Mech Ageing Dev. 2022 Mar 30:111670. doi: 10.1016/j.mad.2022.111670. Online ahead of print.

ABSTRACT

Huntington disease (HD) is a neurodegenerative disorder produced by an expansion of CAG repeats in the HTT gene. Patients of HD show involuntary movements, cognitive decline and psychiatric impairment. People carrying abnormally long expansions of CAGs (more than 35 CAG repeats) produce mutant huntingtin (mHtt), which encodes tracks of polyglutamines (polyQs). These polyQs make the protein prone to aggregate and cause it to acquire a toxic gain of function. Principally affecting the frontal cortex and the striatum, mHtt disrupts many cellular functions. In addition, this protein is expressed ubiquitously, and some reports show that many other cell types are affected by the toxicity of mHtt. Several studies reported that metformin, a widely-used anti-diabetic drug, is neuroprotective in models of HD. Here, we provide a review of the benefits of this substance to treat HD. Metformin is a pleiotropic drug, modulating different targets such as AMPK, insulin signalling and many others. These molecules regulate autophagy, chaperone expression, and more, which in turn reduce mHtt toxicity. Moreover, metformin alters gut microbiome and its metabolic processes. The study of potential targets, interactions between the drug, host and microbiome, or genomic and pharmacogenomic approaches may allow us to design personalised medicine to treat HD.

PMID:35367225 | DOI:10.1016/j.mad.2022.111670

J Biol Chem. 2022 Mar 30:101885. doi: 10.1016/j.jbc.2022.101885. Online ahead of print.

ABSTRACT

The constitutive androstane receptor (CAR) is a nuclear receptor that plays a crucial role in regulating xenobiotic metabolism and detoxification, energy homeostasis, and cell proliferation by modulating the transcription of numerous target genes. CAR activation has been established as the mode of action by which phenobarbital-like non-genotoxic carcinogens promote liver tumor formation in rodents. This paradigm, however, appears to be unrelated to the function of human CAR (hCAR) in hepatocellular carcinoma (HCC), which remains poorly understood. Here, we show that hCAR expression is significantly lower in HCC than that in adjacent non-tumor tissues and, importantly, reduced hCAR expression is associated with a worse HCC prognosis. We also show overexpression of hCAR in human hepatoma cells (HepG2 and Hep3B) profoundly suppressed cell proliferation, cell cycle progression, soft-agar colony formation, and the growth of xenografts in nude mice. RNA-seq analysis revealed that the expression of erythropoietin (EPO), a pleiotropic growth factor, was markedly repressed by hCAR in hepatoma cells. Addition of recombinant EPO in HepG2 cells partially rescued hCAR-suppressed cell viability. Mechanistically, we showed that overexpressing hCAR repressed mitogenic EPO-EPOR signaling through dephosphorylation of STAT3, AKT, and ERK1/2. Furthermore, we found that hCAR downregulates EPO expression by repressing the expression and activity of HNF4α, a key transcription factor regulating EPO expression. Collectively, our results suggest that hCAR plays a tumor suppressive role in HCC development which differs from that of rodent CAR and offers insight into the hCAR-HNF4α-EPO axis in human liver tumorigenesis.

PMID:35367211 | DOI:10.1016/j.jbc.2022.101885

Pharmacogenomics J. 2022 Apr 1. doi: 10.1038/s41397-022-00275-7. Online ahead of print.

ABSTRACT

We constructed a cost-effectiveness model to assess the clinical and economic value of a CDS alert program that provides pharmacogenomic (PGx) testing results, compared to no alert program in acute coronary syndrome (ACS) and atrial fibrillation (AF), from a health system perspective. We defaulted that 20% of 500,000 health-system members between the ages of 55 and 65 received PGx testing for CYP2C19 (ACS-clopidogrel) and CYP2C9, CYP4F2 and VKORC1 (AF-warfarin) annually. Clinical events, costs, and quality-adjusted life years (QALYs) were calculated over 20 years with an annual discount rate of 3%. In total, 3169 alerts would be fired. The CDS alert program would help avoid 16 major clinical events and 6 deaths for ACS; and 2 clinical events and 0.9 deaths for AF. The incremental cost-effectiveness ratio was $39,477/QALY. A PGx-CDS alert program was cost-effective, under a willingness-to-pay threshold of $100,000/QALY gained, compared to no alert program.

PMID:35365779 | DOI:10.1038/s41397-022-00275-7

Stem Cell Reports. 2022 Mar 15:S2213-6711(22)00135-7. doi: 10.1016/j.stemcr.2022.03.002. Online ahead of print.

ABSTRACT

Doxorubicin is a commonly used chemotherapeutic drug, but its use is limited by doxorubicin-induced cardiotoxicity (DIC), which can lead to irreversible heart failure and death. A missense variant rs2229774 (p.S427L) in the retinoic acid receptor gamma (RARG) gene is associated with increased susceptibility to DIC, but the precise mechanism underlying this association is incompletely understood. We performed molecular dynamic simulations to determine the effect of this variant on RARG structure and then validated these predictions using CRISPR-Cas9-genome-edited, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We found that this variant leads to reduced activation of its target genes in response to doxorubicin, including gene pathways involved in DNA repair and consequently an inability to mediate DNA repair after exposure to doxorubicin. Our findings establish a role of RARG p.S427L in attenuating DNA repair in DIC and provide insight into the pathogenesis of this cardiotoxic effect.

PMID:35364012 | DOI:10.1016/j.stemcr.2022.03.002

J Am Assoc Nurse Pract. 2022 Apr 1;34(4):613-615. doi: 10.1097/JXX.0000000000000709.

ABSTRACT

Advances in genomics research and clinical applications continue to accelerate. Coupled with the availability of direct-to-consumer (DTC) marketing of genetic testing and new discoveries, patients are increasingly coming into primary care with genomic questions. This article offers a snapshot of the kinds of questions patients are asking and that providers should be prepared to discuss such as what to do with DTC results or whether pharmacogenetics testing would help make sure "the right" medication is prescribed. Clinicians should understand the value of clinical guidelines (and where to find them), how to find a genetic specialist, what's happening with gene editing (to include gene sequencing), what's on the horizon in cancer care, and what the future might hold.

PMID:35363223 | DOI:10.1097/JXX.0000000000000709

Cancer Chemother Pharmacol. 2022 Apr 1. doi: 10.1007/s00280-022-04422-6. Online ahead of print.

ABSTRACT

Lurbinectedin is an alkylating agent approved for the second-line treatment of small cell lung cancer. Although initial studies showed no association between body surface area (BSA) and drug clearance, the recommended dose is 3.2 mg/m2 every 3 weeks. This recommendation was based on an exposure-response study, which demonstrated that patients with lower BSA had a higher incidence of thrombocytopenia. Herein we present the factors associated with BSA and thrombopoiesis, which may have contributed to the observed relationship.

PMID:35362793 | DOI:10.1007/s00280-022-04422-6

Pharmacogenomics J. 2022 Mar 31. doi: 10.1038/s41397-022-00274-8. Online ahead of print.

ABSTRACT

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

PMID:35361995 | DOI:10.1038/s41397-022-00274-8

Pharmacogenomics J. 2022 Mar 31. doi: 10.1038/s41397-022-00276-6. Online ahead of print.

ABSTRACT

United States clinical practice guidelines for metastatic colorectal cancer recommend use of medications impacted by genetic variants but do not recommend testing. We analyzed real-world treatment using a cancer registry and claims dataset to explore pharmacogenomic (PGx) medication treatment patterns and characterize exposure. In a cohort of 6957 patients, most (86.9%) were exposed to at least one chemotherapy medication with PGx guidelines. In a cohort of 2223 patients with retail pharmacy claims available, most (79.2%) were treated with at least one non-chemotherapy (79.2%) medication with PGx guidelines. PGx-associated chemotherapy exposure was associated with age, race/ethnicity, educational attainment, and rurality. PGx-associated non-chemotherapy exposure was associated with medication use and comorbidities. The potential impact of PGx testing is large and policies aimed at increasing PGx testing at diagnosis may impact treatment decisions for patients with metastatic colorectal cancer as most patients are exposed to medications with pharmacogenomics implications during treatment.

PMID:35361994 | DOI:10.1038/s41397-022-00276-6

Front Genet. 2022 Mar 14;13:878191. doi: 10.3389/fgene.2022.878191. eCollection 2022.

NO ABSTRACT

PMID:35360856 | PMC:PMC8964277 | DOI:10.3389/fgene.2022.878191

Front Pharmacol. 2022 Mar 14;13:848804. doi: 10.3389/fphar.2022.848804. eCollection 2022.

ABSTRACT

Chronic kidney disease (CKD) patients may be more susceptible to adverse drug reactions (ADRs), given their complex medication regimen and altered physiological state driven by a decline in kidney function. This study aimed to describe the relationship between CYP3A5*3 polymorphism and the ADR of antihypertensive drugs in CKD patients. This retrospective, multi-center, observational cohort study was performed among adult CKD patients with a follow-up period of up to 3 years. ADRs were detected through medical records. CYP3A5*3 genotyping was performed using the direct sequencing method. From the 200 patients recruited in this study, 33 (16.5%) were found to have ADRs related to antihypertensive drugs, with 40 ADRs reported. The most frequent ADR recorded was hyperkalemia (n = 8, 20.0%), followed by bradycardia, hypotension, and dizziness, with 6 cases (15.0%) each. The most common suspected agents were angiotensin II receptor blockers (n = 11, 27.5%), followed by angiotensin-converting enzyme inhibitors (n = 9, 22.5%). The CYP3A5*3 polymorphism was not found to be associated with antihypertensive-related ADR across the genetic models tested, despite adjustment for other possible factors through multiple logistic regression (p > 0.05). After adjusting for possible confounding factors, the factors associated with antihypertensive-related ADR were anemia (adjusted odds ratio [aOR] 5.438, 95% confidence interval [CI]: 2.002, 14.288) and poor medication adherence (aOR 3.512, 95% CI: 1.470, 8.388). In conclusion, the CYP3A5*3 polymorphism was not found to be associated with ADRs related to antihypertensives in CKD patients, which requires further verification by larger studies.

PMID:35359836 | PMC:PMC8963814 | DOI:10.3389/fphar.2022.848804

Comput Biol Med. 2022 Mar 26;145:105414. doi: 10.1016/j.compbiomed.2022.105414. Online ahead of print.

ABSTRACT

Voltage-gated sodium channel activity has long been associated with several diseases including epilepsy, chronic pain, cardiovascular diseases, cancers, immune system, neuromuscular and respiratory disorders. The strong participation of these channels in the development of diseases makes them excellent promising therapeutic targets. Voltage-gated Na+ channel blocking peptides come from a wide source of organisms such as venoms. However, the in vitro and in vivo identification and validation of these peptides are time-consuming and resource-intensive. In this work, we developed a bioinformatics tool called PEP-PREDNa + for the highly specific prediction of voltage-gated Na+ channel blocking peptides. PEP-PREDNa+ is based on the random forest algorithm, which presented excellent performance measures during the cross-validation (sensitivity = 0.81, accuracy = 0.83, precision = 0.85, F-score = 0.83, specificity = 0.86, and Matthew's correlation coefficient = 0.67) and testing (sensitivity = 0.88, accuracy = 0.92, precision = 0.96, F-score = 0.91, specificity = 0.96, and Matthew's correlation coefficient = 0.84) phases. The PEP-PREDNa + tool could be very useful in accelerating and reducing the costs of the discovery of new voltage-gated Na+ channel blocking peptides with therapeutic potential.

PMID:35358751 | DOI:10.1016/j.compbiomed.2022.105414

Pharmgenomics Pers Med. 2022 Mar 22;15:249-260. doi: 10.2147/PGPM.S352719. eCollection 2022.

ABSTRACT

PURPOSE: Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes.

PATIENTS AND METHODS: Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects.

RESULTS: Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0-18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17×10-9) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54×10-8). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3×10-5), but not with rs116702638.

CONCLUSION: A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.

PMID:35356681 | PMC:PMC8958266 | DOI:10.2147/PGPM.S352719

Front Genet. 2022 Mar 9;13:820878. doi: 10.3389/fgene.2022.820878. eCollection 2022.

ABSTRACT

The female carriers of BRCA1/2 pathogenic variants (mutations) face a high lifetime risk of developing breast and/or ovarian cancer. However, the risk may differ depending on various genetic and non-genetic elements, including metabolic and hormonal factors. We previously showed that a 6-month Mediterranean dietary intervention trial reduced body weight and the levels of insulin-like growth factor I and other metabolic factors in BRCA mutation carriers. We also found that higher baseline levels of glucose and insulin were significantly associated with BRCA loss-of-function (LOF) variants. In this study, we evaluated whether the BRCA mutation type influences in a different way the metabolic and hormonal response to the dietary intervention in 366 female carriers. The LOF variant carriers randomized in the intervention group (IG) showed significantly higher changes in most considered parameters compared to the control group (CG). The nonsynonymous variant carriers in the IG showed similar changes, but none of them were statistically significant. Performing the "delta" analysis of differences (intention-to-treat analysis), we observed that in LOF variant carriers, the reduction of insulin levels was significantly more pronounced that in nonsynonymous variant carriers. These findings suggest that the changes in insulin levels might be modulated by a different response to the dietary intervention mediated by BRCA LOF variants.

PMID:35356420 | PMC:PMC8959623 | DOI:10.3389/fgene.2022.820878

Pharmacogenomics J. 2022 Mar 30. doi: 10.1038/s41397-022-00273-9. Online ahead of print.

NO ABSTRACT

PMID:35354950 | DOI:10.1038/s41397-022-00273-9

Yonsei Med J. 2022 Apr;63(4):342-348. doi: 10.3349/ymj.2022.63.4.342.

ABSTRACT

PURPOSE: Angiotensin-converting enzyme inhibitors (ACEIs) are medications generally prescribed for patients with high cardiovascular risk; however, they are suboptimally used due to frequent adverse events (AEs). The present study aimed to identify and replicate the genetic variants associated with ACEI-related AEs in the Korean population.

MATERIALS AND METHODS: A two-stage approach employing genome-wide association study (GWAS)-based discovery and replication through target sequencing was used. In total, 1300 individuals received ACEIs from 2001 to 2007; among these, 228 were selected for GWAS. An additional 336 patients were selected for replication after screening 1186 subjects treated from 2008 to 2018. Candidate genes for target sequencing were selected based on the present GWAS, previous GWASs, and data from the PharmGKB database. Furthermore, association analyses were performed between no AE and AE or cough groups after target sequencing.

RESULTS: Five genes, namely CRIM1, NELL1, CACNA1D, VOPP1, and MYBPC1, were identified near variants associated with ACEI-related AEs. During target sequencing of 34 candidate genes, six single-nucleotide polymorphisms (SNPs; rs5224, rs8176786, rs10766756, rs561868018, rs4974539, and rs10946364) were replicated for association with all ACEI-related AEs. Four of these SNPs and rs147912715 exhibited associations with ACEI-related cough, whereas four SNPs (rs5224, rs81767786, rs10766756, and rs4974539 near BDKRB2, NELL1, NELL1 intron, and CPN2, respectively) were significantly associated with both categories of AEs.

CONCLUSION: Several variants, including novel and known variants, were successfully replicated and found to have associations with ACEI-related AEs. These results provide rare and clinically relevant information for safer use of ACEIs.

PMID:35352885 | DOI:10.3349/ymj.2022.63.4.342

CNS Drugs. 2022 Mar 30. doi: 10.1007/s40263-022-00915-3. Online ahead of print.

ABSTRACT

The development of Alzheimer's disease therapeutics has been challenging, with 99% of clinical trials failing to find a significant difference between drug and placebo. While the quest continues for more effective treatments, there is emerging evidence that pharmacogenetic considerations are important factors in regard to metabolism, efficacy, and toxicity of drugs. Currently, there are five US Food and Drug Administration-approved drugs for the treatment of Alzheimer's disease; three acetylcholinesterase inhibitors, memantine, and aducanumab. Introducing a limited genetic panel consisting of APOE4, CYP2D6*10, and BChE*K would optimize acetylcholinesterase inhibitor therapy, facilitate immunotherapy risk assessment, and inform an amyloid-related imaging abnormality surveillance schedule. In view of the genetic heterogeneity of Alzheimer's disease identified in genome-wide association studies, pharmacogenetics is expected to play an increasing role in mechanism-specific treatment strategies and personalized medicine.

PMID:35352296 | DOI:10.1007/s40263-022-00915-3

BMJ. 2022 Mar 29;376:o821. doi: 10.1136/bmj.o821.

NO ABSTRACT

PMID:35351804 | DOI:10.1136/bmj.o821

Expert Rev Neurother. 2022 Mar 30. doi: 10.1080/14737175.2022.2057223. Online ahead of print.

ABSTRACT

INTRODUCTION: Myasthenia gravis (MG) is an antibody-mediated disease that develops in the majority of patients mainly as a result of acetylcholine receptor (AChR) autoantibodies. This process is mediated by a series of immunoregulatory events. Therapeutic targets for MG include suppression of circulating antibodies or antibody production, suppression of complement activation, and immunomodulation of cytokines or T cells. Intravenous immunoglobulin (IVIg) has an effect on all of these mechanisms.

AREAS COVERED: This narrative review explores the broad immunomodulatory effects of IVIg in MG and provides an update on IVIg treatment for MG.

EXPERT OPINION: IVIg has a range of immunomodulatory effects on therapeutic targets relevant to the immunopathogenesis of MG. An emerging area of research is the pharmacogenomics of IVIg in MG related to FcRn and IgG catabolism. New data indicate that the FcRn VNTR3 genotype can affect the efficacy of IVIg in certain MG patients and may have an impact on IgG kinetics and selected dosing. Immune globulin 10% caprylate/chromatography purified (IVIg-C) has been shown to reverse the symptoms of severe acute exacerbation in patients with MG. Available data support the use of IVIg-C as an effective and safe treatment for this severely ill subgroup of patients during a relapse.

PMID:35350948 | DOI:10.1080/14737175.2022.2057223

Gynecol Obstet Invest. 2022 Mar 29. doi: 10.1159/000524265. Online ahead of print.

ABSTRACT

none.

PMID:35350015 | DOI:10.1159/000524265

J Endocrinol Invest. 2022 Mar 29. doi: 10.1007/s40618-022-01778-7. Online ahead of print.

ABSTRACT

PURPOSE: The current clinical practice in reproductive medicine should pose the couple at the centre of the diagnostic-therapeutic management of infertility and requires intense collaboration between the andrologist, the gynaecologist and the embryologist. The andrologist, in particular, to adequately support the infertile couple, must undertake important biological, psychological, economical and ethical task. Thus, this paper aims to provide a comprehensive overview of the multifaceted role of the andrologist in the study of male factor infertility.

METHODS: A comprehensive Medline, Embase and Cochrane search was performed including publications between 1969 and 2021.

RESULTS: Available evidence indicates that a careful medical history and physical examination, followed by semen analysis, always represent the basic starting points of the diagnostic work up in male partner of an infertile couple. Regarding treatment, gonadotropins are an effective treatment in case of hypogonadotropic hypogonadism and FSH may be used in men with idiopathic infertility, while evidence supporting other hormonal and nonhormonal treatments is either limited or conflicting. In the future, pharmacogenomics of FSHR and FSHB as well as innovative compounds may be considered to develop new therapeutic strategies in the management of infertility.

CONCLUSION: To provide a high-level of care, the andrologist must face several critical diagnostical and therapeutical steps. Even though ART may be the final and decisive stage of this decisional network, neglecting to treat the male partner may ultimately increase the risks of negative outcome, as well as costs and psychological burden for the couple itself.

PMID:35349114 | DOI:10.1007/s40618-022-01778-7