Clin Transl Sci. 2021 Sep 29. doi: 10.1111/cts.13159. Online ahead of print.

ABSTRACT

The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single-dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure. The candidate gene analysis showed that the ABCB1 c.3435T>C and c.2677T/G>A, and the SLCO1A2 c.516A>C variants were associated with reduced celiprolol area under the plasma concentration-time curve (AUC0-∞ ). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC0-∞ . A genotype scoring system was developed based on these variants and applied to stratify the participants to low and high celiprolol exposure genotype groups. The mean AUC0-∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC0-∞ in the high exposure group (p = 1.08 × 10-11 ). In addition, the results showed gene-gene interactions in the effects of SLCO1A2 and ABCB1 variants on celiprolol AUC0-∞ (p < 5 × 10-6 ) suggesting an interplay between organic anion transporting polypeptide 1A2 and P-glycoprotein in celiprolol absorption. Taken together, these data indicate that P-glycoprotein and organic anion transporting polypeptide 1A2 play a role in celiprolol pharmacokinetics. Furthermore, patients with ABCB1 and SLCO1A2 genotypes associated with low celiprolol exposure may have an increased risk of poor blood-pressure lowering response to celiprolol.

PMID:34585840 | DOI:10.1111/cts.13159

Mol Psychiatry. 2021 Sep 28. doi: 10.1038/s41380-021-01297-6. Online ahead of print.

ABSTRACT

BACKGROUND: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels.

METHODS: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength.

RESULTS: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18-0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21-0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05-0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = -0.40; 95% CIs: -0.62 to -0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38-1.01; Glu: g = 0.63; 95% CIs: 0.31-0.94) while MCC Glu levels were decreased in the patient group except TRS (g = -0.17; 95% CIs: -0.33 to -0.01).

CONCLUSIONS: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.

PMID:34584230 | DOI:10.1038/s41380-021-01297-6

Sci Rep. 2021 Sep 28;11(1):19222. doi: 10.1038/s41598-021-98877-x.

ABSTRACT

Inter-individual differences of drug responses could be attributed to genetic variants of pharmacogenes such as cytochrome P450 (CYP), phase 2 enzymes, and transporters. In contrast to extensive studies on the genetic polymorphisms of CYP gene, genetic mutation spectrum of other pharmacogenes was under-representative in the pharmacogenetics investigations. Here we studied the genetic variations of 125 pharmacogenes including drug transporters, non-CYP phase 1 enzymes, phase 2 enzymes, nuclear receptors and others in Chinese from the Chinese Millionome Database (CMDB), of which 38,188 variants were identified. Computational analyses of the 2554 exonic variants found 617 deleterious missense variants, 91.1% of which were rare, and of the 54 loss-of-function (splice acceptor, splice donor, start lost, and stop gained) variants, 53 (98.1%) were rare. These results suggested an enrichment of rare variants in functional ones for pharmacogenes. Certain common functional variants including NUDT15 13:48611934 G/A (rs186364861), UGT1A1 2:234676872 C/T (rs34946978), and ALDH2 12:112241766 G/A (rs671) were population-specific for CMDB Chinese because they were absent (with a zero of variant allele frequency) or very rare in other gnomAD populations. These findings might be useful for the further pharmacogenomics research and clinical application in Chinese.

PMID:34584183 | DOI:10.1038/s41598-021-98877-x

Transplant Cell Ther. 2021 Sep 25:S2666-6367(21)01253-7. doi: 10.1016/j.jtct.2021.09.011. Online ahead of print.

ABSTRACT

BACKGROUND: CYP3A5 and CYP3A4 are the predominant enzymes responsible for tacrolimus metabolism, however only a proportion of the population expresses CYP3A5 secondary to genetic variation. CYP3A5 is expressed in both the intestine and the liver and has been shown to impact both oral tacrolimus bioavailability and metabolism. It is recommended to increase the initial tacrolimus dose by 50-100% in patients who are known CYP3A5 expressers, however it is currently unknown whether this dose adjustment is appropriate for intravenous (IV) tacrolimus administration.

OBJECTIVE: The objective of this study was to evaluate the impact of CYP3A5 genotype as well as other pharmacogenes on IV tacrolimus exposure to determine whether the current genotype-guided dosing recommendations are appropriate for this formulation. Additionally, this study aimed to investigate dose conversion requirements among CYP3A5 genotypes when converting from IV to PO tacrolimus.

STUDY DESIGN: This study was a retrospective chart review of all patients who underwent allogeneic stem cell transplant at Michigan Medicine between 6/1/2014 to 3/1/2018 who received IV tacrolimus at the time of their transplant. Secondary use samples were obtained for genotyping CYP3A5, CYP3A4 and ABCB1. Patient demographic information, tacrolimus dosing and troughs, and concomitant medications at the time of tacrolimus trough were retrospectively collected from the patient medical record. The IV dose-controlled concentration (C/D) and the IV:PO exposure ratio was calculated for all tacrolimus doses and patients, respectively. The impact of CYP3A5, CYP3A4, and ABCB1 genotypes on the IV C/D were evaluated with linear mixed modeling. The impact of CYP3A5 genotype on the IV:PO ratio was evaluated while controlling for age and concomitant azole inhibitor.

RESULTS: CYP3A5 and CYP3A4 genotypes were significantly associated with the IV C/D with CYP3A5 expressers having 20% lower and CYP3A4 rapid metabolizers having 20% lower tacrolimus exposure. Neither genotype remained significant in the multivariable model although age, hematocrit, and concomitant strong azole inhibitors were associated with increased IV C/D. When controlling for patient age and sex, CYP3A5 expressers had significantly higher IV/PO ratios than CYP3A5 non-expressers (3.42 vs 2.78, p=0.04). Post-hoc analysis identified the IV/PO ratio may differ among different CYP3A5 genotypes and azole inhibitor combinations.

CONCLUSIONS: This study has demonstrated that the current genotype-guided tacrolimus dose adjustment recommendations are inappropriate for CYP3A5 expressers receiving IV tacrolimus. Although CYP3A5 genotype is likely a minor contributor to IV tacrolimus exposure, genotype, in addition to capturing concomitant CYP3A inhibitors would likely improve IV:PO dose conversion selection.

PMID:34583027 | DOI:10.1016/j.jtct.2021.09.011

PLoS One. 2021 Sep 28;16(9):e0257324. doi: 10.1371/journal.pone.0257324. eCollection 2021.

ABSTRACT

BACKGROUND: High-risk human papillomavirus HPV (HR-HPV) modifies cervical cancer risk in people living with HIV, yet African populations are under-represented. We aimed to compare the frequency, multiplicity and consanguinity of HR-HPVs in HIV-negative and HIV-positive Zimbabwean women.

METHODS: This was a cross-sectional study consisting of women with histologically confirmed cervical cancer attending Parirenyatwa Group of Hospitals in Harare, Zimbabwe. Information on HIV status was also collected for comparative analysis. Genomic DNA was extracted from 258 formalin fixed paraffin embedded tumour tissue samples, and analysed for 14 HR-HPV genotypes. Data was analysed using Graphpad Prism and STATA.

RESULTS: Forty-five percent of the cohort was HIV-positive, with a median age of 51 (IQR = 42-62) years. HR-HPV positivity was detected in 96% of biospecimens analysed. HPV16 (48%), was the most prevalent genotype, followed by HPV35 (26%), HPV18 (25%), HPV58 (11%) and HPV33 (10%), irrespective of HIV status. One third of the cohort harboured a single HPV infection, and HPV16 (41%), HPV18 (21%) and HPV35 (21%) were the most prevalent. HIV status did not influence the prevalence and rate of multiple HPV infections (p>0.05). We reported significant (p<0.05) consanguinity of HPV16/18 (OR = 0.3; 95% CI = 0.1-0.9), HPV16/33 (OR = 0.3; 95% CI = 0.1-1.0), HPV16/35 (OR = 3.3; 95% CI = 2.0-6.0), HPV35/51 (OR = 6.0; 95%CI = 1.8-15.0); HPV39/51 (OR = 6.4; 95% CI = 1.8-15), HPV31/52 (OR = 6.2; 95% CI = 1.8-15), HPV39/56 (OR = 11 95% CI = 8-12), HPV59/68 (OR = 8.2; 95% CI = 5.3-12.4), HPV66/68 (OR = 7; 95% CI = 2.4-13.5), independent of age and HIV status.

CONCLUSION: We found that HIV does not influence the frequency, multiplicity and consanguinity of HR-HPV in cervical cancer. For the first time, we report high prevalence of HPV35 among women with confirmed cervical cancer in Zimbabwe, providing additional evidence of HPV diversity in sub-Saharan Africa. The data obtained here probes the need for larger prospective studies to further elucidate HPV diversity and possibility of selective pressure on genotypes.

PMID:34582476 | DOI:10.1371/journal.pone.0257324

Clin Pharmacol Ther. 2021 Sep 28. doi: 10.1002/cpt.2428. Online ahead of print.

ABSTRACT

Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events-in particular, myelotoxicity. Thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium® Expanded Multi-Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (1) poor/intermediate, or (2) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (HR=2.90, 95%CI: 1.58-5.31, p=0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (aHR=2.67, 95% CI: 1.44-4.94, p=0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions.

PMID:34582038 | DOI:10.1002/cpt.2428

Pharmacogenomics. 2021 Sep 28. doi: 10.2217/pgs-2021-0087. Online ahead of print.

ABSTRACT

Mycophenolic acid (MPA) is a common immunosuppressive drug for kidney transplantation patients, and is characterized by a narrow therapeutic index and significant individual variability. UGTs are the main enzymes responsible for the metabolism of MPA. Although, many studies have focused on the relationship between UGT polymorphisms and pharmacokinetics and adverse reactions of MPA, the conclusion are controversial. We reviewed the relevant literature and summarized the significant influences of UGT polymorphisms, such as UGT1A8 (rs1042597, rs17863762), UGT1A9 (rs72551330, rs6714486, rs17868320, rs2741045, rs2741045) and UGT2B7 (rs7438135, rs7439366, rs7662029), on the pharmacokinetics of MPA and its metabolites and adverse reactions. The review provides a reference for guiding the individualized administration of MPA and reducing adverse reactions to MPA.

PMID:34581204 | DOI:10.2217/pgs-2021-0087

Clin Pharmacol Ther. 2021 Sep 28. doi: 10.1002/cpt.2429. Online ahead of print.

ABSTRACT

A previous study in 356 healthy Finnish volunteers showed that glycochenodeoxycholate-3-O-glucuronide (GCDCA-3G) and glycodeoxycholate-3-O-glucuronide (GDCA-3G) are promising biomarkers of organic anion transporting polypeptide 1B1 (OATP1B1). In the same cohort, we now evaluated the performances of two other OATP1B1 biomarkers, coproporphyrin I (CPI) and III (CPIII), and compared them to GCDCA-3G and GDCA-3G. Based on decreased (*5 and *15) and increased (*14 and *20) function SLCO1B1 haplotypes, we stratified the participants to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Fasting plasma CPI concentration was 68% higher in the poor (95% confidence interval, 44%, 97%; P=1.74×10-10 ), 7% higher in the decreased (0%, 15%; P=0.0385), 10% lower in the increased (3%, 18%; P=0.0087), and 23% lower in the highly increased (1%, 40%; P=0.0387) function group than in the normal function group. CPIII concentration was 27% higher (7%, 51%; P=0.0071) in the poor function group than in the normal function group. CPI and CPIII detected poor OATP1B1 function with areas under the precision-recall curve (AUPRC) of 0.388 (95% confidence interval, 0.197, 0.689) and 0.0798 (0.0485, 0.203), and receiver operating characteristic curve (AUROC) of 0.888 (0.851, 0.919) and 0.731 (0.682, 0.776). The AUPRC and AUROC of GCDCA-3G were, however, 0.389 (0.258, 0.563) and 0.100 (-0.0046, 0.204; P=0.0610) larger than those of CPI, and 0.697 (0.555, 0.831) and 0.257 (0.141, 0.373; P<0.0001) larger than those of CPIII. In conclusion, these data indicate that plasma CPI outperforms CPIII in detecting altered OATP1B1 function, but GCDCA-3G is an even more sensitive OATP1B1 biomarker than CPI.

PMID:34580865 | DOI:10.1002/cpt.2429

Thorax. 2021 Sep 27:thoraxjnl-2020-215523. doi: 10.1136/thoraxjnl-2020-215523. Online ahead of print.

ABSTRACT

INTRODUCTION: Asthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Each endotype is likely characterised by distinct molecular mechanisms that identify optimal therapies.

METHODS: We applied unsupervised (without a priori clinical criteria) principal component analysis on sputum airway cells RNA-sequencing transcriptomic data from 19 asthmatics from the Severe Asthma Research Program at baseline and 6-8 weeks follow-up after a 40 mg dose of intramuscular corticosteroids. We investigated principal components PC1, PC3 for association with 55 clinical variables.

RESULTS: PC3 was associated with baseline Th2 clinical features including blood (rank-sum p=0.0082) and airway (rank-sum p=0.0024) eosinophilia, FEV1 change (Kendall tau-b R=-0.333 (-0.592 to -0.012)) and follow-up FEV1 albuterol response (Kendall tau-b R=0.392 (0.079 to 0.634)). PC1 with blood basophlia (rank-sum p=0.0191). The top 5% genes contributing to PC1, PC3 were enriched for distinct immune system/inflammation ontologies suggesting distinct subject-specific clusters of transcriptomic response to corticosteroids. PC3 association with FEV1 change was reproduced in silico in a comparable independent 14-subject (baseline, 8 weeks after daily inhaled corticosteroids (ICS)) airway epithelial cells microRNAome dataset.

CONCLUSIONS: Transcriptomic PCs from this unsupervised methodology define molecular pharmacogenomic endotypes that may yield novel biology underlying different subject-specific responses to corticosteroid therapy in asthma, and optimal personalised asthma care. Top contributing genes to these PCs may suggest new therapeutic targets.

PMID:34580195 | DOI:10.1136/thoraxjnl-2020-215523

Mayo Clin Proc. 2021 Sep 25:S0025-6196(21)00551-6. doi: 10.1016/j.mayocp.2021.05.030. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the relations between caffeine-derived metabolites (methylxanthines) and plasma lipids by use of population-based data from 2 European countries.

METHODS: Families were randomly selected from the general population of northern Belgium (FLEMENGHO), from August 12, 1985, until November 22, 1990, and 3 Swiss cities (SKIPOGH), from November 25, 2009, through April 4, 2013. We measured plasma concentrations (FLEMENGHO, SKIPOGH) and 24-hour urinary excretions (SKIPOGH) of 4 methylxanthines-caffeine, paraxanthine, theobromine, and theophylline-using ultra-high-performance liquid chromatography-tandem mass spectrometry. We used enzymatic methods to estimate total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels and the Friedewald equation for low-density lipoprotein cholesterol levels in plasma. We applied sex-specific mixed models to investigate associations between methylxanthines and plasma lipids, adjusting for major confounders.

RESULTS: In both FLEMENGHO (N=1987; 1055 [53%] female participants) and SKIPOGH (N=990; 523 [53%] female participants), total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels increased across quartiles of plasma caffeine, paraxanthine, and theophylline (total cholesterol levels by caffeine quartiles in FLEMENGHO, male participants: 5.01±0.06 mmol/L, 5.05±0.06 mmol/L, 5.27±0.06 mmol/L, 5.62±0.06 mmol/L; female participants: 5.24±0.06 mmol/L, 5.15±0.05 mmol/L, 5.25±0.05 mmol/L, 5.42±0.05 mmol/L). Similar results were observed using urinary methylxanthines in SKIPOGH (total cholesterol levels by caffeine quartiles, male participants: 4.54±0.08 mmol/L, 4.94±0.08 mmol/L, 4.87±0.08 mmol/L, 5.27±0.09 mmol/L; female participants: 5.12±0.07 mmol/L, 5.21±0.07 mmol/L, 5.28±0.05 mmol/L, 5.28±0.07 mmol/L). Furthermore, urinary caffeine and theophylline were positively associated with high-density lipoprotein cholesterol in SKIPOGH male participants.

CONCLUSION: Plasma and urinary caffeine, paraxanthine, and theophylline were positively associated with plasma lipids, whereas the associations involving theobromine were less clear. We postulate that the positive association between caffeine intake and plasma lipids may be related to the sympathomimetic function of methylxanthines, mitigating the overall health-beneficial effect of caffeine intake.

PMID:34579945 | DOI:10.1016/j.mayocp.2021.05.030

Genome Med. 2021 Sep 27;13(1):152. doi: 10.1186/s13073-021-00968-x.

ABSTRACT

Deep learning is a subdiscipline of artificial intelligence that uses a machine learning technique called artificial neural networks to extract patterns and make predictions from large data sets. The increasing adoption of deep learning across healthcare domains together with the availability of highly characterised cancer datasets has accelerated research into the utility of deep learning in the analysis of the complex biology of cancer. While early results are promising, this is a rapidly evolving field with new knowledge emerging in both cancer biology and deep learning. In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools. We provide specific examples of how deep learning may be applied in cancer diagnosis, prognosis and treatment management. We also assess the current limitations and challenges for the application of deep learning in precision oncology, including the lack of phenotypically rich data and the need for more explainable deep learning models. Finally, we conclude with a discussion of how current obstacles can be overcome to enable future clinical utilisation of deep learning.

PMID:34579788 | DOI:10.1186/s13073-021-00968-x

Nutrients. 2021 Sep 16;13(9):3212. doi: 10.3390/nu13093212.

ABSTRACT

Autism spectrum disorder (ASD) is a disruptive neurodevelopmental disorder manifested by abnormal social interactions, communication, emotional circuits, and repetitive behaviors and is more often diagnosed in boys than in girls. It is postulated that ASD is caused by a complex interaction between genetic and environmental factors. Epigenetics provides a mechanistic link between exposure to an unbalanced maternal diet and persistent modifications in gene expression levels that can lead to phenotype changes in the offspring. To better understand the impact of the early development environment on the risk of ASD in offspring, we assessed the effect of maternal high-fat (HFD), high-carbohydrate, and mixed diets on molecular changes in adolescent and young adult offspring frontal cortex and hippocampus. Our results showed that maternal HFD significantly altered the expression of 48 ASD-related genes in the frontal cortex of male offspring. Moreover, exposure to maternal HFD led to sex- and age-dependent changes in the protein levels of ANKRD11, EIF4E, NF1, SETD1B, SHANK1 and TAOK2, as well as differences in DNA methylation levels in the frontal cortex and hippocampus of the offspring. Taken together, it was concluded that a maternal HFD during pregnancy and lactation periods can lead to abnormal brain development within the transcription and translation of ASD-related genes mainly in male offspring.

PMID:34579089 | DOI:10.3390/nu13093212

Medicina (Kaunas). 2021 Sep 10;57(9):955. doi: 10.3390/medicina57090955.

ABSTRACT

Pharmacogenomic (PGx) information can guide drug and dose selection, optimize therapy outcomes, and/or decrease the risk of adverse drug events (ADEs). This report demonstrates the impact of a pharmacist-led medication evaluation, with PGx assisted by a clinical decision support system (CDSS), of a patient with multiple comorbidities. Following several sub-optimal pharmacotherapy attempts, PGx testing was recommended. The results were integrated into the CDSS, which supported the identification of clinically significant drug-drug, drug-gene, and drug-drug-gene interactions that led to the phenoconversion of cytochrome P450. The pharmacist evaluated PGx results, concomitant medications, and patient-specific factors to address medication-related problems. The results identified the patient as a CYP2D6 intermediate metabolizer (IM). Duloxetine-mediated competitive inhibition of CYP2D6 resulted in phenoconversion, whereby the patient's CYP2D6 phenotype was converted from IM to poor metabolizer for CYP2D6 co-medication. The medication risk score suggested a high risk of ADEs. Recommendations that accounted for PGx and drug-induced phenoconversion were accepted. After 1.5 months, therapy changes led to improved pain control, depression status, and quality of life, as well as increased heart rate, evidenced by patient-reported improved sleep patterns, movement, and cognition. This case highlights the pharmacist's role in using PGx testing and a CDSS to identify and mitigate medication-related problems to optimize medication regimen and medication safety.

PMID:34577878 | DOI:10.3390/medicina57090955

Pharmaceuticals (Basel). 2021 Sep 6;14(9):905. doi: 10.3390/ph14090905.

ABSTRACT

Dermatologic pathologies are the fourth most common cause of non-fatal disease worldwide; however, they produce a psychosocial, economic, and occupational impact equal to or greater than other chronic conditions. The most prevalent are actinic keratosis, followed by basal-cell carcinoma, in a lesser proportion acne vulgaris, psoriasis, and hidradenitis suppurativa, among others, and more rarely dermatitis herpetiformis. To treat actinic keratosis and basal-cell carcinoma, 5-fluorouracil (5-FU) 0.5% is administered topically with good results, although in certain patients it produces severe toxicity. On the other hand, dapsone is a drug commonly used in inflammatory skin conditions such as dermatitis herpetiformis; however, it occasionally causes hemolytic anemia. Additionally, biologic drugs indicated for the treatment of moderate-to-severe psoriasis and hidradenitis suppurativa have proved to be effective and safe; nevertheless, a small percentage of patients do not respond to treatment with biologics in the long term or they are ineffective. This interindividual variability in response may be due to alterations in genes that encode proteins involved in the pathologic environment of the disease or the mechanism of action of the medication. Pharmacogenetics studies the relationship between genetic variations and drug response, which is useful for the early identification of non-responsive patients and those with a higher risk of developing toxicity upon treatment. This review describes the pharmacogenetic recommendations with the strongest evidence at present for the treatments used in dermatology, highlighting those included in clinical practice guides. Currently, we could only find pharmacogenetic clinical guidelines for 5-FU. However, the summary of product characteristics for dapsone contains a pharmacogenetic recommendation from the United States Food and Drug Administration. Finally, there is an enormous amount of information from pharmacogenetic studies in patients with dermatologic pathologies (mainly psoriasis) treated with biologic therapies, but they need to be validated in order to be included in clinical practice guides.

PMID:34577605 | DOI:10.3390/ph14090905

Pharmaceuticals (Basel). 2021 Sep 3;14(9):899. doi: 10.3390/ph14090899.

ABSTRACT

BACKGROUND: This study measures the use of drugs within the therapeutic areas of antithrombotic agents (B01), the cardiovascular system (C), analgesics (N02), psycholeptics (N05), and psychoanaleptics (N06) among the general population (GP) in comparison to persons with diabetes in Denmark. The study focuses on drugs having pharmacogenomics (PGx) based dosing guidelines for CYP2D6, CYP2C19, and SLCO1B1 to explore the potential of applying PGx-based decision-making into clinical practice taking drug-drug interactions (DDI) and drug-gene interactions (DGI) into account.

METHODS: This study is cross-sectional, using The Danish Register of Medicinal Product Statistics as the source to retrieve drug consumption data.

RESULTS: The prevalence of use in particular for antithrombotic agents (B01) and cardiovascular drugs (C) increases significantly by 4 to 6 times for diabetic users compared to the GP, whereas the increase for analgesics (N02), psycoleptics, and psychoanaleptics (N06) was somewhat less (2-3 times). The five most used PGx drugs, both in the GP and among persons with diabetes, were pantoprazole, simvastatin, atorvastatin, metoprolol, and tramadol. The prevalence of use for persons with diabetes compared to the GP (prevalence ratio) increased by an average factor of 2.9 for all PGx drugs measured. In addition, the prevalence of use of combinations of PGx drugs was 4.6 times higher for persons with diabetes compared to GP. In conclusion, the findings of this study clearly show that a large fraction of persons with diabetes are exposed to drugs or drug combinations for which there exist PGx-based dosing guidelines related to CYP2D6, CYP2C19, and SLCO1B1. This further supports the notion of accessing and accounting for not only DDI but also DGI and phenoconversion in clinical decision-making, with a particular focus on persons with diabetes.

PMID:34577599 | DOI:10.3390/ph14090899

Int J Mol Sci. 2021 Sep 10;22(18):9815. doi: 10.3390/ijms22189815.

ABSTRACT

Pharmacogenetics is one of the cornerstones of Personalized Precision Medicine that needs to be implemented in the routine of our patients' clinical management in order to tailor their therapies as much as possible, with the aim of maximizing efficacy and minimizing toxicity. This is of great importance, especially in pediatric cancer and even more in complex malignancies such as neuroblastoma, where the rates of therapeutic success are still below those of many other types of tumors. The studies are mainly focused on germline genetic variants and in the present review, state of the art is presented: which are the variants that have a level of evidence high enough to be implemented in the clinic, and how to distinguish them from the ones that still need validation to confirm their utility. Further aspects as relevant characteristics regarding ontogeny and future directions in the research will also be discussed.

PMID:34575974 | DOI:10.3390/ijms22189815

Int J Mol Sci. 2021 Sep 10;22(18):9800. doi: 10.3390/ijms22189800.

ABSTRACT

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions.

PMID:34575958 | DOI:10.3390/ijms22189800

J Pers Med. 2021 Sep 8;11(9):896. doi: 10.3390/jpm11090896.

ABSTRACT

Pharmacogenomic (PGx) testing is being increasingly recognized by clinicians as an essential tool to guide medication decisions for treatment of psychiatric illnesses. Extensive implementation of PGx testing, however, varies by setting and location. In this retrospective study, we reviewed charts from 592 patients diagnosed with a psychiatric disorder at the Loyola University Medical Center, for whom PGx testing was performed. Information collected included demographics at the time of testing, psychiatric diagnosis, medical and psychiatric history and medications prior and after PGx testing. Of the 592 charts analyzed, the most common primary diagnoses were depression (52%) and anxiety (12%). Prior to PGx testing, 72% of patients were prescribed three or more medications, whereas, after testing, only 44% were prescribed three or more medications included in the test panel (p < 0.0001). The most common clinical consideration on the PGx reports was recommendation to reduce dosages (33%). After PGx testing, the proportion of patients taking incongruent medications decreased from 26% to 19% and that of patients taking congruent medications increased from 74% to 81% (p = 0.006). The results from this retrospective data analysis demonstrated a reduction in polypharmacy and an increase in recommendation-congruent medication prescribing resulting from implementation of PGx testing.

PMID:34575674 | DOI:10.3390/jpm11090896

J Pers Med. 2021 Aug 31;11(9):877. doi: 10.3390/jpm11090877.

ABSTRACT

The exponential expansion of genomic data coupled with the lack of appropriate clinical categorization of the variants is posing a major challenge to conventional medications for many common and rare diseases. To narrow this gap and achieve the goals of personalized medicine, a collaborative effort should be made to characterize the genomic variants functionally and clinically with a massive global genomic sequencing of "healthy" subjects from several ethnicities. Familial-based clustered diseases with homogenous genetic backgrounds are amongst the most beneficial tools to help address this challenge. This review will discuss the diagnosis, management, and clinical monitoring of familial hypercholesterolemia patients from a wide angle to cover both the genetic mutations underlying the phenotype, and the pharmacogenomic traits unveiled by the conventional and novel therapeutic approaches. Achieving a drug-related interactive genomic map will potentially benefit populations at risk across the globe who suffer from dyslipidemia.

PMID:34575654 | DOI:10.3390/jpm11090877

J Pers Med. 2021 Aug 28;11(9):853. doi: 10.3390/jpm11090853.

ABSTRACT

Syndrome of inappropriate antidiuretic hormone (SIADH) is a common cause of hyponatremia, and many cases represent adverse reactions to drugs that alter ion channel conductance within the peptidergic nerve terminals of the posterior pituitary. The frequency of drug-induced SIADH increases with age; as many as 20% of patients residing in nursing homes have serum sodium levels below 135 mEq/L. Mild hyponatremia is associated with cognitive changes, gait instability, and falls. Severe hyponatremia is associated with cerebral edema, seizures, permanent disability, and/or death. Although pharmacogenetic tests are now being deployed for some drugs capable of causing SIADH (e.g., antidepressants, antipsychotics, and opioid analgesics), the implementation of these tests has been based upon the prior known association of these drugs with other serious adverse drug reactions (e.g., electrocardiographic abnormalities). Work is needed in large observational cohorts to quantify the strength of association between pharmacogene variants and drug-induced SIADH so that decision support can be developed to identify patients at high risk.

PMID:34575630 | DOI:10.3390/jpm11090853