JAMA Netw Open. 2022 Feb 1;5(2):e2148172. doi: 10.1001/jamanetworkopen.2021.48172.

ABSTRACT

IMPORTANCE: The Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) demonstrated the efficacy of icosapent ethyl (IPE) for high-risk patients with hypertriglyceridemia and known cardiovascular disease or diabetes and at least 1 other risk factor who were treated with statins.

OBJECTIVE: To estimate the cost-effectiveness of IPE compared with standard care for high-risk patients with hypertriglyceridemia despite statin treatment.

DESIGN, SETTING, AND PARTICIPANTS: An in-trial cost-effectiveness analysis was performed using patient-level study data from REDUCE-IT, and a lifetime analysis was performed using a microsimulation model and data from published literature. The study included 8179 patients with hypertriglyceridemia despite stable statin therapy recruited between November 21, 2011, and May 31, 2018. Analyses were performed from a US health care sector perspective. Statistical analysis was performed from March 1, 2018, to October 31, 2021.

INTERVENTIONS: Patients were randomly assigned to IPE, 4 g/d, or placebo and were followed up for a median of 4.9 years (IQR, 3.5-5.3 years). The cost of IPE was $4.16 per day after rebates using SSR Health net cost (SSR cost) and $9.28 per day with wholesale acquisition cost (WAC).

MAIN OUTCOMES AND MEASURES: Main outcomes were incremental quality-adjusted life-years (QALYs), total direct health care costs (2019 US dollars), and cost-effectiveness.

RESULTS: A total of 4089 patients (2927 men [71.6%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive IPE, and 4090 patients (2895 men [70.8%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive standard care. Treatment with IPE yielded more QALYs than standard care both in trial (3.34 vs 3.27; mean difference, 0.07 [95% CI, 0.01-0.12]) and over a lifetime projection (10.59 vs 10.35; mean difference, 0.24 [95% CI, 0.15-0.33]). In-trial, total health care costs were higher with IPE using either SSR cost ($18 786) or WAC ($24 544) than with standard care ($17 273; mean difference from SSR cost, $1513 [95% CI, $155-$2870]; mean difference from WAC, $7271 [95% CI, $5911-$8630]). Icosapent ethyl cost $22 311 per QALY gained using SSR cost and $107 218 per QALY gained using WAC. Over a lifetime, IPE was projected to be cost saving when using SSR cost ($195 276) compared with standard care ($197 064; mean difference, -$1788 [95% CI, -$9735 to $6159]) but to have higher costs when using WAC ($202 830) compared with standard care (mean difference, $5766 [95% CI, $1094-$10 438]). Compared with standard care, IPE had a 58.4% lifetime probability of costing less and being more effective when using SSR cost and an 89.4% probability of costing less than $50 000 per QALY gained when using SSR cost and a 72.5% probability of costing less than $50 000 per QALY gained when using WAC.

CONCLUSIONS AND RELEVANCE: This study suggests that, both in-trial and over the lifetime, IPE offers better cardiovascular outcomes than standard care in REDUCE-IT participants at common willingness-to-pay thresholds.

PMID:35157055 | PMC:PMC8844997 | DOI:10.1001/jamanetworkopen.2021.48172

Asian J Psychiatr. 2022 Feb 9;70:103018. doi: 10.1016/j.ajp.2022.103018. Online ahead of print.

ABSTRACT

OBJECTIVES: Early-onset Bipolar disorder (EOBD), has a more malignant course with high recurrence risk and there is a need for population-specific pharmaco-genomic study.

METHODS: This study is a prospective and retrospective observational study. Both newly diagnosed patients and those on follow-up with a diagnosis of bipolar I disorder with onset before 18 years of age and on lithium prophylaxis as part of treatment-as-usual were recruited for the study. Response to treatment was assessed at the end of two years follow up using ALDA scale. Ten single nucleotide polymorphisms associated with treatment response based on previous studies were chosen for analysis.

RESULTS: Of 162 who had EOBD, sixty-four fulfilled inclusion criteria and fifty-seven completed the study. TT and TG genotypes of rs75222709 on AL157359.3 gene were found to be significantly different between non-responders(N = 43) and healthy controls (N = 220). The frequency of the GA genotype of the single nucleotide polymorphism rs17204573 of the RORA (Retinoic Acid related orphan receptor alpha) gene was significantly lower among subjects (27.3%, N = 54) as compared to controls (42.9%, OR:0.5, CI: 0.26-0.96, p value 0.035). However, the significance of both disappeared after Bonferroni correction. Among clinical factors female gender was significantly associated with lithium non-response.

CONCLUSION: Although conducting pharmaco-genomic studies with large sample size is a challenge for low and middle-income countries, future studies can help improve the long-term outcome of youth with EOBD.

PMID:35158158 | DOI:10.1016/j.ajp.2022.103018

J Am Geriatr Soc. 2022 Feb 14. doi: 10.1111/jgs.17679. Online ahead of print.

NO ABSTRACT

PMID:35157308 | DOI:10.1111/jgs.17679

J Am Heart Assoc. 2022 Feb 12:e024159. doi: 10.1161/JAHA.121.024159. Online ahead of print.

ABSTRACT

Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.

PMID:35156424 | DOI:10.1161/JAHA.121.024159

Biomed Res Int. 2022 Feb 2;2022:1375892. doi: 10.1155/2022/1375892. eCollection 2022.

ABSTRACT

Diabetes is a metabolic disease with multifactorial causes which requires lifelong drug therapy as well as lifestyle changes. There is now growing scientific evidence to support the effectiveness of the use of herbal supplements in the prevention and control of diabetes. Curcumin is one of the most studied bioactive components of traditional medicine, but its physicochemical characteristics are represented by low solubility, poor absorption, and low efficacy. Nanotechnology-based pharmaceutical formulations can help overcome the problems of reduced bioavailability of curcumin and increase its antidiabetic effects. The objectives of this review were to review the effects of nanocurcumin on DM and to search for databases such as PubMed/MEDLINE and ScienceDirect. The results showed that the antidiabetic activity of nanocurcumin is due to complex pharmacological mechanisms by reducing the characteristic hyperglycemia of DM. In light of these results, nanocurcumin may be considered as potential agent in the pharmacotherapeutic management of patients with diabetes.

PMID:35155670 | PMC:PMC8828342 | DOI:10.1155/2022/1375892

Oxid Med Cell Longev. 2022 Feb 4;2022:6025900. doi: 10.1155/2022/6025900. eCollection 2022.

ABSTRACT

The use of phytochemicals is gaining interest for the treatment of metabolic syndromes over the synthetic formulation of drugs. Senna is evolving as one of the important plants which have been vastly studied for its beneficial effects. Various parts of Senna species including the root, stem, leaves, and flower are found rich in numerous phytochemicals. In vitro, in vivo, and clinical experiments established that extracts from Senna plants have diverse beneficial effects by acting as a strong antioxidant and antimicrobial agent. In this review, Senna genus is comprehensively discussed in terms of its botanical characteristics, traditional use, geographic presence, and phytochemical profile. The bioactive compound richness contributes to the biological activity of Senna plant extracts. The review emphasizes on the in vivo and in vitro antioxidant and anti-infectious properties of the Senna plant. Preclinical studies confirmed the beneficial effects of the Senna plant extracts and its bioactive components in regard to the health-promoting activities. The safety, side effects, and therapeutic limitations of the Senna plant are also discussed in this review. Additional research is necessary to utilize the phenolic compounds towards its use as an alternative to pharmacological treatments and even as an ingredient in functional foods.

PMID:35154569 | PMC:PMC8837466 | DOI:10.1155/2022/6025900

Oxid Med Cell Longev. 2022 Feb 1;2022:3079577. doi: 10.1155/2022/3079577. eCollection 2022.

ABSTRACT

Andrographolide (ANDRO), a bitter diterpene lactone found in Andrographis paniculata (Burm.f.) Nees, possesses several biological effects such as antioxidant, anti-inflammatory, and organo-protective effects. Scientific reports suggest that it also has neuroprotective capacity in various test systems. The purpose of this review was to synthesize the neuropharmacological properties of ANDRO and highlight the molecular mechanisms of action that highlight these activities. A careful search was done in PubMed and Google Scholar databases using specific keywords. Findings suggest that ANDRO possess neuroprotective, analgesic, and antifatigue effects. Prominent effects were stated on neuro-inflammation, cerebral ischemia, Alzheimer's and Parkinson's diseases, multiple sclerosis, and brain cancer in mice and rats. Furthermore, ANDRO and its derivatives can enhance memory and learning capacity in experimental animals (rats) without causing any toxicity in the brain. Thus, ANDRO may be one of the most promising plant-based psychopharmacological lead compounds for new drug development.

PMID:35154564 | PMC:PMC8825670 | DOI:10.1155/2022/3079577

Front Immunol. 2022 Jan 27;12:815121. doi: 10.3389/fimmu.2021.815121. eCollection 2021.

ABSTRACT

Heterogeneous genetic and environmental factors contribute to the psoriasis phenotype, resulting in a wide range of patient response to targeted therapies. Here, we investigate genetic factors associated with response to the IL-12/23 inhibitor ustekinumab in psoriasis. To date, only HLA-C*06:02 has been consistently reported to associate with ustekinumab response in psoriasis. Genome-wide association testing was performed on the continuous outcome of percent change in Psoriasis Area Severity Index (PASI) at 12 weeks of ustekinumab therapy relative to baseline. A total of 439 European ancestry individuals with psoriasis were included [mean age, 46.6 years; 277 men (63.1%)]. 310 (70.6%) of the participants comprised the discovery cohort and the remaining 129 (29.4%) individuals comprised the validation cohort. Chromosome 4 variant rs35569429 was significantly associated with ustekinumab response at 12 weeks at a genome-wide significant level in the discovery cohort and replicated in the validation cohort. Of psoriasis subjects with at least one copy of the deletion allele of rs35569429, 44% achieved PASI75 (75% improvement in PASI from baseline) at week 12 of ustekinumab treatment, while for subjects without the deletion allele, 75% achieved PASI75 at week 12. We found that differences in treatment response increased when rs35569429 was considered alongside HLA-C*06:02. Psoriasis patients with the deletion allele of rs35569429 who were HLA-C*06:02 negative had a PASI75 response rate of 35% at week 12, while those without the deletion allele who were HLA-C*06:02 positive had a PASI75 response rate of 82% at week 12. Through GWAS, we identified a novel SNP that is potentially associated with response to ustekinumab in psoriasis.

PMID:35154085 | PMC:PMC8830831 | DOI:10.3389/fimmu.2021.815121

Clin Pharmacol Ther. 2022 Feb 12. doi: 10.1002/cpt.2557. Online ahead of print.

ABSTRACT

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a Phase-I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.

PMID:35152405 | DOI:10.1002/cpt.2557

Eur Neuropsychopharmacol. 2022 Feb 10;56:100-111. doi: 10.1016/j.euroneuro.2022.01.008. Online ahead of print.

ABSTRACT

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. Polymorphisms in cytochrome P450 genes (CYP450) were demonstrated to play a significant role in antidepressant response and side effects, but their effect in real-world clinical practice is poorly known. We determined the metabolic status of CYP2C19 based on the combination of *1, *2, *3 and *17 alleles extracted from genome-wide data in 1239 patients with MDD, pharmacologically treated in a naturalistic setting. Symptom improvement and side effects were assessed using the Montgomery and Åsberg Depression Rating Scale and the Udvalg for Kliniske Undersøgelse scale, respectively. We tested if symptom improvement, response and side effects were associated with CYP2C19 metabolic status adjusting for potential confounders. We considered patients treated with drugs for depression having CYP2C19 genotyping recommended by guidelines (T1 Drugs); secondarily, with all psychotropic drugs having CYP2C19 as relevant metabolic path (T2 Drugs). In the group treated with T1 drugs (n = 540), poor metabolizers (PMs) showed higher response and higher symptom improvement compared to normal metabolizers (p = 0.023 and p = 0.009, respectively), but also higher risk of autonomic and neurological side effects (p = 0.022 and p = 0.022 respectively). In patients treated with T2 drugs (n = 801), similar results were found. No associations between metabolizer status and other types of side effects were found (psychic and other side effects). Our study suggests potential advantages of CYP2C19 pharmacogenetic testing to guide treatment prescription, that may not be limited to the drugs currently recommended by guidelines.

PMID:35152032 | DOI:10.1016/j.euroneuro.2022.01.008

Clin Res Hepatol Gastroenterol. 2022 Feb 10:101880. doi: 10.1016/j.clinre.2022.101880. Online ahead of print.

ABSTRACT

BACKGROUND: Homozygous Recombination Deficiency (HRD) is associated with sensitivity to PARP-inhibitors (PARPi) in different cancer types. In pancreatic adenocarcinoma (PA) the main cause of HRD is BRCA1/2 germline mutation and patients with mutations in BRCA1/2 may benefit from PARPi. Recently other mechanisms leading to HRD were described in different cancer types, including gene mutations and epigenetic changes such as promoter hypermethylation. In PA, BRCA1 promoter hypermethylation, a known mechanism of gene silencing was recently described. However, results are discordant between North American studies (0.7% of PA) and Asian ones (up to 60% of PA) and the association with HRD is not clear.

METHODS: Here, we developed 2 quantifications methods to explore BRCA1 and RAD51C promoter methylation in a series of 121 Formalin Fixed-Paraffin-Embedded (FFPE) specimens from resected PA without neoadjuvant treatment. The methylation-specific PCR was done with 2 different methods after DNA bisulfite conversion: a digital droplet PCR, and a PCR followed by capillary electrophoresis, to score the methylated / non methylated ratios in tumor samples. Methods were validated for specificity and sensibility using 100, 20, 10, 5 and 0% methylated commercial DNA for fragment analysis with a detection cutoff of 5-10%. Limit of blank was defined as 5 dropplets/20µL for RAD51C and 1 dropplet/20µL for BRCA1 for ddPCR. Samples were reviewed by a pathologist, macrodissected before DNA extraction to obtain 50-60% of tumoral cells. DNAs were treated for bisulfite conversion and analyzed using both methods in parallel to known positive and negative controls in each run.

RESULTS AND CONCLUSION: No methylation at BRCA1 or RAD51C was found in this series of PA suggesting that HRD gene promoter methylation is a rare event in European patients.

PMID:35151910 | DOI:10.1016/j.clinre.2022.101880

J Affect Disord. 2022 Feb 10:S0165-0327(22)00171-9. doi: 10.1016/j.jad.2022.02.015. Online ahead of print.

ABSTRACT

BACKGROUND: Understanding the genetic underpinnings of antidepressant treatment response in unipolar major depressive disorder (MDD) can be useful in identifying patients at risk for poor treatment response or treatment resistant depression. A polygenic risk score (PRS) is a useful tool to explore genetic liability of a complex trait such as antidepressant treatment response. Here, we review studies that use PRSs to examine genetic overlap between any trait and antidepressant treatment response in unipolar MDD.

METHODS: A systematic search of literature was conducted in PubMed. Our search included studies examining associations between PRSs of psychiatric as well as non-psychiatric traits and antidepressant treatment response in patients with unipolar MDD. A quality assessment of the included studies was performed.

RESULTS: In total, eleven articles were included which contained PRSs for 30 traits. Studies varied in sample size and endpoints used for antidepressant treatment response. Overall, PRSs for attention-deficit hyperactivity disorder, the personality trait openness, coronary artery disease, obesity, and stroke have been associated with antidepressant treatment response in patients with unipolar MDD.

LIMITATIONS: The endpoints used by included studies differed significantly, therefore it was not possible to perform a meta-analysis.

CONCLUSIONS: Associations between a PRS and antidepressant treatment response have been reported for a number of traits in patients with unipolar MDD. PRSs could be informative to predict antidepressant treatment response in this population, given advances in the field. Most importantly, there is a need for larger study cohorts and the use of standardized outcome measures.

PMID:35151671 | DOI:10.1016/j.jad.2022.02.015

Gynecol Oncol. 2022 Feb 9:S0090-8258(22)00076-2. doi: 10.1016/j.ygyno.2022.01.036. Online ahead of print.

ABSTRACT

OBJECTIVE: Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive type of endocervical adenocarcinoma (ECA) with distinct histopathologic features and unfavorable treatment outcomes, but no genomic prognostic factor has been revealed. We aimed to systematically investigate the somatic alterations of GCA at genome-wide level and evaluate their prognostic value.

METHODS: We performed whole-exome sequencing (WES) on 25 pairs of tumor and matched normal samples to characterize the genomic features of Chinese patients with GCA and investigated their relations to histopathological characterizations and prognosis. The prognostic value of the genomic alterations was evaluated in a total of 58 GCA patients.

RESULTS: Mutations were commonly observed in reported GCA-related driver genes, including TP53 (32%), CDKN2A (20%), SKT11 (20%), BRCA2 (12%), SMAD4 (12%), and ERBB2 (12%). Recurrent novel trunk mutations were also observed in PBRM1 (12%), FRMPD4 (12%), and NOP2 (8%) with high variant allele frequency. Moreover, enrichment of the APOBEC signature was attributed to frequent gain of somatic copy number alteration (SCNA) of APOBEC3B (20%), which perfectly matched the nuclear-positive staining of APOBEC3B through immunohistochemistry. In contrast, APOBEC3B alteration was absent in patients with conventional type of ECA (N = 52). Notably, positive APOBEC3B was consistently enriched in patients with favorable prognosis in both the discovery cohort and an additional 33 GCA patients, thus indicating a significant association with lower relapse risk of GCA independent of cancer stage (P = 0.02).

CONCLUSION: Our results can aid understanding of the molecular basis of GCA in the Chinese population by providing genomic profiles and highlighting the potential prognostic value of APOBEC3B for GCA through routine clinical IHC.

PMID:35151492 | DOI:10.1016/j.ygyno.2022.01.036

Cancer Treat Rev. 2022 Feb 1;104:102340. doi: 10.1016/j.ctrv.2022.102340. Online ahead of print.

ABSTRACT

Molecular heterogeneity characterizes tumours' evolution and adaptation and, because of its dynamics and continuous changes under external pressure, it is one of the major causes of drug resistance, contributing to therapy failure. Several studies reported evidence of molecular events occuring in individual tumours, including monoclonal or polyclonal resistance, and primary or secondary resistance mechanisms. While primary resistance is a phenomenon already present at the diagnosis of a tumor, the acquired one is strongly related to the selective pressure of treatments administered. Therefore, the pharmacological characteristics of a drug, including its potency, binding affinity and structure, largely influence the mechanism of resistance that will arise at the progression of the disease. As an example, the lung cancer experience clearly demonstrated that the highest is the potency of a drug on its target, the more are the possibilities that the mechanism of resistance will arise independently of the target itself. The present review is focused on tumour heterogeneity and its relation to resistance to targeted-therapy, based on treatment selective pressure across different tumour types, including lung, colorectal, prostate, breast cancer and melanoma. The mechanisms of resistance based on the drug potency and the selective pressure of treatments are discussed, leading to new drug developments or new therapeutic combinations.

PMID:35151155 | DOI:10.1016/j.ctrv.2022.102340

Allergy. 2022 Feb 12. doi: 10.1111/all.15254. Online ahead of print.

NO ABSTRACT

PMID:35150450 | DOI:10.1111/all.15254

Basic Clin Pharmacol Toxicol. 2022 Feb 11. doi: 10.1111/bcpt.13715. Online ahead of print.

ABSTRACT

Metabolic abnormalities have been associated with olanzapine treatment. We assessed if olanzapine has dose-dependent effects on metabolic parameters with changes for weight, blood pressure, lipid and glucose profiles being modelled using linear mixed-effects models. The risk of metabolic abnormalities including early weight gain (EWG) (≥5% during first month) was assessed using mixed-effect logistic regression models. In 392 olanzapine-treated patients (median age 38.0 years, interquartile range [IQR]=26.0-53.3, median dose 10.0mg/day, IQR=5.0-10.0 for a median follow-up duration of 40.0 days, IQR=20.7-112.2), weight gain was not associated with olanzapine dose (p=0.61) although it was larger for doses > vs. ≤10mg/day (2.54±5.55 vs. 1.61±4.51% respectively, p=0.01). Treatment duration and co-prescription of >2 antipsychotics, antidepressants, benzodiazepines and/or antihypertensive agents were associated with larger weight gain (p<0.05). Lower doses were associated with increases in total and HDL cholesterol, systolic and diastolic blood pressure (p<0.05), whereas higher doses were associated with glucose increases (p=0.01). Patients receiving >10mg/day were at higher EWG risk (odds risk: 2.15, 1.57-2.97). EWG might be prominent in high-dose olanzapine-treated patients with treatment duration and co-prescription of other medications being weight gain moderators. The lack of major dose-dependent patterns for weight gain emphasizes that olanzapine-treated patients are at weight gain risk regardless the dose.

PMID:35150056 | DOI:10.1111/bcpt.13715

Br J Clin Pharmacol. 2022 Feb 11. doi: 10.1111/bcp.15267. Online ahead of print.

ABSTRACT

AIMS: Studies implicated a role for a genetic variant in CEP72 in vincristine-induced peripheral neuropathy. This study aims to evaluate this association in a cohort of brain tumors patients, to perform a cross-disease meta-analysis and explore the protein-coding region of CEP72.

METHODS: 104 vincristine-treated brain tumor patients were genotyped for CEP72 rs924607, and sequenced for the protein-coding region. Data regarding patient and treatment characteristics, and peripheral neuropathy, were collected. Logistic regression and meta-analysis were performed for rs924607 replication. A weighted burden analysis was applied to evaluate impact of overall genetic variation in CEP72.

RESULTS: Analysis of 24 cases and 80 controls did not show a significant association between CEP72 rs924607 and neuropathy (OR (95%-CI) 2.076 (0.359-11.989), p=0.414). When combined with eight cohorts (1,095 cancer patients), a significant increase in risk for neuropathy was found for patients with a TT genotype (OR (95%-CI) 2.15 (1.35-3.43), p=0.001). Additionally, a missense variant (rs12522955) was significantly associated (OR (95%-CI) 2.3 (1.2-4.4), p=0.041) and patients with severe neuropathy carried more impactful variants in CEP72 coding regions (p=0.039).

CONCLUSIONS: The association of CEP72 rs924607 in vincristine-induced neuropathy was not confirmed in a cohort of brain tumor patients, but did contribute to its suggested effect when combined in a cross-disease meta-analysis. The importance of other genetic variations in CEP72 on vincristine-induced neuropathy was demonstrated. This study contributes to evidence of the importance of genetic variants in CEP72 in development of vincristine-induced toxicity, and provides guidance for future prospective studies.

PMID:35150001 | DOI:10.1111/bcp.15267

Pharmacogenomics J. 2022 Feb 11. doi: 10.1038/s41397-022-00269-5. Online ahead of print.

ABSTRACT

Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab. Array genotyping and exome sequencing were performed on DNA samples from 1075 patients. Variants in the UGT1A1 gene were strongly associated with maximum bilirubin elevations in sarilumab-treated patients (rs4148325; p = 2.88 × 10-41) but were not associated with aminotransferase elevations. No other independent loci showed evidence of association with bilirubin elevations after sarilumab treatment. These findings suggest that most bilirubin increases during sarilumab treatment are related to genetic variation in UGT1A1 rather than underlying liver injury.

PMID:35149777 | DOI:10.1038/s41397-022-00269-5

Biomed Pharmacother. 2022 Feb 8;148:112684. doi: 10.1016/j.biopha.2022.112684. Online ahead of print.

ABSTRACT

BACKGROUND: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting. However, this medication has also been associated with QT prolongation. Pharmacogenomic information on therapeutic response to ondansetron exists, but no investigation has been performed on genetic factors that influence the cardiac safety of this medication.

METHODS: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62). Electrocardiograms were conducted at baseline, and 5- and 30-min post-ondansetron administration, to determine the effect of ondansetron treatment on QT interval. Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data.

RESULTS: In the entire cohort, 62 patients (24.1%) met the criteria for prolonged QT, with 1.2% of the cohort exhibiting unsafe QT prolongation. The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9.8 × 10-4). CYP2D6 activity score was not associated with prolonged QT. Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2.00 × 10-7) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1.97 × 10-7).

CONCLUSIONS: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits. These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication.

PMID:35149390 | DOI:10.1016/j.biopha.2022.112684

Rev Neurol (Paris). 2022 Feb 8:S0035-3787(22)00001-7. doi: 10.1016/j.neurol.2021.11.009. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: This article reviews the genetics of multiple sclerosis (MS), as well as intra-familial concordance and clinical correlations between different members of a family. Indeed, significant findings have been made on these topics in recent years.

RECENT FINDINGS: The influence of specific genes on the clinical or radiological presentation of MS has been described as well as preliminary findings in the field of pharmacogenomics. Within familial forms of MS, correlations on specific aspects of the disease have been described, such as the age of onset or the clinical course between siblings.

SUMMARY: The genetic contribution to the risk of developing MS is now estimated to be about 50%, with the genes involved mainly located within the major histocompatibility complex. Familial MS represents 12.6% of all MS cases, with the risk depending on the degree of genetic proximity to the index case. Furthermore, these familial cases seem to have a different clinical presentation from sporadic cases such as earlier worsening of disability and more severe long-term disability. Clinical correlations between different members of a family with MS have also been described, such as a similar age of onset between siblings, but deep clinical and radiological phenotyping is warranted to investigate MS disease severity concordance within familial cases of MS.

PMID:35148907 | DOI:10.1016/j.neurol.2021.11.009