Nucleic Acids Res. 2022 Apr 26:gkac289. doi: 10.1093/nar/gkac289. Online ahead of print.

ABSTRACT

Establishing the relationship between protein-coding genes and phenotypes has the potential to inform on the molecular etiology of diseases. Here, we describe ExPheWas (exphewas.ca), a gene-based phenome-wide association study browser and platform that enables the conduct of gene-based Mendelian randomization. The ExPheWas data repository includes sex-stratified and sex-combined gene-based association results from 26 616 genes with 1746 phenotypes measured in up to 413 133 individuals from the UK Biobank. Interactive visualizations are provided through a browser to facilitate data exploration supported by false discovery rate control, and it includes tools for enrichment analysis. The interactive Mendelian randomization module in ExPheWas allows the estimation of causal effects of a genetically predicted exposure on an outcome by using genetic variation in a single gene as the instrumental variable.

PMID:35474380 | DOI:10.1093/nar/gkac289

Nat Genet. 2022 Apr 26. doi: 10.1038/s41588-022-01079-y. Online ahead of print.

NO ABSTRACT

PMID:35474365 | DOI:10.1038/s41588-022-01079-y

Sci Rep. 2022 Apr 26;12(1):6793. doi: 10.1038/s41598-022-11273-x.

NO ABSTRACT

PMID:35474346 | DOI:10.1038/s41598-022-11273-x

Nord J Psychiatry. 2022 Apr 26:1-4. doi: 10.1080/08039488.2022.2065531. Online ahead of print.

ABSTRACT

BACKGROUND: Diazepam is one of the most commonly prescribed pharmaceuticals for the treatment of alcohol withdrawal syndrome (AWS). However, diazepam sometimes is ineffective, and some patients experience dose-dependent adverse drug reactions (ADR). Previous studies have shown that diazepam metabolism involves the CYP3A4 and CYP3A5 isoenzymes, whose activity is highly variable between individuals, which may contribute to differences in clinical response.

PURPOSE: The study aimed to investigate the effects of the genetic polymorphisms CYP3A4*22 and CYP3A5*3 on the efficacy and safety of diazepam in patients with AWS.

MATERIALS AND METHODS: One hundred male AWS patients received 30 mg/day diazepam by intramuscular injections for 5 days. Genotyping for CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) was performed by real-time polymerase chain reaction with allele-specific hybridization. The efficacy and safety assessments were performed using psychometric scales.

RESULTS: Patients who carry CT and TT genotypes by polymorphic marker C > T intron 6 (rs35599367) of the CYP3A4 gene had a higher risk for ADR and demonstrated lower safety of diazepam therapy (p < 0.001; two-way ANOVA).

CONCLUSION: These results suggest that genotyping for common CYP3A variants might have the potential to guide benzodiazepine withdrawal treatment.

PMID:35471917 | DOI:10.1080/08039488.2022.2065531

Pharmacogenomics. 2022 Apr 26. doi: 10.2217/pgs-2022-0015. Online ahead of print.

ABSTRACT

Objective: To assess whether the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) might be influenced by haem oxygenase-1 (HMOX1) and haemopexin (HPX) gene polymorphisms. Methods: A dynamic anti-tuberculosis treatment cohort was constructed, and the 1:4 matched nested case-control study was analysed. Eight single nucleotide polymorphisms (SNPs) of the two genes were selected for genotyping and Bonferroni correction was performed to correct for multiple comparison. Results: Overall, 7.8% of patients developed ATDH. SNP rs1807714 in the HMOX1 gene had decreased effects on the risk of moderate and severe hepatotoxicity under the dominant and additive models, and hepatocellular injury under the additive model. SNP rs2682099 in the HPX gene had increased effects on the risk of moderate and severe hepatotoxicity under the recessive model. However, these associations disappeared after Bonferroni correction. Conclusion: HMOX1 and HPX gene polymorphisms might not be associated with susceptibility to ATDH in the Chinese population.

PMID:35470713 | DOI:10.2217/pgs-2022-0015

Immunol Allergy Clin North Am. 2022 May;42(2):335-355. doi: 10.1016/j.iac.2022.01.006. Epub 2022 Mar 31.

ABSTRACT

Hypersensitivity reactions are caused by many structurally unrelated drugs used for many different diseases. These reactions vary in severity and can be fatal. Only a minority of patients are affected by drug hypersensitivity reactions. Predisposition seems to be mediated by genetic factors, particularly within the HLA system. Apart from HLA-B∗57:01 testing, which is routine to prevent abacavir hypersensitivity, uptake of HLA testing into clinical practice has been slow and challenging. As genomic medicine becomes mainstream, it will be important for genetic testing in this area to move from the current reactive strategy to a more pre-emptive approach.

PMID:35469622 | DOI:10.1016/j.iac.2022.01.006

Pharmacogenomics. 2022 Apr 26. doi: 10.2217/pgs-2022-0013. Online ahead of print.

ABSTRACT

Aim: To assess the perspectives and experiences of patients who participated in a pharmacist-provided clinical pharmacogenomics (PGx) service. Methods: We conducted individual semistructured interviews with 16 patients who received a pharmacist-provided PGx service. Qualitative data were analyzed to identify pertinent themes. Results: The major themes identified were: heterogeneity of patient PGx experiences and preferences, pharmacists as appropriate providers of PGx services, considerations regarding the use of PGx results in routine healthcare, and perceived applications of PGx testing. Theme-derived considerations included the need to establish appropriate pre-genotyping expectations, individualize patient education, facilitate collaboration with patients' providers and sustainably update patients' PGx information over time. Conclusion: Patient-specific perspectives such as these are important to consider when providing clinical PGx services, with intention of optimizing patient experiences.

PMID:35469451 | DOI:10.2217/pgs-2022-0013

Pharmacogenomics. 2022 Apr 26. doi: 10.2217/pgs-2022-0017. Online ahead of print.

ABSTRACT

Aim: To carry out a case-control study of the association of GST gene polymorphisms in pediatric asthma-related oxidative stress. Materials & methods: Asthma patients (n = 250) and age-matched healthy subjects (n = 250) DNA were genotyped for GSTM1/GSTT1 (+/+, +/-, -/+ and -/-) frequencies using multiplex-PCR and plasma oxidative stress markers (examined spectrophotometrically). Results: Asthma patients had significantly more common null-genotype GSTM1-/GSTT1- (10.4%; p = 0.002) and elevated levels of malondialdehyde, protein carbonyl and 8-hydroxy-2-deoxyguanosine as compared with controls. In addition, the level of plasma glutathione, GST activity and ferric-reducing ability were significantly decreased as compared with controls. Conclusion: Our data revealed significant associations between GSTM1-/GSTT1- genotype and oxidative stress markers in asthmatic children, which may very likely contribute to increased incidence of bronchial asthma.

PMID:35469450 | DOI:10.2217/pgs-2022-0017

NPJ Precis Oncol. 2022 Apr 25;6(1):29. doi: 10.1038/s41698-022-00271-x.

ABSTRACT

Leiomyosarcoma (LMS) is a rare, aggressive, mesenchymal tumor. Subsets of LMS have been identified to harbor genomic alterations associated with homologous recombination deficiency (HRD); particularly alterations in BRCA2. Whereas genomic loss of heterozygosity (gLOH) has been used as a surrogate marker of HRD in other solid tumors, the prognostic or clinical value of gLOH in LMS (gLOH-LMS) remains poorly defined. We explore the genomic drivers associated with gLOH-LMS and their clinical import. Although the distribution of gLOH-LMS scores are similar to that of carcinomas, outside of BRCA2, there was no overlap with previously published gLOH-associated genes from studies in carcinomas. We note that early stage tumors with elevated gLOH demonstrated a longer disease-free interval following resection in LMS patients. Taken together, and despite similarities to carcinomas in gLOH distribution and clinical import, gLOH-LMS are driven by different genomic signals. Additional studies will be required to isolate and confirm the unique differences in biological factors driving these differences.

PMID:35468996 | DOI:10.1038/s41698-022-00271-x

BMC Res Notes. 2022 Apr 25;15(1):148. doi: 10.1186/s13104-021-05821-3.

ABSTRACT

OBJECTIVE: The nucleoside diphosphate linked moiety X (Nudix)-Type motif 15 (NUDT15) enzyme is involved in thiopurine metabolism. Genetic variants in the NUDT15 gene result in decreased NUDT15 activity, which in addition to decreased thiopurine S-methyltransferase (TPMT) activity, contributes to thiopurine toxicity. Current standard approaches of NUDT15 genetic analysis have mainly been targeting several common variants. We aimed to develop a clinical-grade DNA-based assay for genetic analysis of the NUDT15 gene using Sanger di-deoxy sequencing.

RESULTS: Sanger sequencing results were fully concordant with the expected NUDT15 genotype in all 17 cell line samples with known NUDT15 variants (accuracy = 100%; 95% CI 80.49 to 100.00%). Precision studies showed 100% intra-run repeatability and 100% inter-run reproducibility, respectively. Genetic analysis of the NUDT15 gene was performed for 80 patients of Asian ethnicity with wildtype TPMT. 76% (N = 61) of the studied individuals had NUDT15 *1/*1 diplotype. 25% (N = 14) of Chinese and 36% (N = 5) of Malays were found to carry at least 1 non-functional NUDT15 allele. Our study confirmed a high frequency of NUDT15 c.415C>T and c.55_56insGAGTCG variants in the Chinese and Malay ethnic groups in Singapore, highlighting the importance of determining NUDT15 genotype prior to thiopurine dosing.

PMID:35468862 | DOI:10.1186/s13104-021-05821-3

J Pediatr Hematol Oncol Nurs. 2022 May-Jun;39(3):168-177. doi: 10.1177/10434542211055999.

ABSTRACT

Background: Pharmacogenetic (PGx) testing, a component of personalized medicine, aims to ensure treatment efficacy while reducing side effects and symptoms. Before this testing becomes routine in the pediatric oncology population, nurses need to understand the knowledge and concerns of providers, patients, and family members with regard to the timing, extent, interpretation, and incorporation of PGx testing. Methods: As part of a comprehensive PGx study (larger study) for children diagnosed with cancer, we surveyed providers and caregivers of children with cancer about their knowledge of and comfort with PGx testing. Caregivers who declined to participate in the larger PGx study were also asked to participate in the survey. Chi-square tests and a two-sample t-test were used to compare variables. Results: One hundred and two participants from the larger PGx study and 12 families who refused (response rate of 77% and 54%, respectively) as well as 29 providers (88%) completed surveys. Families not on the study were less interested in and comfortable with PGx results. Both groups were concerned about health or life insurance discrimination and payment. Providers would like support in ordering PGx testing and interpreting PGx. Discussion: Providers remain wary of most PGx testing, uncomfortable with interpreting and applying the results. Families are interested in the possibilities of personalized prescribing while worried about who has access to their child's genetic information. Further education on relevant tests for providers, including nurses, and the testing process for families, including details on privacy and sharing of genetic information, appear necessary.

PMID:35467433 | DOI:10.1177/10434542211055999

Antimicrob Agents Chemother. 2022 Apr 25:e0219121. doi: 10.1128/aac.02191-21. Online ahead of print.

ABSTRACT

Vancomycin dosing used in neonates results frequently in insufficient concentrations. A vancomycin dose-optimization protocol consisting of an individualization of loading and maintenance doses (administered during continuous infusion) through a previously validated pharmacokinetic model was implemented in our center. This monocenter retrospective study aimed to compare vancomycin average concentration (Cavg) in the therapeutic range (15 to 25 mg/L) and biological and clinical parameters before and after implementation of this protocol. A total of 60 and 59 courses of vancomycin treatment in 45 and 49 patients were analyzed in groups before and after implementation, respectively. Initial vancomycin Cavg were more frequently in the therapeutic range in the group after implementation (74.6% versus 28.3%, P < 0.001), with 1.6-fold higher Cavg (20.3 [17.0-22.2] mg/L versus 12.9 [11.3-17.0] mg/L, P < 0.001). Considering all Cavg during longitudinal therapeutic drug monitoring (TDM), the frequency of therapeutic Cavg was higher in the group after implementation (74.8% [n = 103] versus 31% [n = 116], P < 0.001). The dose optimization protocol was also associated with a reduced time to obtain a negative blood culture (P < 0.001) and fewer antibiotic switches (P = 0.025), without increasing the frequency of nephrotoxicity. Clinical outcomes also appeared to be improved, with less periventricular leukomalacia (P = 0.021), trended toward less respiratory instability (P = 0.15) and a shorter duration of vasoactive drug use (P = 0.18) for neonates receiving personalized doses of vancomycin. This personalized vancomycin dose protocol improves vancomycin exposure in neonates, with good safety, and suggests an improvement in biological and clinical outcomes.

PMID:35465728 | DOI:10.1128/aac.02191-21

Hypertension. 2022 Apr 25:101161HYPERTENSIONAHA12217982. doi: 10.1161/HYPERTENSIONAHA.122.17982. Online ahead of print.

ABSTRACT

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising. NAFLD/nonalcoholic steatohepatitis (NASH) is associated not only with hepatic morbidity and mortality but also with an increased cardiovascular risk. NAFLD and cardiovascular disease (CVD) share several risk factors, such as obesity, metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease. This review summarizes the evidence linking cardiometabolic risk factors and NAFLD in the context of risk for CVD. The cause of NAFLD/NASH is complex, involving a range of factors from genetics to lifestyle and energy balance. Genetically driven high liver fat content does not appear to be causally associated with increased CVD risk. In contrast, metabolic dysfunction not only predisposes to liver pathology but also leads to a significantly higher CVD risk. Given that NAFLD pathophysiology is influenced by multiple factors, each patient is unique as to their risk of developing CVD and liver pathology. At the same time, the rising burden of NAFLD/NASH is closely linked with the global increase in metabolic disorders, including obesity and type 2 diabetes. Therefore, both personalized therapeutic approaches that recognize individual pathophysiology, as well as public health policies that address the root causes of cardiometabolic risk factors for NAFLD may be needed to effectively address the NAFLD/NASH epidemic.

PMID:35465684 | DOI:10.1161/HYPERTENSIONAHA.122.17982

Front Pharmacol. 2022 Apr 6;13:876392. doi: 10.3389/fphar.2022.876392. eCollection 2022.

ABSTRACT

The latest consensus has changed CYP2D6 genotyping among Chinese population, while its impact on metoprolol tolerance and adverse events in elderly Chinese patients with cardiovascular diseases remains unclear. In this study, we prospectively included elderly patients who started metoprolol treatment for cardiovascular indications. According to the latest consensus on CYP2D6 genotype-to-phenotype translation, the patients were categorized as normal, intermediate, or poor metabolizers (NMs, IMs, or PMs, respectively) by detecting the presence of the CYP2D6*1, *2, *5, *10, and *14. Logistic regression model was used to analyze the correlation between the CYP2D6 phenotype and incidence of adverse events, which were assessed over a 12-week period. In this study, there were 651 (62.7%) NMs, 385 (37.1%) IMs, and 3 (0.3%) PMs. After 12 weeks of follow-up, compared with NMs, IMs had the lower maintenance dose [50.0 (25.0-50.0) mg/day vs. 25.0 (25.0-50.0) mg/day, p < 0.001] and lower weight-adjusted maintenance doses (0.52 ± 0.25 mg/day/kg vs. 0.42 ± 0.22 mg/day/kg, p < 0.001), and had higher incidence of postural hypotension (6.0% vs. 10.9%, p = 0.006), bradycardia (21.5% vs. 28.6%, p = 0.011), asystole (0.8% vs. 3.1%, p = 0.009) and syncope (2.0% vs. 6.2%, p = 0.001). In logistic regression model, the overall incidence of adverse events was 1.37-fold larger in IMs than in NMs (odds ratio = 1.37, 95% confidence interval = 1.05-1.79, p = 0.021). We conclude that IMs have lower tolerance and higher incidence of metoprolol-related adverse events than NMs in elderly Chinese patients with cardiovascular diseases. CYP2D6 genotyping is justifiable in elderly patients to minimize the risk of adverse events and ensure the benefits of metoprolol.

PMID:35462926 | PMC:PMC9019718 | DOI:10.3389/fphar.2022.876392

Pharmacogenomics J. 2022 Apr 23. doi: 10.1038/s41397-022-00271-x. Online ahead of print.

ABSTRACT

One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.

PMID:35461379 | DOI:10.1038/s41397-022-00271-x

Cell Death Dis. 2022 Apr 22;13(4):398. doi: 10.1038/s41419-022-04741-9.

ABSTRACT

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma.

PMID:35459212 | DOI:10.1038/s41419-022-04741-9

Int J Mol Sci. 2022 Apr 14;23(8):4280. doi: 10.3390/ijms23084280.

ABSTRACT

Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type of cancer associated with a huge death rate. This high mortality is mainly a consequence of the development of drug resistance, which is one of the major challenges to overcome in breast cancer treatment. As a result, research has been focused on finding novel therapeutical weapons, specifically ones that allow for a personalized treatment, based on patients' characteristics. Although the scientific community has been concerned about guaranteeing the quality of life of cancer patients, researchers are also aware of the increasing costs related to cancer treatment, and efforts have been made to find alternatives to the development of new drugs. The development of new drugs presents some disadvantages as it is a multistep process that is time- and money-consuming, involving clinical trials that commonly fail in the initial phases. A strategy to overcome these disadvantages is drug repurposing. In this review, we focused on describing potential repurposed drugs in the therapy of breast cancer, considering their pharmacogenomic profile, to assess the relationship between patients' genetic variations and their response to a certain therapy. This review supports the need for the development of further fundamental studies in this area, in order to investigate and expand the knowledge of the currently used and novel potential drugs to treat breast cancer. Future clinical trials should focus on developing strategies to group cancer patients according to their clinical and biological similarities and to discover new potential targets, to enable cancer therapy to be more effective and personalized.

PMID:35457144 | DOI:10.3390/ijms23084280

Pharmaceutics. 2022 Apr 17;14(4):878. doi: 10.3390/pharmaceutics14040878.

ABSTRACT

Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic review was performed to evaluate the influence of SLC and ABC polymorphisms and their combinations on efficacy and safety in AML cohorts. Anthracycline intake was especially influenced by SLCO1B1 polymorphisms, associated with lower hepatic uptake, showing higher survival rates and toxicity in AML studies. The variant alleles of ABCB1 were related to anthracycline intracellular accumulation, increasing complete remission, survival and toxicity. Similar findings have been suggested with ABCC1 and ABCG2 polymorphisms. Polymorphisms of SLC29A1, responsible for cytarabine uptake, demonstrated significant associations with survival and response in Asian populations. Promising results were observed with SLC and ABC combinations regarding anthracycline toxicities. Knowledge of the role of transporter pharmacogenetics could explain the differences observed in drug disposition in the blast. Further studies including novel targeted therapies should be performed to determine the influence of genetic variability to individualize chemotherapy schemes.

PMID:35456712 | DOI:10.3390/pharmaceutics14040878

Pharmaceutics. 2022 Apr 2;14(4):776. doi: 10.3390/pharmaceutics14040776.

ABSTRACT

Osteoporosis is a skeletal disorder defined by a decreased bone mineral density (BMD) and an increased susceptibility to fractures. Bisphosphonates and selective oestrogen receptor modulators (SERM) are among the most widely used drugs. They inhibit bone resorption by targeting the mevalonate and oestrogen pathways, respectively. The aim of this study was to determine if common variants of genes in those pathways influence drug responses. We studied 192 women treated with oral aminobisphosphonates and 51 with SERMs. Genotypes at 154 SNPs of the mevalonate pathway and 806 in the oestrogen pathway were analyzed. Several SNPs located in genes FDPS and FNTA were associated with the bisphosphonate-induced changes in hip bone mineral density (BMD), whereas polymorphisms of the PDSS1, CYP19A1, CYP1A1, and CYP1A2 genes were associated with SERM-induced changes in spine BMD. After multivariate analyses, genotypes combining genes FDPS and FNTA showed a stronger association with bisphosphonate response (r = 0.34; p = 0.00009), whereas the combination of CYP19A1 and PDSS1 genotypes was associated with the response to SERMs (r = 0.62, p = 0.0003). These results suggest that genotyping genes in these pathways may help predict the response to antiresorptive drugs and hence make personalized therapeutic choices.

PMID:35456610 | DOI:10.3390/pharmaceutics14040776

Genes (Basel). 2022 Mar 28;13(4):599. doi: 10.3390/genes13040599.

ABSTRACT

Personalized medicine, an approach to care in which individual characteristics are used for targeting interventions and maximizing health outcomes, is rapidly becoming a reality for many diseases. Childhood asthma is a heterogeneous disease and many children have uncontrolled symptoms. Therefore, an individualized approach is needed for improving asthma outcomes in children. The rapidly evolving fields of genomics and pharmacogenomics may provide a way to achieve asthma control and reduce future risks in children with asthma. In particular, pharmacogenomics can provide tools for identifying novel molecular mechanisms and biomarkers to guide treatment. Emergent high-throughput technologies, along with patient pheno-endotypization, will increase our knowledge of several molecular mechanisms involved in asthma pathophysiology and contribute to selecting and stratifying appropriate treatment for each patient.

PMID:35456405 | DOI:10.3390/genes13040599