J Pers Med. 2023 Jun 21;13(7):1025. doi: 10.3390/jpm13071025.

ABSTRACT

Although the use of genomics to inform clinical care is increasing, clinicians feel underprepared to integrate personalized medicine (PM) into care decisions. The educational needs of physician residents and fellows, also known as graduate medical trainees (GMTs), have been overlooked. We administered an anonymous, web-based survey to all GMTs participating in training programs affiliated with our institution to evaluate their knowledge, skills, and attitudes toward PM. Of the 1190 GMTs contacted, 319 (26.8%) returned surveys. Most (88.4%) respondents reported receiving PM education in the past. Although the respondents agreed that knowledge of disease genetics (80.9%) or pharmacogenetics (87.1%) would likely lead to improved clinical outcomes, only 33.2% of the respondents felt sufficiently informed about PM. The respondents who had received PM education in residency and/or fellowship had significantly higher self-reported knowledge, ability, awareness, and adoption of PM than those who had not received this education (p < 0.0001, p < 0.0001, p < 0.0001, and p < 0.01, respectively). Targeted training is needed to improve GMTs' confidence in interpreting and explaining genetic test results. The ideal timing for this education appears to be in residency and/or fellowship rather than in medical school.

PMID:37511638 | DOI:10.3390/jpm13071025

Biomedicines. 2023 Jul 24;11(7):2088. doi: 10.3390/biomedicines11072088.

ABSTRACT

BACKGROUND: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders.

METHODS: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership.

RESULTS: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes.

CONCLUSIONS: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs.

PMID:37509727 | DOI:10.3390/biomedicines11072088

Biomedicines. 2023 Jul 12;11(7):1966. doi: 10.3390/biomedicines11071966.

ABSTRACT

Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) affects the quality of life of patients suffering from it. The search for a suitable biomarker has been conducted over the last decades. Interleukin 5 receptor subunit alpha (IL-5Rα) involves the activation, maintenance, and survival of eosinophils, which are highly tied to chronic inflammatory processes of the airways, like asthma or CRSwNP. In this study, we evaluate the utility of IL5RA as a genetic biomarker in CRSwNP. IL5RA mRNA expression level was analyzed in different groups of patients by performing qPCR assays. A significant increase in IL5RA expression was observed in CRSwNP patients, especially those with asthma and atopy. We found differences in expression levels when comparing groups with or without polyposis or asthma, as well as some atypical cases related to eosinophil levels. That opens a path to future studies to further characterize groups of patients with common features in the context of pharmacogenetics and in an era towards developing a more precise personalized treatment with IL-5Rα as a therapeutic target for CRSwNP.

PMID:37509606 | DOI:10.3390/biomedicines11071966

Biomedicines. 2023 Jun 21;11(7):1776. doi: 10.3390/biomedicines11071776.

ABSTRACT

Conventional therapy options for chronic pain are still insufficient and patients most frequently request alternative medical treatments, such as medical cannabis. Although clinical evidence supports the use of cannabis for pain, very little is known about the efficacy, dosage, administration methods, or side effects of widely used and accessible cannabis products. A possible solution could be given by pharmacogenetics, with the identification of several polymorphic genes that may play a role in the pharmacodynamics and pharmacokinetics of cannabis. Based on these findings, data from patients treated with cannabis and genotyped for several candidate polymorphic genes (single-nucleotide polymorphism: SNP) were collected, integrated, and analyzed through a machine learning (ML) model to demonstrate that the reduction in pain intensity is closely related to gene polymorphisms. Starting from the patient's data collected, the method supports the therapeutic process, avoiding ineffective results or the occurrence of side effects. Our findings suggest that ML prediction has the potential to positively influence clinical pharmacogenomics and facilitate the translation of a patient's genomic profile into useful therapeutic knowledge.

PMID:37509416 | DOI:10.3390/biomedicines11071776

Cancers (Basel). 2023 Jul 12;15(14):3583. doi: 10.3390/cancers15143583.

ABSTRACT

Acute myeloid leukemia (AML) is a clonal hematopoietic disease that arises from chromosomal and genetic aberrations in myeloid precursor cells. AML is one of the most common types of acute leukemia in adults; however, it is relatively rare overall, comprising about 1% of all cancers. In the last decade or so, numerous genome-wide association studies (GWAS) have been conducted to screen between hundreds of thousands and millions of variants across many human genomes to discover genetic polymorphisms associated with a particular disease or phenotype. In oncology, GWAS has been performed in almost every commonly occurring cancer. Despite the increasing number of studies published regarding other malignancies, there is a paucity of GWAS studies for AML. In this review article, we will summarize the current status of GWAS in AML.

PMID:37509244 | DOI:10.3390/cancers15143583

Bioengineering (Basel). 2023 Jun 21;10(7):747. doi: 10.3390/bioengineering10070747.

ABSTRACT

The complex pathobiology of lung cancer, and its spread worldwide, has prompted research studies that combine radiomic and genomic approaches. Indeed, the early identification of genetic alterations and driver mutations affecting the tumor is fundamental for correctly formulating the prognosis and therapeutic response. In this work, we propose a radiogenomic workflow to detect the presence of KRAS and EGFR mutations using radiomic features extracted from computed tomography images of patients affected by lung adenocarcinoma. To this aim, we investigated several feature selection algorithms to identify the most significant and uncorrelated sets of radiomic features and different classification models to reveal the mutational status. Then, we employed the SHAP (SHapley Additive exPlanations) technique to increase the understanding of the contribution given by specific radiomic features to the identification of the investigated mutations. Two cohorts of patients with lung adenocarcinoma were used for the study. The first one, obtained from the Cancer Imaging Archive (TCIA), consisted of 60 cases (25% EGFR, 23% KRAS); the second one, provided by the Azienda Ospedaliero-Universitaria 'Ospedali Riuniti' of Foggia, was composed of 55 cases (16% EGFR, 28% KRAS). The best-performing models proposed in our study achieved an AUC of 0.69 and 0.82 on the validation set for predicting the mutational status of EGFR and KRAS, respectively. The Multi-layer Perceptron model emerged as the top-performing model for both oncogenes, in some cases outperforming the state of the art. This study showed that radiomic features can be associated with EGFR and KRAS mutational status in patients with lung adenocarcinoma.

PMID:37508774 | DOI:10.3390/bioengineering10070747

Antibiotics (Basel). 2023 Jul 21;12(7):1214. doi: 10.3390/antibiotics12071214.

ABSTRACT

(1) Background: Ceftolozane/tazobactam (C/T) is a novel β-lactam/β-lactamase inhibitor with excellent activity against the multidrug-resistant (MDR) P. aeruginosa. Continuous infusion (CI) dosing allows the optimization of pharmacokinetic and pharmacodynamic (PK/PD) properties of β-lactam antibiotics and may support patients' treatment as outpatients. (2) Methods: Adult patients receiving their entire course of C/T as a CI in the outpatient setting were retrospectively included in the study. The primary outcome evaluated was clinical resolution. The secondary outcomes evaluated were PK/PD target attainment (ƒT > 4 × MIC) and microbiologic clearance at the end of treatment. Therapeutic drug monitoring to assess C/T concentration was performed. (3) Results: Three patients were enrolled in the study and received 9 g of C/T in CI every 24 h. One patient received an additional course of antimicrobial therapy due to disease exacerbation six months after initial treatment, accounting for four evaluated treatments. The primary outcome was achieved in 3/4 treatments and the secondary outcome was achieved in 4/4 and 3/3, respectively. In all patients, free ceftolozane concentrations were >10 times higher than the EUCAST breakpoint (4 mg/L). (4) Conclusions: Elastomeric infusion of C/T delivered in CI can be an effective and convenient way to treat acute diseases caused by MDR-P. aeruginosa, avoid hospital admission, and contribute to infection control strategies. Despite the small number of enrolled patients, clinical and microbiological results support this strategy.

PMID:37508309 | DOI:10.3390/antibiotics12071214

Curr Pharm Teach Learn. 2023 Jul 26:S1877-1297(23)00182-X. doi: 10.1016/j.cptl.2023.07.006. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: To assess pharmacy students' understanding of the importance of genetic counseling through a didactic lecture and active in-class learning exercise in a required pharmacogenomics course.

EDUCATIONAL ACTIVITY AND SETTING: During the second year, students are enrolled in a two-credit hour pharmacogenomics course which is taught by multiple faculty members from various disciplines. The pharmacy students were taught the clinical importance of genetic results and counseling patients on their individualized reports by a clinical laboratory geneticist and a clinical genetic counselor. After completion of the didactic portion of the class, students practiced genetic counseling skills through role playing with clinical cases involving genetic reports. Students' knowledge of clinical applications of pharmacogenomic data was assessed prior to and following the counseling experience.

FINDINGS: A paired sample t-test was chosen to analyze the data to determine if there was a difference in mean scores upon the completion of the lecture. There was a statistically significant mean difference between the total scores for the pretest (mean (M) = 37.89, SD = 6.66) and the total scores for the posttest (M = 48.33, SD = 5.24); t(140) = 17.53, P < .001, α = 0.05. The effect size for this analysis (d = 1.74) surpassed Cohen's determination for large effect (d = 0.8).

SUMMARY: The genetic counseling lecture and activity increased the students' overall awareness of the importance of how sensitive genetic information is reported and delivered to patients.

PMID:37507313 | DOI:10.1016/j.cptl.2023.07.006

Annu Rev Pharmacol Toxicol. 2023 Jul 28. doi: 10.1146/annurev-pharmtox-051921-091209. Online ahead of print.

ABSTRACT

Interindividual variability in genes encoding drug-metabolizing enzymes, transporters, receptors, and human leukocyte antigens has a major impact on a patient's response to drugs with regard to efficacy and safety. Enabled by both technological and conceptual advances, the field of pharmacogenomics is developing rapidly. Major progress in omics profiling methods has enabled novel genotypic and phenotypic characterization of patients and biobanks. These developments are paralleled by advances in machine learning, which have allowed us to parse the immense wealth of data and establish novel genetic markers and polygenic models for drug selection and dosing. Pharmacogenomics has recently become more widespread in clinical practice to personalize treatment and to develop new drugs tailored to specific patient populations. In this review, we provide an overview of the latest developments in the field and discuss the way forward, including how to address the missing heritability, develop novel polygenic models, and further improve the clinical implementation of pharmacogenomics. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37506333 | DOI:10.1146/annurev-pharmtox-051921-091209

Curr Rheumatol Rep. 2023 Jul 28. doi: 10.1007/s11926-023-01113-w. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Axial spondyloarthritis (AxSpA) is among the rheumatology's most heritable complex diseases, yet precision medicine at clinics still needs to be explored. We reviewed the emerging concepts and recent developments in polygenic risk scores, Mendelian randomization, pharmacogenomics, single-cell sequencing, and spatial transcriptomics.

RECENT FINDINGS: Polygenic risk score has resulted in encouraging results with potential diagnostic utility as it appears to outperform current diagnostic tools. Its performance and generalizability vary with ethnicity. Mendelian randomization has elucidated multiple causal associations, particularly between inflammatory bowel disease and AxSpA. Single-cell transcriptomics (particularly scRNA-seq and scATAC-seq) has identified numerous cell types, including synovial and blood immunological cells, to understand the contribution of both innate and adaptative immunity in AxSpA. Current molecular tools provide an exciting opportunity to advance precision medicine for AxSpA patients. However, extensive research and implementation strategies are still required before they can have an impact in the clinic.

PMID:37505349 | DOI:10.1007/s11926-023-01113-w

Biomol Ther (Seoul). 2023 Jul 28. doi: 10.4062/biomolther.2023.116. Online ahead of print.

ABSTRACT

The LEPR (leptin receptor) genotype is associated with obesity. Gut microbiome composition differs between obese and nonobese adults. However, the impact of LEPR genotype on gut microbiome composition in humans has not yet been studied. In this study, the association between LEPR single nucleotide polymorphism (rs1173100, rs1137101, and rs790419) and the gut microbiome composition in 65 non-obese Korean adults was investigated. Leptin, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels were also measured in all participants. Mean ± SD (standard deviation) of age, body mass index, and leptin hormone levels of participants was 35.2 ± 8.1 years, 21.4 ± 1.8 kg/m2, and 7989.1 ± 6687.4 pg/mL, respectively. Gut microbiome analysis was performed at the phylum level by 16S rRNA sequencing. Among the 11 phyla detected, only one showed significantly different relative abundances between LEPR genotypes. The relative abundance of Candidatus Saccharibacteria was higher in the G/A genotype group than in the G/G genotype group for the rs1137101 single nucleotide polymorphism (p=0.0322). Participant characteristics, including body mass index, leptin levels, and other lipid levels, were similar between the rs1137101 G/G and G/A genotypes. In addition, the relative abundances of Fusobacteria and Tenericutes showed significant positive relationship with plasma leptin concentrations (p=0.0036 and p=0.0000, respectively). In conclusion, LEPR genotype and gut microbiome may be associated even in normal-weight Korean adults. However, further studies with a greater number of obese adults are needed to confirm whether LEPR genotype is related to gut microbiome composition.

PMID:37503756 | DOI:10.4062/biomolther.2023.116

Pharmacogenomics. 2023 Jul 28. doi: 10.2217/pgs-2023-0068. Online ahead of print.

ABSTRACT

Background: Cytochrome P450 (CYP) genetic variation largely impacts drug response. However, many CYP star alleles (haplotypes) lack functional annotation, impeding our understanding of drug metabolism mechanisms. We aimed to investigate the impact of missense variant combinations on CYP protein structures. Methods: Normal mode analysis was conducted on 261 missense variants within 91 CYP haplotypes. CYP2D6*2 and CYP2D6*17 were prioritized for molecular dynamics simulation. Results: Normal mode analysis and molecular dynamics highlight the effects of known CYP missense variants on protein stability and conformational dynamics. Missense variants within haplotypes may have intermodulating effects on protein structure and function. Conclusion: This study highlights the utility of multiscale modeling in interpreting CYP missense variants and particularly their combinations within various star alleles.

PMID:37503750 | DOI:10.2217/pgs-2023-0068

Pharmacogenomics. 2023 Jul 28. doi: 10.2217/pgs-2023-0058. Online ahead of print.

ABSTRACT

Aim: We investigated if single-nucleotide polymorphisms (SNPs) in ATP-binding cassette (ABC) drug transporters alter gene expression and tenofovir disposition in South African women taking Truvada® for HIV prevention. Materials & methods: In 393 women, real-time PCR was used to determine the associations between six SNPs in ABC transporter genes, mRNA expression and circulating-tenofovir. Results: Univariable and multivariable analyses showed that CT and TT relative to CC genotypes for the ABCC4(3463C/T) SNP had significantly higher tenofovir levels. In contrast, the AA genotype for the ABCC4(4976A/G) SNP showed significantly less tenofovir, while mRNA expression was increased. Conclusion: SNPs in the ABCC4 gene may differentially affect gene expression and circulating tenofovir. Their impact may inform on low PrEP efficacy and discern effective drugs in clinical trials of African women enriched for certain genotypes.

PMID:37503696 | DOI:10.2217/pgs-2023-0058

Pharmacogenomics. 2023 Jul 28. doi: 10.2217/pgs-2023-0054. Online ahead of print.

ABSTRACT

Aim: Examining the association between HLA-A/B alleles and different carbamazepine (CBZ)-induced cutaneous adverse reactions in the Chinese population. Methods: A systematic review and meta-analysis of case-control studies was conducted. A systematic search was conducted of PubMed, Embase, the Cochrane Library, National Knowledge Infrastructure, the Chinese Biomedical Literature database and Wanfang Digital Periodicals. Results: 23 studies with a total of 1174 patients were included. In the Han population, HLA-B*15:02 is significantly associated with the increased risk of CBZ-related Stevens-Johnson syndrome/toxic epidermal necrolysis, and this correlation was not related to geographic distribution. HLA-A*31:01, B*38:02 are associated with CBZ-related maculopapular eruption in South Han population. HLA-A*31:01 is associated with CBZ-DRESS in Taiwan Han population. Conclusion: HLA-B*15:02, A*31:01 and B*38:02 genes were found to be involved in the occurrence of CBZ cutaneous adverse reactions in Han Chinese.

PMID:37503628 | DOI:10.2217/pgs-2023-0054

Cancer Chemother Pharmacol. 2023 Jul 27. doi: 10.1007/s00280-023-04569-w. Online ahead of print.

ABSTRACT

PURPOSE: Because of the large interindividual variability of afatinib pharmacokinetics and adverse events, we evaluated the effects of polymorphisms in pregnane X receptor (NR1I2) and ABC transporters (ABCB1, ABCG2, and ABCC2) on the pharmacokinetics of afatinib.

METHODS: The steady-state area under the concentration-time curve (AUC)0-24 of afatinib was analyzed using blood sampling just prior to and at 1, 2, 4, 6, 8, 12, and 24 h on day 15 after administration.

RESULTS: The median oral clearance (CL/F) of afatinib in patients with the NR1I2 7635A allele was significantly lower than those in patients with the 7635G/G genotype (42.0 and 60.0 L/h, respectively, P = 0.025). There were no significant differences in afatinib CL/F between genotypes for NR1I2 8055C > T, -25385C > T, ABCB1, ABCG2, and ABCC2 polymorphisms. Based on the area under the receiver-operating characteristic curve, the threshold afatinib AUC0-24 value for prediction of dose reduction or withdrawal was 689 ng·h/mL at the best sensitivity (81.0%) and specificity (72.7%). In multivariate logistic regression analysis, an afatinib AUC0-24 above 689 ng·h/mL was independently associated with increased risk of dose reduction or withdrawal (OR: 11.66, P = 0.012).

CONCLUSIONS: The NR1I2 7635A allele was related to a lower afatinib CL/F. Based on the AUC of 689 ng h/mL and CL/F, the optimal doses for patients with the NR1I2 7635G/G genotype and 7635A allele were recommended to be set at 40 and 30 mg/day, respectively, and subsequent adjustment of the maintenance dose based on the plasma concentrations of afatinib may be necessary to avoid afatinib-related adverse events.

PMID:37500985 | DOI:10.1007/s00280-023-04569-w

Front Pharmacol. 2023 Jul 11;14:1201566. doi: 10.3389/fphar.2023.1201566. eCollection 2023.

ABSTRACT

Metoclopramide is indicated for the management of gastroesophageal reflux, gastric stasis, nausea, and vomiting. Metoclopramide-induced acute dystonic reactions (MIADRs), along with repetitive involuntary protrusion of the tongue, are well-known phenomena in children and young adults that may appear after the first dose. The drug is primarily metabolized via oxidation by the cytochrome P450 enzyme CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2. A recommendation to decrease metoclopramide dosing in patients with severely limited to no CYP2D6 activity (i.e., poor metabolizers, PMs) is included in the drug label. It is important to note, however, that a requirement or recommendation for pre-emptive testing for CYP2D6 metabolizer status is not included in the drug label. We present two cases of acute dystonia in two non-consanguineous male adolescents: one following metoclopramide and cimetidine administration in a 14-year-old to treat gastroesophageal reflux, and another following metoclopramide and pantoprazole administration in a 17-year-old with acute gastroenteritis. A retrospective pharmacogenetic analysis revealed both patients as CYP2D6 PMs.

PMID:37497103 | PMC:PMC10366597 | DOI:10.3389/fphar.2023.1201566

Pharmacogenet Genomics. 2023 Jul 24. doi: 10.1097/FPC.0000000000000504. Online ahead of print.

ABSTRACT

OBJECTIVE: The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of SLCO1B1 c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of ABCG2 c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of CYP2C9*2 and *3 alleles with intolerance to fluvastatin.

METHODS: We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data.

RESULTS: We confirmed the association of SLCO1B1 c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08-3.25, P = 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49-19.9, P = 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but SLCO1B1 c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01-4.39, P = 0.047).

CONCLUSION: The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.

PMID:37490620 | DOI:10.1097/FPC.0000000000000504

Psychiatr Q. 2023 Jul 25. doi: 10.1007/s11126-023-10044-9. Online ahead of print.

ABSTRACT

Major depression is a frequent condition which variably responds to treatment. In view of its high prevalence, the presence of treatment resistance in major depression significantly impacts on quality of life. Tailoring pharmacological treatment based on genetic polymorphisms is a current trend to personalizing pharmacological treatment in patients with major depressive disorders. Current guidelines for the use of genetic tests in major depression issued by the Clinical Pharmacogenomics Implementation Consortium (CPIC) are based on CYP2D6 and CYP2C19 polymorphisms which constitute the strongest evidence for pharmacogenomic guided treatment. There is evidence of increased clinical response to pharmacological treatment in major depression although largely in non-treatment resistant patients from Western countries. In this study, well characterised participants (N = 15) with complex, largely treatment resistant unipolar major depression were investigated, and clinical improvement was measured at baseline and at week-8 after the pharmacogenomics-guided treatment with the Montgomery Åsberg Depression Rating Scale (MÅDRS). Results suggested a statistically significant improvement (p = 0.01) of 16% at endpoint in the whole group and a larger effect in case of changes in medication regime (28%, p = 0.004). This small but appreciable effect can be understood in the context of the level of treatment resistance in the group. To our knowledge, this is the first study from the Middle East demonstrating the feasibility of this approach in the treatment of complex major depressive disorders.

PMID:37490261 | DOI:10.1007/s11126-023-10044-9

Drug Saf. 2023 Jul 25. doi: 10.1007/s40264-023-01333-0. Online ahead of print.

ABSTRACT

Janus kinase inhibitors (JAKi) have enormous appeal as immune-modulating therapies across many chronic inflammatory diseases, but recently this promise has been overshadowed by questions regarding associated cardiovascular and cancer risk emerging from the ORAL Surveillance phase 3b/4 post-marketing requirement randomized controlled trial. In that study of patients with rheumatoid arthritis with existing cardiovascular risk, tofacitinib, the first JAKi registered for chronic inflammatory disease, failed to meet non-inferiority thresholds when compared with tumor necrosis factor inhibitors for both incident major adverse cardiovascular events and incident cancer. While this result was unexpected by many, subsequently published observational data have also supported this finding. Notably, however, such a risk has largely not yet been demonstrated in patients outside the specific clinical situation examined in the trial, even in the face of many studies examining this. Nevertheless, this signal has practically re-aligned approaches to both tofacitinib and other JAKi to varying extents, in other patient populations and contexts: within rheumatoid arthritis, but also in psoriatic arthritis, axial spondyloarthritis, inflammatory bowel disease, atopic dermatitis, and beyond. Application to individual patients can be more challenging but remains important to harness the substantive potential of JAKi to the maximum extent safely possible. This review not only explores the evolution of the regulatory response to the signal, its informing data, biological plausibility, and its impact on guidelines, but also the many factors that clinicians must consider in navigating cardiovascular and cancer risk for their patients considering JAKi as immune-modulating therapy.

PMID:37490213 | DOI:10.1007/s40264-023-01333-0

Int J Stroke. 2023 Jul 25:17474930231190259. doi: 10.1177/17474930231190259. Online ahead of print.

ABSTRACT

BACKGROUND: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions.

AIMS: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke.

METHODS: We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank.

RESULTS: Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)).

CONCLUSION: These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention.

DATA ACCESS STATEMENT: UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables.

PMID:37489815 | DOI:10.1177/17474930231190259