Gut. 2021 Apr 26:gutjnl-2021-324789. doi: 10.1136/gutjnl-2021-324789. Online ahead of print.

ABSTRACT

OBJECTIVE: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine.

DESIGN: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine.

RESULTS: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine.

CONCLUSION: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.

TRIAL REGISTRATION NUMBER: ISRCTN45176516.

PMID:33903149 | DOI:10.1136/gutjnl-2021-324789

Stroke. 2021 Apr 27:STROKEAHA120033041. doi: 10.1161/STROKEAHA.120.033041. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain.

METHODS: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791).

RESULTS: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86-0.94]; q value=7.43×10-5), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92-0.98]; q value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65-0.77]; q value=5.11×10-14); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06-1.45]; q value=0.03). No associations were found in relation to stroke outcome.

CONCLUSIONS: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.

PMID:33902302 | DOI:10.1161/STROKEAHA.120.033041

Pharmacol Ther. 2021 Apr 23:107861. doi: 10.1016/j.pharmthera.2021.107861. Online ahead of print.

ABSTRACT

Adequate food intake and relative abundance of dietary nutrients have undisputed effects on the brain function. There is now substantial evidence that dietary nutrition aids in the prevention and remediation of neurologic symptoms in diverse pathological conditions. The newly described influences of dietary factors on the alterations of mitochondrial dysfunction, epigenetic modification and neuroinflammation are important mechanisms that are responsible for the action of nutrients on the brain health. In this review, we discuss the state of evidence supporting that distinct dietary interventions including dietary supplement and dietary restriction have the ability to tackle neurological disorders using Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis as examples. Additionally, it is also highlighting that diverse potential mechanisms such as metabolic control, epigenetic modification, neuroinflammation and gut-brain axis are of utmost importance for nutrient supply to the risk of neurologic condition and therapeutic response. Finally, we also highlight the novel concept that dietary nutrient intervention reshapes metabolism-epigenetics-immunity cycle to remediate brain dysfunction. Targeting metabolism-epigenetics-immunity network will delineate a new blueprint for combating neurological weaknesses.

PMID:33901506 | DOI:10.1016/j.pharmthera.2021.107861

Basic Clin Pharmacol Toxicol. 2021 Apr 26. doi: 10.1111/bcpt.13593. Online ahead of print.

ABSTRACT

Anthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline-induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision-making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline-induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision-making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions.

PMID:33900042 | DOI:10.1111/bcpt.13593

Leuk Lymphoma. 2021 Apr 26:1-12. doi: 10.1080/10428194.2021.1913140. Online ahead of print.

ABSTRACT

Methotrexate (MTX), an antimetabolite for the treatment of leukemia, could cause neutropenia and subsequently fever, which might lead to treatment delay and affect prognosis. Here, we aimed to predict neutropenia and fever related to high-dose MTX using artificial intelligence. This study included 139 pediatric patients newly diagnosed with standard- or intermediate risk B-cell acute lymphoblastic leukemia. Fifty-seven SNPs of 16 genes were genotyped. Univariate and multivariate analysis were used to select SNPs and clinical covariates for model developing. Five machine learning algorithms combined with four resampling techniques were used to build optimal predictive model. The combination of random forest with adaptive synthetic appeared to be the best model for neutropenia (sensitivity = 0.935, specificity = 0.920, AUC = 0.927) and performed best for fever (sensitivity = 0.818, specificity = 0.924, AUC = 0.870). By machine learning, we have developed and validated comprehensive models to predict the risk of neutropenia and fever. Such models may be helpful for medical oncologists in quick decision-making.

PMID:33899650 | DOI:10.1080/10428194.2021.1913140

J Transl Autoimmun. 2021 Apr 5;4:100096. doi: 10.1016/j.jtauto.2021.100096. eCollection 2021.

ABSTRACT

Psoriasis is an autoimmune disease associated with interleukins, their receptors, key transcription factors and more recently, antimicrobial peptides (AMPs). Cathelicidin LL-37 is an AMP proposed to play a fundamental role in psoriasis etiology. With our proprietary software SNPClinic v.1.0, we analyzed 203 common SNPs (MAF frequency ​> ​1%) in proximal promoters of 22 genes associated with psoriasis. These include nine genes which protein products are classic drug targets for psoriasis (TNF, IL17A, IL17B, IL17C, IL17F, IL17RA, IL12A, IL12B and IL23A). SNPClinic predictions were run with DNAseI-HUP chromatin accessibility data in eight psoriasis/epithelia-relevant cell lines from ENCODE including keratinocytes (NHEK), TH1 and TH17 lymphocytes. Results were ranked quantitatively by transcriptional relevance according to our novel Functional Impact Factor (FIF) parameter. We found six rSNPs in five genes (CAMP/cathelicidin, S100A7/psoriasin, IL17C, IL17RA and TNF) and each was confirmed as true rSNP in at least one public eQTL database including GTEx portal and ENCODE (Phase 3). Predicted regulatory SNPs in cathelicidin, IL17C and IL17RA genes may explain hyperproliferation of keratinocytes. Predicted rSNPs in psoriasin, IL17C and cathelicidin may contribute to activation and polarization of lymphocytes. Predicted rSNPs in TNF gene are concordant with the epithelium-mesenchymal transition. In spite that these results must be validated in vitro and in vivo with a functional genomics approach, we propose FOXP2, RUNX2, NR2F1, ELF1 and HESX1 transcription factors (those with the highest FIF on each gene) as novel drug targets for psoriasis. Furthermore, four out of six rSNPs uncovered by SNPClinic v.1.0 software, could also be validated in the clinic as companion diagnostics/pharmacogenetics assays for psoriasis prescribed drugs that block TNF-α (e.g. Etanercept), IL-17 (e.g. Secukinumab) and IL-17 receptor (Brodalumab).

PMID:33898962 | PMC:PMC8060581 | DOI:10.1016/j.jtauto.2021.100096

Front Cell Dev Biol. 2021 Apr 7;9:631011. doi: 10.3389/fcell.2021.631011. eCollection 2021.

ABSTRACT

One of the vital challenges for cancer diseases is efficient biomarkers monitoring formation and development are limited. Omics data integration plays a crucial role in the mining of biomarkers in the human condition. As the link between omics study on biomarkers discovery and cancer diseases is deepened, defining the principal technologies applied in the field is a must not only for the current period but also for the future. We utilize topic modeling to extract topics (or themes) as a probabilistic distribution of latent topics from the dataset. To predict the future trend of related cases, we utilize the Prophet neural network to perform a prediction correction model for existing topics. A total of 2,318 pieces of literature (from 2006 to 2020) were retrieved from MEDLINE with the query on "omics" and "cancer." Our study found 20 topics covering current research types. The topic extraction results indicate that, with the rapid development of omics data integration research, multi-omics analysis (Topic 11) and genomics of colorectal cancer (Topic 10) have more studies reported last 15 years. From the topic prediction view, research findings in multi-omics data processing and novel biomarker discovery for cancer prediction (Topic 2, 3, 10, 11) will be heavily focused in the future. From the topic visuallization and evolution trends, metabolomics of breast cancer (Topic 9), pharmacogenomics (Topic 15), genome-guided therapy regimens (Topic 16), and microRNAs target genes (Topic 17) could have more rapidly developed in the study of cancer treatment effect and recurrence prediction.

PMID:33898421 | PMC:PMC8058380 | DOI:10.3389/fcell.2021.631011

Cent Eur J Immunol. 2021;46(1):92-98. doi: 10.5114/ceji.2021.104425. Epub 2021 Mar 15.

ABSTRACT

The present study aimed to analyse and compare the distribution of MICA (rs1051792) and NKG2D/KLRK1 (rs1154831, rs1049174, rs2255336) polymorphisms in 61 Greek and 100 Polish patients with rheumatoid arthritis in relation to the presence of the HLA-DRB1 shared epitope and clinical parameters. Genotyping of selected polymorphism was performed using real-time PCR. HLA-DRB1 shared epitope alleles segregated differently in Greek and Polish patients but in both populations were detected in over 60% of cases. The rs1051792-A variant was more common among SE-positive Polish patients (p = 0.003) while the rs1049174-G allele was more frequently observed in Greeks than in Poles (p < 0.001). Moreover, among Greek patients, the rs1051792-GG homozygotes more frequently presented with anti-CCP antibodies and rheumatoid factor (RF), while carriers of the rs1049174-G variant and rs1154831-CC homozygotes were characterized by lower disease activity scores (p < 0.05 in all cases). These results imply that, in addition to the HLA-DRB1 SE alleles, MICA and NKG2D polymorphisms may also play a role in rheumatoid arthritis.

PMID:33897289 | PMC:PMC8056341 | DOI:10.5114/ceji.2021.104425

Psychopharmacol Bull. 2021 Jan 12;51(1):69-80.

ABSTRACT

INTRODUCTION: Fluvoxamine is commonly administered to patients with recurrent depressive disorder. Some of these patients do not show adequate response to the therapy with fluvoxamine, whereas many of them experience dose-dependent adverse drug reactions. Previous research revealed that CYP2D6 is involved in the metabolism of fluvoxamine, the activity of which is highly dependent on the polymorphism of the gene encoding it.

OBJECTIVE: The objective of this study was to investigate the effect of polymorphisms of the CYP3A4, CYP2C9, CYP3A5, ABCB1, CYP2C19, SCL6A4, and 5-HTR2A genes on the concentration/dose indicator of fluvoxamine and on the CYP3A expression level obtained by measuring the miR-27b plasma concentration levels in patients suffering from a recurrent depressive disorder.

MATERIAL AND METHODS: Our study included 105 patients with recurrent depressive disorder (average age - 37.5 ± 13.2 years). The treatment regimen included fluvoxamine in an average daily dose of 117.6 ± 44.3 mg per week. Therapy efficacy was assessed using the international psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels, we performed the real-time polymerase chain reaction. The activity of CYP3A was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of the given isoenzyme and its metabolite in urine (6b-HC/cortisol). Therapeutic drug monitoring has been performed using HPLC-MS/MS.

RESULTS: Our study didn't reveal any statistically significant results in terms of the treatment efficacy and safety of the therapy. We also didn't reveal a statistical significance for the concentration/dose indicator of fluvoxamine in patients with different genotypes. Analysis of the results of the pharmacotranscriptomic part of the study didn't demonstrate the statistically significant difference in the miR-27b plasma levels in patients with different genotypes. At the same time, correlation analysis didn't reveal a statistically significant relationship between the fluvoxamine efficacy profile evaluated by changes in HAMD scale scores and the miR-27b plasma concentration: rs = -0.012, p = 0.63. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = -0.175, p = 0.30. In addition, we didn't reveal the relationship between the CYP3A enzymatic activity and the miR-27b plasma concentration: rs = -0.197, p < 0.32. However, the difference in the CYP3A enzymatic activity in carriers of AG and GG genotypes of the 6986A > G polymorphism of CYP3A5 gene has been revealed: (AG) 4.72 [1.18; 8.45] vs (GG) 9.23 [5.12; 15.53], p-value = 0.23.

CONCLUSION: Thus, the effect of genetic polymorphism of the CYP3A4, CYP2C9, CYP2C9, CYP3A5, ABCB1, CYP2C19, CYP2C19, CYP2C19, SCL6A4, 5-HTR2A gene on the efficacy and safety profiles of fluvoxamine was not demonstrated in a group of 105 patients with depressive disorder and alcohol use disorder.

PMID:33897064 | PMC:PMC8063127

Expert Opin Drug Metab Toxicol. 2021 Apr 26. doi: 10.1080/17425255.2021.1922668. Online ahead of print.

ABSTRACT

INTRODUCTION: : Antipsychotic medications are used to treat a number of conditions in children and adolescents. While side effect profiles from second generation antipsychotics (SGAs) may differ from older antipsychotics, they do not come without risk. Knowing which children may be at higher risk for specific outcomes is important clinical information for prescribers. Common side effects and toxicities of SGAs in children include movement disorders, weight gain, and hormonal changes. There are also rare, but potentially dangerous adverse events including neuroleptic malignant syndrome, hypersensitivity and suicidal ideation.

AREAS COVERED: This review will summarize and comment on clinical, pharmacological, and genetic factors having evidence as predictors of SGA-associated side effects and toxicities in children.

EXPERT OPINION: : Observations across studies note that older children and those that do not respond early in treatment may be more at risk for movement disorders, while younger, antipsychotic naive children are at increased risk for weight gain. Relatively fewer studies have looked at pharmacogenetic relationships, although variations in pharmacokinetic and pharmacodynamic genes hold promise to advance drug dosing or selection strategies. Future efforts to assimilate multiple clinical, pharmacological, and genetic factors to facilitate predictive analytics and clinical decision support for prescribers will advance precision care to patients.

PMID:33896324 | DOI:10.1080/17425255.2021.1922668

Clin Pharmacol Ther. 2021 Apr 24. doi: 10.1002/cpt.2274. Online ahead of print.

ABSTRACT

Low- and middle-income countries (LMICs) have the highest rates of mortality and morbidity globally, but lag behind high-income countries in the number of clinical trials and trained researchers, as well as research data pertaining to their populations. Lack of local clinical pharmacology and pharmacometrics expertise, limited training opportunities, and lack of local genomic data may contribute to health inequalities and limit the application of precision medicine. Continuing to develop health care infrastructure, including well designed clinical pharmacology training and data collection in LMICs, can help address these challenges. International collaboration aimed at improving training and infrastructure and encouraging locally driven research and clinical trials will be of benefit. This review describes several examples where clinical pharmacology expertise could be leveraged, including opportunities for pharmacogenomics expertise that could drive improved recommendations for clinical guidelines. Also described are clinical pharmacology and pharmacometrics training programs in Africa, and the personal experience of a Tanzanian researcher currently on a training sabbatical in the United States, as illustrative examples of how training in clinical pharmacology can be effectively implemented in LMICs. These training efforts will benefit from advocacy for employment opportunities and career development pathways for clinical pharmacologists that are gradually being recognized and developed in LMICs. Clinical pharmacologists have a key role to play in global health, and development of training and research infrastructure to advance this expertise in LMICs will be of tremendous benefit.

PMID:33893656 | DOI:10.1002/cpt.2274

J Am Pharm Assoc (2003). 2021 Apr 5:S1544-3191(21)00156-4. doi: 10.1016/j.japh.2021.04.001. Online ahead of print.

ABSTRACT

BACKGROUND: Nearly 300 medications contain pharmacogenomic information in their labeling approved by the U.S. Food and Drug Administration. As this number continues to grow, community pharmacists will be called on to use available pharmacogenomic data at the point of dispensing.

OBJECTIVE: This qualitative study aimed to describe how pharmacists envision the integration of pharmacogenomic data into the current workflows of community pharmacy practice.

METHODS: Community pharmacists from a regional supermarket chain pharmacy in the greater Pittsburgh area were interviewed using a semistructured interview guide. Participating pharmacists were presented with 3 clinical scenarios, followed by questions, to gain insight into how they envisioned the integration of pharmacogenomic data into community pharmacy workflow. The interview transcriptions were transcribed and coded. The content was analyzed to deduce the final themes. Supporting quotes were selected to illustrate each theme.

RESULTS: Ten community pharmacists from 3 different pharmacy locations participated in the study. A thematic analysis produced 6 themes: (1) integrating pharmacogenomic data into the dispensing software, (2) receiving an alert for pharmacogenomic information within the dispensing software, (3) accessing pharmacogenomic clinical guidelines to guide drug-decision-making, (4) contacting the prescriber by adding a task to the call queue, (5) placing a mandatory counseling alert on medications that were adjusted using pharmacogenomic data, and (6) counseling the patient on the first refill of a medication that was adjusted using pharmacogenomic data.

CONCLUSION: This study describes how pharmacists envisioned the integration of pharmacogenomic data into community pharmacy workflow. The participants sought the integration of pharmacogenomic data into existing dispensing software, alerts for actionable prescribing changes using patient-specific pharmacogenomic data when available, and access to clinical decision support. In addition, the participants preferred to engage prescribers and receive alerts to counsel patients at prescription pick-up. These findings are key to integrating pharmacogenomic data into community pharmacy practice.

PMID:33893058 | DOI:10.1016/j.japh.2021.04.001

J Pharm Biomed Anal. 2021 Apr 14;200:114077. doi: 10.1016/j.jpba.2021.114077. Online ahead of print.

ABSTRACT

Drug resistance and adverse reactions to oxaliplatin remain a considerable issue in clinical practice. Emerging evidence has suggested that alterations in the lipid metabolism during drug therapy affect cancer cells. To gain insight into the important process of lipid metabolism, we investigated the lipid and gene expression profile changes in HT29 cells treated with oxaliplatin. A total of 1403 lipid species from 16 lipid classes were identified by UHPLC-MS. Interestingly, phospholipids, including phosphatidylglycerol (PG), phosphatidic acid (PA), phosphatidylcholine (PC), and most of phosphatidylethanolamine (PE) with polyunsaturated fatty acid (PUFA) chains, were significantly higher due to oxaliplatin treatment, while triacylglycerols (TAGs) with a saturated fatty acid chain or monounsaturated fatty acid were significantly downregulated. Gene Set Enrichment Analysis (GSEA) based on RNA sequencing data suggested that neutral lipid metabolism was enriched in the control group, whereas the phospholipid metabolic process was enriched in the oxaliplatin-treated group. We observed that altered lipid metabolism enzyme genes were involved in the synthesis and lipolysis of TAGs and the Lands cycle pathway based on the network between the core lipid-related gene and lipid species, which was further verified by qRT-PCR. In summary, our findings revealed that oxaliplatin impressed a specific lipid profile signature and lipid transcriptional reprogramming in HT29 cells, which provides new insights into biomarker discovery and pathways for overcoming drug resistance and adverse reactions.

PMID:33892396 | DOI:10.1016/j.jpba.2021.114077

Drug Discov Today. 2021 Apr 20:S1359-6446(21)00203-8. doi: 10.1016/j.drudis.2021.04.015. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) has essential roles in identifying optimal drug responders, optimizing dosage regimens and avoiding adverse events. Population-specific therapeutic interventions that tackle the genetic root causes of clinical outcomes are an important precision medicine strategy. In this perspective, we discuss next-generation sequencing genotyping and its significance for population-specific PGx applications. We emphasize the potential of NGS for preemptive pharmacogenotyping, which is crucial to population-specific clinical studies and patient care. We also provide examples that use publicly available population-based genomics data for population-specific PGx studies. Last, we discuss the remaining challenges and regulatory efforts towards improvements in this field.

PMID:33892143 | DOI:10.1016/j.drudis.2021.04.015

Br J Clin Pharmacol. 2021 Apr 22. doi: 10.1111/bcp.14869. Online ahead of print.

ABSTRACT

AIM: People living with HIV (PLWH) have a high burden of comorbidities and concomitant medication use. Aim of this study was to analyze the prevalence, predictors and patterns of polypharmacy (PP) in a large therapeutic drug monitoring (TDM) registry.

METHODS: We searched our TDM registry and categorized co-medications into 26 drug classes. We included patients with at least one medication recorded: PP and severe PP (sPP) were defined as the concomitant use of ≥5 or ≥10 non-antiretroviral/non-antitubercular drugs. Multivariable binary logistic analysis were conducted for identifying PP/sPP predictors. A hierarchical average-linkage cluster analysis was performed among drug classes.

RESULTS: We included 2432 participants (1158 PLWH) aged 49.6 years (± 14.4) in the 2016-2020 period. A higher number of concomitant medications (4 vs. 3.1, p<0.001) and a higher prevalence of PP (26.1% vs. 21.8%, p=0.015) were recorded in controls. At multivariable binary logistic analysis older age, female gender and HIV-positive serostatus (p=0.015) were independent predictors of PP; older age and year of inclusion were independent predictors of sPP. Cluster analysis showed that patients receiving oral drug for type-2-diabetes have a high probability of receiving several other drugs; a cluster of co-medications was observed with opioids, diuretics and central nervous system affecting drugs.

CONCLUSION: We observed a moderately high prevalence of polypharmacy in middle-aged PLWH: advanced age and female gender were associated with the greatest prevalence. The observation of co-medication clusters suggests groups of comorbidities but also identifies groups of patients at risk of similar drug to drug interactions.

PMID:33890312 | DOI:10.1111/bcp.14869

Hum Reprod. 2021 Apr 23:deab068. doi: 10.1093/humrep/deab068. Online ahead of print.

ABSTRACT

STUDY QUESTION: Does the presence of single nucleotide polymorphisms (SNPs) in the FSH receptor gene (FSHR) and/or FSH beta subunit-encoding gene (FSHB) influence ovarian response in predicted normal responders treated with rFSH?

SUMMARY ANSWER: The presence of FSHR SNPs (rs6165, rs6166, rs1394205) has a statistically significant impact in ovarian response, although this effect is of minimal clinical relevance in predicted normal responders treated with a fixed dose of 150 IU rFSH.

WHAT IS KNOWN ALREADY: Ovarian reserve markers have been a breakthrough in response prediction following ovarian stimulation. However, a significant percentage of patients show a disproportionate lower ovarian response, as compared with their actual ovarian reserve. Studies on pharmacogenetics have demonstrated a relationship between FSHR or FSHB genotyping and drug response, suggesting a potential effect of individual genetic variability on ovarian stimulation. However, evidence from these studies is inconsistent, due to the inclusion of patients with variable ovarian reserve, use of different starting gonadotropin doses, and allowance for dose adjustments during treatment. This highlights the necessity of a well-controlled prospective study in a homogenous population treated with the same fixed protocol.

STUDY DESIGN, SIZE, DURATION: We conducted a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia), from November 2016 until June 2019. All patients underwent ovarian stimulation followed by oocyte retrieval in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Blood sampling and DNA extraction was performed prior to oocyte retrieval, followed by genotyping of four SNPs from FSHR (rs6165, rs6166, rs1394205) and FSHB (rs10835638).

PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible were predicted normal responder women <38 years old undergoing their first or second ovarian stimulation cycle. Laboratory staff and clinicians were blinded to the clinical results and genotyping, respectively. The prevalence of hypo-responders, the number of oocytes retrieved, the follicular output rate (FORT), and the follicle to oocyte index (FOI) were compared between different FSHR and FSHB SNPs genotypes.

MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of derived allele homozygous SNPs in the FSHR was rs6166 (genotype G/G) 15.8%, rs6165 (genotype G/G) 34.8%, and rs1394205 (genotype A/A) 14.1%, with significant differences between Caucasian and Asian women (P < 0.001). FSHB variant rs10835638 (c.-211 G>T) was very rare (0.5%). Genetic model analysis revealed that the presence of the G allele in FSHR variant rs6166 resulted in less oocytes retrieved when compared to the AA genotype (13.54 ± 0.46 vs 14.81 ± 0.61, estimated mean difference (EMD) -1.47 (95% CI -2.82 to -0.11)). In FSHR variant rs1394205, a significantly lower number of oocytes was retrieved in patients with an A allele when compared to G/G (13.33 ± 0.41 vs 15.06 ± 0.68, EMD -1.69 (95% CI -3.06 to -0.31)). A significantly higher prevalence of hypo-responders was found in patients with the genotype A/G for FSHR variant rs6166 (55.9%, n = 57) when compared to A/A (28.4%, n = 29), ORadj 1.87 (95% CI 1.08-3.24). No significant differences were found regarding the FORT across the genotypes for FSHR variants rs6166, rs6165, or rs1394205. Regarding the FOI, the presence of the G allele for FSHR variant rs6166 resulted in a lower FOI when compared to the A/A genotype, EMD -13.47 (95% CI -22.69 to -4.24). Regarding FSHR variant rs6165, a lower FOI was reported for genotype A/G (79.75 ± 3.35) when compared to genotype A/A (92.08 ± 6.23), EMD -13.81 (95% CI -25.41 to -2.21).

LIMITATIONS, REASONS FOR CAUTION: The study was performed in relatively young women with normal ovarian reserve to eliminate biases related to age-related fertility decline; thus, caution is needed when extrapolating results to older populations. In addition, no analysis was performed for FSHB variant rs10835638 due to the very low prevalence of the genotype T/T (n = 2).

WIDER IMPLICATIONS OF THE FINDINGS: Based on our results, genotyping FSHR SNPs rs6165, rs6166, rs1394205, and FSHB SNP rs10835638 prior to initiating an ovarian stimulation with rFSH in predicted normal responders should not be recommended, taking into account the minimal clinical impact of such information in this population. Future research may focus on other populations and other genes related to folliculogenesis or steroidogenesis.

STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Theramex, and Institut Biochimique SA (IBSA). N.L.V. and M.T.H. report consultancy and conference fees from Merck, Ferring, and MSD, outside the submitted work. P.D. has received honoraria for lecturing and/or research grants from MSD, Ferring International, and Merck. D.S. reports grants and/or personal fees from MSD, Ferring International, Merck Serono, Cook, and Gedeon Richter. A.R.N., B.A.M., C.S., J.M., L.H.L., P.Q.M.M., H.T., and S.G. report no conflict of interests.

TRIAL REGISTRATION NUMBER: NCT03007043.

PMID:33889959 | DOI:10.1093/humrep/deab068

Pharmacogenomics. 2021 Apr 23. doi: 10.2217/pgs-2021-0019. Online ahead of print.

ABSTRACT

Aim: The aim of this study is to explore how SNPs may affect the response to anti-TNF-α therapy in the major autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases and Spondyloarthritis. Methodology: We conducted a systematic overview on the field, by assessing all studies that examined the association between polymorphisms and response to anti-TNF-α therapy in participants of European descent. Results: In total, six independent SNPs located in FCGR2A, FCGR3A, TNF-α and TNFRSF1B genes were significantly associated with response to TNF-α blockers, found mainly in disease-subgroup analyses. Conclusion: No common pharmacogenetic variant was identified for all autoimmune diseases under study, suggesting the requirement of more studies in the field in order to capture such predictive variants that will aid treatment selection.

PMID:33887993 | DOI:10.2217/pgs-2021-0019

Int J Cardiol. 2021 Apr 19:S0167-5273(21)00665-3. doi: 10.1016/j.ijcard.2021.04.029. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically.

METHODS: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding).

RESULTS: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77-1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66-1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62-1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively.

CONCLUSION: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

PMID:33887342 | DOI:10.1016/j.ijcard.2021.04.029

Expert Opin Drug Metab Toxicol. 2021 Apr 22. doi: 10.1080/17425255.2021.1921146. Online ahead of print.

ABSTRACT

INTRODUCTION: : Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane.

AREAS COVERED: : We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combination therapy have not yet led to a potential dose adjustment for mitotane.

EXPERT OPINION: : Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage.

PMID:33886381 | DOI:10.1080/17425255.2021.1921146

Soc Stud Sci. 2021 Apr 22:3063127211005539. doi: 10.1177/03063127211005539. Online ahead of print.

ABSTRACT

Personalized medicine raises the stakes of pharmaceutical market regulation. Drawing on pragmatist valuation studies and science and technology studies literature on personalized medicine and pharmaceutical markets, this article demonstrates how complex negotiations about the value of a pharmaceutical can constitute a market in various ways, while also shaping the concerned patient populations. Tracing the path of a pharmacogenetic treatment, Spinraza, from its approval by the European Medicines Agency to its adoption in the publicly funded Danish healthcare system, we show how the market was formatted through particular stratifications of the patient population. We conceptualize these seemingly technical moves as strategies of stratification, that is, the application of techniques to assemble and divide data - and what data are meant to represent - into groups delineated by certain characteristics. We argue that stakeholders' use of strategies of stratification has important implications not only for market access, but also for the delineation of diseases and patient populations. Hence, it is crucial to make intelligible the mutual constitution of pharmaceutical markets and patient populations and the political efforts of delineating and connecting the two.

PMID:33885344 | DOI:10.1177/03063127211005539