLC29A1, the median duration of PFS was 5.4 months for AA and 10.5 months for CA and CC (P = 0.002, HR: 3.704, 95% CI: 1.615-8.497). For the rs2807312 in TLE4, the median duration of PFS was 5.7 months for TT and 10.4 months for CT and CC (P = 0.005, HR: 4.948, 95% CI: 1.612-15.190). In survival analysis with a multi-gene model, the TT genotype of rs2807312 had the worst PFS regardless of other genetic polymorphisms, whereas the CA genotype of rs693955 or the CT genotype of rs2807312 without the AA genotype of rs693955 had the best PFS compared with those of other genetic groups (P < 0.001).

CONCLUSIONS: Genetic polymorphisms of rs1044457 in CMPK1, rs693955 in SLC29A1, and rs2807312 in TLE4 were significantly associated with the 6-month PFS rate and/or the duration of PFS. Further studies with a larger sample size and expression study would be helpful to validate the association of genetic polymorphisms and clinical efficacy of gemcitabine.

PMID:34438242 | DOI:10.1016/j.esmoop.2021.100236

PLoS Genet. 2021 Aug 26;17(8):e1009732. doi: 10.1371/journal.pgen.1009732. Online ahead of print.

ABSTRACT

Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction.

PMID:34437536 | DOI:10.1371/journal.pgen.1009732

Biomed Pharmacother. 2021 Aug 19;142:112055. doi: 10.1016/j.biopha.2021.112055. Online ahead of print.

ABSTRACT

The most common mental illness is depression; however, its pathogenesis is not fully understood. One of the factors that may influence its development and the effectiveness of therapy are the cytochromes of the p450 complex. CYP3A5 and CYP2C19 are involved in the metabolism of drugs used in the treatment of depression. These cytochromes can also generate reactive oxygen species, which are known to participate in the pathogenesis of depression. The aim of the study was to determine the frequency of CYP3A5*3 and CYP2C19*2 variants among a group of patients with depression to identify any potential association with disease development and progression, and the effectiveness of pharmacotherapy. A group of 103 patients suffering from recurrent depressive disorder and another of 93 healthy individuals were investigated using RFLP. It was found that the CYP3A5*3 allele may have a protective role in the development of depression (p = 0.0036). Heterozygous CYP3A5*1/*3 was more common in controls than the patients (p = 0.0300). Homozygotes were associated with an earlier onset than heterozygotes (p = 0.0292). For CYP2C19, patients with at least one CYP2C19*2 allele revealed better treatment results expressed as percentage change in Hamilton Depression Rating Scale (p = 0.0239). The identification of CYP3A5 and CYP2C19 allelic variants may be useful when assessing the effectiveness of pharmacotherapy.

PMID:34435592 | DOI:10.1016/j.biopha.2021.112055

Expert Opin Pharmacother. 2021 Aug 26:1-13. doi: 10.1080/14656566.2021.1967319. Online ahead of print.

ABSTRACT

INTRODUCTION: Cluster analysis has identified distinct groups of type 2 diabetes (T2D) subjects with distinct metabolic characteristics. Thus, personalizing pharmacologic therapy to individual phenotypic and pathophysiologic characteristics has potential to improve metabolic control and reduce risk of microvascular and macrovascular complications.

AREAS COVERED: The authors review the classification of T2D, genetic markers, pathophysiology and natural history of T2D, the ABCDE approach to therapy, the ADA/EASD stepwise approach to therapy, available antidiabetic agents, and provide a more rational therapeutic approach based upon pathophysiology and cardiovascular and renal outcome trials.

EXPERT OPINION: Although insulin resistance is the earliest detectable abnormality, overt T2D does not occur in the absence of progressive beta cell failure. Because of the complex etiology of T2D (Ominous Octet), initiation of therapy with combined agents that (i) target both insulin resistance and beta cell dysfunction and (ii) prevent macrovascular, as well as microvascular, complications will be required. The ratio of C-peptide at 120 minutes (OGTT) to baseline C-peptide predicts with high sensitivity who will respond to metformin, the response to glucose-lowering agents and provides a useful tool to guide optimal glucose lowering therapy.

PMID:34435523 | DOI:10.1080/14656566.2021.1967319

J Extracell Vesicles. 2021 Aug;10(10):e12136. doi: 10.1002/jev2.12136. Epub 2021 Aug 18.

ABSTRACT

Proliferation and survival of prostate cancer cells are driven by the androgen receptor (AR) upon binding to androgen steroid hormones. Manipulating the AR signalling axis is the focus for prostate cancer therapy; thus, it is crucial to understand the role of androgens and AR on extracellular vesicle (EV) secretion and cargo. In this study, we report that plasma-derived circulating vesicles consisting of CD9 and double-positive for CD9 and Prostate Specific Membrane Antigen (PSMA) are increased in patients with advanced metastatic prostate cancer, whereas double positives for CD9 and CD63 small extracellular vesicles (S-EVs) are significantly higher in patients with localised prostate cancer. Androgen manipulation by dihydrotestosterone (DHT) and the clinical antagonist enzalutamide (ENZ) altered the heterogeneity and size of CD9 positive S-EVs in AR expressing prostate cancer cells, while assessment of the total number and protein cargo of total S-EVs was unaltered across different treatment groups. Furthermore, hormone stimulation caused strong and specific effects on the small RNA cargo of S-EVs. A total of 543 small RNAs were found to be regulated by androgens including miR-19-3p and miR-361-5p. Analysis of S-EVs heterogeneity and small RNA cargo may provide clinical utility for prostate cancer and be informative to understand further the mechanism of resistance to androgen targeted therapy in castration-resistant prostate cancer.

PMID:34434533 | PMC:PMC8374107 | DOI:10.1002/jev2.12136

Br J Clin Pharmacol. 2021 Aug 25. doi: 10.1111/bcp.15056. Online ahead of print.

ABSTRACT

AIM: Tenofovir and para-aminosalicylic acid (PAS) may be co-prescribed to treat patients with concomitant infections of human immunodeficiency virus and Mycobacterium tuberculosis bacteria. Both drugs are known to have remarkable renal uptake transporter-mediated clearance. Owing to the lack of clinical studies on drug-drug interaction between the two drugs, we conducted a translational clinical study to investigate the effect of PAS on tenofovir pharmacokinetics.

METHODS: Initially, we studied in vitro renal uptake transporter-mediated drug-drug interactions using stably transfected cells with human organic anion transporters (organic anion transporter 1 and 3 [OAT1 and OAT3]). Later, we estimated clinical drug interactions using static and physiologically based pharmacokinetic (PBPK) modeling. Finally, we investigated the effects of PAS-calcium formulation (PAS-Ca) on tenofovir disoproxil fumarate pharmacokinetics in healthy male Korean subjects.

RESULTS: PAS inhibited OAT1- and OAT3-mediated tenofovir uptake in vitro. The PBPK drug-drug interaction model suggested a 1.26-fold increase in tenofovir peak plasma concentration when co-administered with PAS. By contrast, an open-label, randomized, crossover clinical trial evaluating the effects of PAS-Ca on tenofovir pharmacokinetics showed significantly altered geometric mean ratio (90% confidence intervals) of maximum plasma concentration (Cmax ) and area under the curve (AUC0-inf ) by 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively.

CONCLUSIONS: Our study findings suggest that the PAS-Ca formulation significantly reduced systemic exposure to tenofovir through an unexplained mechanism, which was contrary to the initial prediction. Caution should be exercised while predicting in vivo PK profiles from in vitro data, particularly when there are potential confounders such as pharmaceutical interactions.

PMID:34432302 | DOI:10.1111/bcp.15056

Clin Transl Sci. 2021 Aug 25. doi: 10.1111/cts.13121. Online ahead of print.

ABSTRACT

Personal genomic educational testing (PGET) has been suggested as a strategy to improve student learning for pharmacogenomics (PGx), but no randomized studies have evaluated PGET's educational benefit. We investigated the effect of PGET on student knowledge, comfort, and attitudes related to PGx in a nonblinded, randomized controlled trial. Consenting participants were randomized to receive PGET or no PGET (NPGET) during 4 subsequent years of a PGx course. All participants completed a pre-survey and post-survey designed to assess (1) PGx knowledge, (2) comfort with PGx patient education and clinical skills, and (3) attitudes toward PGx. Instructors were blinded to PGET assignment. The Wilcoxon Rank Sum test was used to compare pre-survey and post-survey PGx knowledge, comfort, and attitudes. No differences in baseline characteristics were observed between PGET (n = 117) and NPGET (n = 116) participants. Among all participants, significant improvement was observed in PGx knowledge (mean 57% vs. 39% correct responses; p < 0.001) with similar results for student comfort and attitudes. Change in pre/post-PGx knowledge, comfort, and attitudes were not significantly different between PGET and NPGET groups (mean 19.5% vs. 16.7% knowledge improvement, respectively; p = 0.41). Similar results were observed for PGET participants carrying a highly actionable PGx variant versus PGET participants without an actionable variant. Significant improvement in Likert scale responses were observed in PGET versus NPGET for questions that assessed student engagement (p = 0.020) and reinforcement of course concepts (p = 0.006). Although some evidence of improved engagement and participation was observed, the results of this study suggest that PGET does not directly improve student PGx knowledge, comfort, and attitudes.

PMID:34431601 | DOI:10.1111/cts.13121

Ann Transl Med. 2021 Jul;9(14):1211. doi: 10.21037/atm-20-7153.

ABSTRACT

Dual antiplatelet therapy is frequently prescribed for patients undergoing carotid artery stenting (CAS), however clopidogrel resistance might cause thromboembolic complications. The role of testing for clopidogrel resistance in patients undergoing CAS is unclear. In this study, we aimed to review the periprocedural thromboembolic outcomes in clopidogrel resistant patients who underwent CAS. We conducted a review of PubMed, EMBASE, and the Cochrane Library up to October 7, 2020. Studies were included that investigated at least ten patients aged 18 years or older with a symptomatic carotid artery stenosis requiring CAS. Studies were excluded that investigated patients with a carotid artery dissection, case reports, case series of less than ten patients, reviews, commentaries, letters to the editors, and conference abstracts. The primary endpoint was the incidence of thromboembolic events. One hundred seventy-seven unique articles were identified of which three studies were included in our systematic review. The sample sizes ranged from 76 to 449 patients and the follow-up duration from 24 hours to 2 years postprocedural. Two retrospective observational studies determined clopidogrel resistance using measurement of P2Y12 reaction units, and one historical cohort study used genetic testing. Two studies concluded that clopidogrel resistance was a risk factor for thromboembolic complications, the other found higher values of P2Y12 reaction units in patients with thromboembolic events compared to those without. In conclusion, current literature supports a possible relationship between clopidogrel resistance and thromboembolic complications in patients who underwent CAS. Preprocedural testing for clopidogrel resistance might therefore be of additional value. Randomized studies using a valid, reliable clopidogrel resistance test and clinical endpoints, are however required to make a definitive statement and to determine the impact of the thromboembolic complications. This study was registered within PROSPERO (CRD42020197318).

PMID:34430652 | PMC:PMC8350701 | DOI:10.21037/atm-20-7153

Pharmgenomics Pers Med. 2021 Aug 16;14:1027-1040. doi: 10.2147/PGPM.S316711. eCollection 2021.

ABSTRACT

BACKGROUND: Genetic variation influences drug reaction or adverse prognosis. The purpose of this research was to genotype very important pharmacogenetic (VIP) variants in the Tibetan population.

METHODS AND MATERIALS: Blood samples from 200 Tibetans were randomly collected and 59 VIP variants were genotyped, and then compared our data to 26 other populations in the 1000 project to further analyze and identify significant difference.

RESULTS: The results showed that on comparing with most of the 26 populations from the 1000 project, rs4291 (ACE), rs1051296 (SLC19A1) and rs1065852 (CYP2D6) significantly differed in the Tibetan population. Furthermore, three significant loci were related to drug response. In addition, the allele frequency of Tibetans least differed from that of East Asian populations, and most differed from that of Americans.

CONCLUSION: Three significant loci of variation ACE rs4291, SLC19A1 rs1051296 and CYP2D6 rs1065852 were associated with drug response. This result will contribute to improving the information of the Tibetan in the pharmacogenomics database, and providing a theoretical basis for clinical individualised drug use in Tibetans.

PMID:34429635 | PMC:PMC8379641 | DOI:10.2147/PGPM.S316711

Pharmgenomics Pers Med. 2021 Aug 16;14:1015-1025. doi: 10.2147/PGPM.S320816. eCollection 2021.

ABSTRACT

BACKGROUND: Schizophrenia is a severe mental disorder that often manifests within the first three decades of life. Its prognosis is uncertain and may result in a prolonged treatment that could extend throughout the entire lifespan of the patient. Antipsychotic drugs are characterized by a high interindividual variability when considering therapeutic effect and emergence of adverse effects. Such interindividual variability is thought to be associated primarily with pharmacokinetic matters.

OBJECTIVE: The objective of this study was to evaluate the economic impact of the application of the 5-Step Precision Medicine model (5SPM), an approach based on the pharmacogenetic analysis of the primary genes involved in the metabolism of the therapy for each patient, restructuring treatment as necessary.

PATIENTS AND METHODS: One hundred eighty-eight psychiatry patients were analysed for single nucleotide polymorphisms on genes CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5 and ABCB1. Information on patients' diagnosis, pharmacotherapy, and hospitalizations was collected.

RESULTS: We achieved a cost-benefit ratio of 3.31-3.59 with a reduction of direct cost (hospitalizations plus pharmacotherapy) with a reduction of total cost in 67% of the patients who underwent the clinical intervention.

CONCLUSION: A rational Precision Medicine-based approach to psychiatric patients could result in a reduction on number of drugs required to control exacerbations, and the underlying pathologies, reducing the risk of adverse effects and improving adherence to treatment, leading to a potential decrease in direct costs. This methodology has been shown to be cost-dominant and, being based on a pharmacogenetic analysis, it has a lifelong nature, as the data obtained can be applied to other medical disciplines.

PMID:34429634 | PMC:PMC8379643 | DOI:10.2147/PGPM.S320816

Pharmgenomics Pers Med. 2021 Aug 14;14:997-1014. doi: 10.2147/PGPM.S322463. eCollection 2021.

ABSTRACT

BACKGROUND: Long non-coding RNAs (lncRNAs) play essential roles in molecular diagnosis and therapeutic response in several diseases.

PURPOSE: For the first time, we aimed to evaluate the association of four lncRNAs TUG1 (rs7284767G/A), MIAT (rs1061540T/C), MALAT1 (rs3200401C/T), and SENCR (rs12420823C/T) variants with susceptibility to diabetic retinopathy (DR), disease severity, and early therapeutic response to intravitreous anti-vascular endothelial growth factor aflibercept therapy.

PATIENTS AND METHODS: This case-control study enrolled 126 adult patients with type 2 diabetes. TaqMan assays using Real-Time PCR were run for genotyping. Multivariable regression analyses were applied to assess the role of each polymorphism after the adjustment of covariates.

RESULTS: Carriers of TUG1 A/G and MIAT T/C and C/C genotypes were more likely to develop DR [OR=3.15 (95% CI=1.15-8.64), and OR=4.31 (95% CI=1.78-10.47)], while MALAT1 T/C conferred protection (OR=0.40, 95% CI=0.16-0.99). For TUG1, MALAT1, MIAT, and SENCR genotype combinations, GTCT and GCCC had a higher disease risk (P=0.012). For disease severity, MIAT T/T homozygosity was associated with higher DR grade [33.3% (T/T) vs 10% (C/C) and 4.2% (C/T) carriers, P=0.012]. Otherwise, patients with the SENCR T variant exhibited better pre-treatment best-corrected visual acuity level (p=0.021). Following aflibercept administration, carrying the TUG1 A or MIAT T/C was associated with a poor therapeutic response (OR=5.02, 95% CI=1.60-15.76, and OR=10.23, 95% CI=1.51-69.15, respectively).

CONCLUSION: The lncRNAs TUG1 (rs7284767G/A) and MIAT (rs1061540T/C) were associated with increased DR susceptibility and poor response to aflibercept treatment, while MALAT1 (rs3200401C/T) conferred protection to DR. These genetic determinants could be useful in DR risk stratification and pharmacogenetics after validation in large-scale studies.

PMID:34429633 | PMC:PMC8374537 | DOI:10.2147/PGPM.S322463

Nat Commun. 2021 Aug 24;12(1):5086. doi: 10.1038/s41467-021-25177-3.

ABSTRACT

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs' recapitulation of human tumors.

PMID:34429404 | DOI:10.1038/s41467-021-25177-3

Respir Med. 2021 Aug 10;187:106573. doi: 10.1016/j.rmed.2021.106573. Online ahead of print.

ABSTRACT

BACKGROUND: Combination treatments, targeting multiple disease processes, benefit subjects with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, predicting treatment response and exacerbation risk remain challenging.

OBJECTIVE: To identify genetic associations with AECOPD risk and response to combination therapy (fluticasone furoate, umeclidinium bromide and vilanterol).

METHODS: The genetic basis of AECOPD disease was investigated in 19,841 subjects from 23 clinical studies and 2 disease cohorts to identify exacerbation disease targets. AECOPD pharmacogenetic effects were examined in 8439 moderate to severe COPD patients with exacerbation rate, lung function and quality of life endpoints; results were followed up in an additional 2201 subjects.

RESULTS: We did not identify significant associations in the AECOPD disease analysis. In the AECOPD pharmacogenetics analysis, rs56195836 (MAPK8) was significantly associated with moderate to severe exacerbation rate in subjects on fluticasone furoate with baseline blood eosinophils ≥150 cells/μl (P = 1.8 × 10-8). Post-hoc, one variant was associated with on-treatment moderate to severe exacerbation rate stratifying by exacerbation history. AZU1 rs1962343 was significantly associated in subjects with frequent moderate exacerbation history when treated with fluticasone furoate/vilanterol (P = 1.1 × 10-8). Neither of these signals was supported in independent follow-up.

CONCLUSION: Common genetic variants do not play major roles in AECOPD disease nor predict response to triple therapy or its components in moderate to very severe COPD.

PMID:34428673 | DOI:10.1016/j.rmed.2021.106573