Crit Rev Oncol Hematol. 2021 Mar 29:103312. doi: 10.1016/j.critrevonc.2021.103312. Online ahead of print.

ABSTRACT

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in more than one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0-2, OR 2.53, 95%CI [1.48-4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95%CI [1.16-3.73], FDR-corrected p-value 0.042).

PMID:33794308 | DOI:10.1016/j.critrevonc.2021.103312

JCO Oncol Pract. 2021 Apr 1:OP2001072. doi: 10.1200/OP.20.01072. Online ahead of print.

NO ABSTRACT

PMID:33793308 | DOI:10.1200/OP.20.01072

Compr Physiol. 2021 Apr 1;11(2):1759-1783. doi: 10.1002/cphy.c200013.

ABSTRACT

Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for its ability to directly act on the liver to increase de novo glucose production and to inhibit glycogen breakdown, glucagon lowers body weight by decreasing food intake and by increasing metabolic rate. Glucagon further promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects in the heart. Interestingly, recent decades have witnessed a remarkable renaissance of glucagon's biology with the acknowledgment that glucagon has pharmacological value beyond its classical use as rescue medication to treat severe hypoglycemia. In this article, we summarize the multifaceted nature of glucagon with a special focus on its hepatic action and discuss the pharmacological potential of either agonizing or antagonizing the glucagon receptor for health and disease. © 2021 American Physiological Society. Compr Physiol 11:1759-1783, 2021.

PMID:33792899 | DOI:10.1002/cphy.c200013

Clin Pharmacol Ther. 2021 Apr 1. doi: 10.1002/cpt.2244. Online ahead of print.

ABSTRACT

Liver-derived small extracellular vesicles (sEV), prepared from small sets of banked serum samples using a novel two-step protocol, were deployed as liquid biopsy to study the induction of cytochromes P450 (CYP3A4, CYP3A5, CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (non-pregnant [T0], 1st , 2nd and 3rd [T3] trimester females; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold-increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg x 7 days [3.5 (2.5-4.5), N = 4, P = 0.029] and 600 mg x 14 days [3.7 (2.1-6.0), N = 5, P = 0.018] consistent with the mean oral midazolam area under the plasma concentration time curve (AUC) ratio in the same subjects [0.28 (0.22-0.34), P <0.0001; 0.17 (0.13-0.22), P < 0.0001]. Compared to CYP3A4, liver sEV CYP3A5 protein (subjects genotyped CYP3A5*1/*3) was weakly induced (≤ 1.5-fold). It was also possible to measure liver sEV-catalysed dextromethorphan (DEX) O-demethylation to dextrorphan (DXO), correlated with sEV CYP2D6 expression (r = 0.917, P = 0.0001; N = 10) and 3hr plasma DXO-to-DEX concentration ratio (r = 0.843, P = 0.002; N = 10), and show that CYP2D6 was not induced by RIF. Non-parametric analysis of liver sEV revealed significantly higher CYP3A4 (3.2-fold; P = 0.003) and CYP2D6 (3.7-fold; P = 0.03) protein expression in T3 versus T0 females. In contrast, expression of both OATPs in liver sEV was unaltered by RIF administration and pregnancy.

PMID:33792897 | DOI:10.1002/cpt.2244

Clin Pharmacol Ther. 2021 Mar 31. doi: 10.1002/cpt.2246. Online ahead of print.

ABSTRACT

The metabolic activity of the polymorphic CYP2D6 enzyme is dependent on the CYP2D6 genotype; however, the guidelines for translating the genotype into phenotype, which are of relevance for adequate drug dose personalization, are ambiguous. In the present study, retrospective therapeutic drug monitoring data from 4,700 CYP2D6 genotyped patients treated with risperidone, venlafaxine, and/or aripiprazole were analyzed to quantify the effect of CYP2D6 genotype on the CYP2D6 metabolic activities, as measured by metabolic ratios of these substrates. The patients were categorized into diplotypes based on the presence of normal function (CYP2D6Norm), nonfunctional (CYP2D6Nonf) and decreased function (CYP2D6Decr i.e. CYP2D6*9, CYP2D6*10, and CYP2D6*41) CYP2D6 haplotypes. Significant correlations between the metabolic ratios were observed in patients (n=77-103) co-treated with risperidone and venlafaxine, risperidone and aripiprazole, or venlafaxine and aripiprazole (ρ = 0.874, 0.785, and 0.644, respectively; p<0.001 for all). Relative metabolic CYP2D6 diplotype activity was calculated based on that the metabolic ratios, where median values for CYP2D6Nonf/Nonf and CYP2D6Norm/Norm subgroups were set to 0% and 100%, respectively. The relative CYP2D6 activities were: 7.0% for CYP2D6Nonf/*41, 16.7% for CYP2D6Nonf/*9-10, 13.2% for CYP2D6*41/*41, 24.9% for CYP2D6*41/*9-10, 33.1% for CYP2D6*9-10/*9-10, 41.3% for CYP2D6Nonf/Norm, 55.0% for CYP2D6*41/Norm, 58.9% for CYP2D6*9-10/Norm, and 149.2% for CYP2D6Norm/Normx2. Compared to the CYP2D6Norm alleles, the activity scores of CYP2D6*41 and CYP2D6*9-10 alleles were estimated to be one sixth and one third, respectively. The results of this highly powered study provide a solid basis for the translation of the CYP2D6 genotype into a drug metabolic phenotype.

PMID:33792048 | DOI:10.1002/cpt.2246

Front Pediatr. 2021 Mar 11;9:592571. doi: 10.3389/fped.2021.592571. eCollection 2021.

ABSTRACT

Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and contribute to the high mortality rates among neonates. Most HNDs are incurable, and the search for new and effective treatments is hampered by challenges peculiar to the human brain, which is guarded by the near-impervious blood-brain barrier. Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), a gene-editing tool repurposed from bacterial defense systems against viruses, has been touted by some as a panacea for genetic diseases. CRISPR has expedited the research into HNDs, enabling the generation of in vitro and in vivo models to simulate the changes in human physiology caused by genetic variation. In this review, we describe the basic principles and workings of CRISPR and the modifications that have been made to broaden its applications. Then, we review important CRISPR-based studies that have opened new doors to the treatment of HNDs such as fragile X syndrome and Down syndrome. We also discuss how CRISPR can be used to generate research models to examine the effects of genetic variation and caffeine therapy on the developing brain. Several drawbacks of CRISPR may preclude its use at the clinics, particularly the vulnerability of neuronal cells to the adverse effect of gene editing, and the inefficiency of CRISPR delivery into the brain. In concluding the review, we offer some suggestions for enhancing the gene-editing efficacy of CRISPR and how it may be morphed into safe and effective therapy for HNDs and other brain disorders.

PMID:33791256 | PMC:PMC8006930 | DOI:10.3389/fped.2021.592571

Front Genet. 2021 Mar 15;12:626685. doi: 10.3389/fgene.2021.626685. eCollection 2021.

ABSTRACT

BACKGROUND: The rapid spread of personalized medicine requires professionals to manage the "omics revolution." Therefore, the genetics/genomics literacy of healthcare professionals should be in line with the continuous advances in this field, in order to implement its potential implications for diagnosis, control and treatment of diseases. The present study investigates the effectiveness of a distance learning course on genetics and genomics targeted at medical doctors.

METHODS: In the context of a project funded by the Italian Ministry of Health, we developed a distance learning course, entitled Genetics and Genomics practice. The course focused on genetic/genomics testing, pharmacogenetics and oncogenomics and was developed according to andragogical training methods (Problem-based Learning and Case-based Learning). We used a pre-test vs. post-test study design to assess knowledge improvement on a set of 10 Multiple Choice Questions (MCQs). We analyzed the proportion of correct answers for each question pre and post-test and the mean score difference stratified by gender, age, professional status and medical discipline. Moreover, the test was submitted to the participants 8 months after the conclusion of the course (follow-up), in order to assess the retained knowledge.

RESULTS: The course was completed by 1,637 Italian physicians, most of which were primary care physicians (20.8%), public health professionals (11.5%) and specialist pediatricians (10.6%). The proportion of correct answers increased in the post-test for all the MCQs. The overall mean score significantly increased, from 59.46 in the pre-test to 71.42 in the post-test (p < 0.0001). The comparison in test performance between follow-up and pre-test demonstrated an overall knowledge improvement.

CONCLUSION: Genomics literacy among healthcare professionals is essential to ensure optimal translation to healthcare delivery of research. The results of this course suggest that distance-learning training in genetic/genomics practice represents an effective method to improve physicians' knowledge in the immediate and mid-term time scale. A preprint version of this paper is available at: https://www.researchsquare.com/article/rs-10083/v1.

PMID:33790945 | PMC:PMC8005606 | DOI:10.3389/fgene.2021.626685

Int J Gen Med. 2021 Mar 25;14:1093-1100. doi: 10.2147/IJGM.S298597. eCollection 2021.

ABSTRACT

INTRODUCTION: Warfarin has been in use for more than 60 years; however, it has serious side effects including major bleeding. The high interpatient variability in the required dose impacts the sensitivity and responsiveness to warfarin in different patients. This study aims to assess the influence of CDHR3, CACNAC1, and LTA gene polymorphisms on the variability of warfarin dose requirements and susceptibility to coronary heart disease in the Jordanian population.

METHODS: This study was conducted in the anti-coagulation clinic in Queen Alia Heart Institute in Amman, with 212 patients in total. Three SNPs were genotyped within CDHR3 (rs10270308), CACNAC1 (rs216013), and LTA (rs1041981) genes.

RESULTS: Our findings revealed that patients with LTA polymorphism are more prone to warfarin sensitivity than others. Furthermore, carriers of the LTA polymorphism needed a lower initial dose of warfarin and are associated with less variation in doses required to achieve target INR.

CONCLUSION: The current study could help in understanding the role of genetic variability in warfarin dosing and matching patients to different treatment options. Clinical applications of these findings for warfarin treatment may also contribute to improving the efficacy and safety of warfarin treatment in Jordanian patients with cardiovascular disease.

PMID:33790638 | PMC:PMC8006967 | DOI:10.2147/IJGM.S298597

Gut. 2021 Mar 31:gutjnl-2020-323276. doi: 10.1136/gutjnl-2020-323276. Online ahead of print.

ABSTRACT

OBJECTIVE: Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.

DESIGN: We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.

RESULTS: We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.

CONCLUSION: These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

PMID:33789967 | DOI:10.1136/gutjnl-2020-323276

Pharmacogenomics. 2021 Apr 1. doi: 10.2217/pgs-2020-0140. Online ahead of print.

ABSTRACT

Aim: This study investigated major allelic variants of CYP2D6, CYP3A4 and CYP3A5 in Egyptians, an Arabic population for which there is little information regarding these important pharmacogenes. Patients & methods: CYP2D6*2, *4, *5, *10, *41 and gene copy number variation, as well as CYP3A4*22 and CYP3A5*3 were determined with commercially available TaqMan assays in 145 healthy study participants. Results: The CYP2D6 alleles identified suggest that the prevalence of poor metabolizers is low as none were found among the 145 subjects investigated. The frequency for CYP3A5 nonexpressers was 74.5% and the CYP3A4*22 allele frequency was low at 2.0%. Conclusion: These preliminary findings indicate that pharmacogene variation in Egyptians is different from those of other Middle Eastern/Arabic populations and warrants further investigation.

PMID:33789449 | DOI:10.2217/pgs-2020-0140

Br J Pharmacol. 2021 Mar 30. doi: 10.1111/bph.15470. Online ahead of print.

ABSTRACT

The effectiveness of antidepressants in the treatment of major depressive disorder (MDD) varies considerably between patients. With these interindividual differences and a number of antidepressants to choose from, the first choice of treatment often fails to produce improvement in the patient's condition. A substantial part of the variation in response to antidepressants can be explained by genetic factors. Accordingly, variants related to drug metabolism in two pharmacogenes, CYP2D6 and CYP2C19, have already been translated into guidelines for antidepressant prescriptions. The role of variants in other genes that influence antidepressant responses is not yet understood. Furthermore, rare and individual variants account for a substantial part of genetic differences in antidepressant efficacy. Recent years have brought a tremendous increase in the accessibility of genome sequencing in terms of data availability and its clinical use. In this review, we summarize recent developments and current issues in the personalization of MDD treatment through pharmacogenomics.

PMID:33786859 | DOI:10.1111/bph.15470

STAR Protoc. 2021 Feb 3;2(1):100213. doi: 10.1016/j.xpro.2020.100213. eCollection 2021 Mar 19.

ABSTRACT

The protocol provided here describes methodologies for making a highly cost-effective, chemically defined medium for culturing hiPSCs we call B8 medium. The typical cost of B8 medium is US$10 per liter, which with modifications included here is more affordable than standard media. We provide simple protocols for making B8 supplement aliquots, making the basal media DMEM/F12, Matrigel-coated plates, thawing, passaging, culturing, and cryopreserving hiPSCs. We show typical differentiation results and provide a comprehensive troubleshooting guide. For complete details on the use and execution of this protocol, please refer to Kuo et al. (2020).

PMID:33786455 | PMC:PMC7988236 | DOI:10.1016/j.xpro.2020.100213

Clin Cancer Res. 2021 Mar 30:clincanres.4730.2020. doi: 10.1158/1078-0432.CCR-20-4730. Online ahead of print.

ABSTRACT

PURPOSE: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide (TMZ) in patients with recurrent high-grade astrocytoma.

EXPERIMENTAL DESIGN: This two-stage phase 1 trial determined the maximum tolerated dose (MTD) of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) TMZ using a Bayesian Optimal Interval design; then a randomized cohort-expansion compared the progression-free survival rate at 4 month (PFS4) of the two arms for an efficient determination of a TMZ schedule to combine with zotiraciclib at MTD. Pharmacokinetics (PK) and pharmacogenomic (PG) profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.

RESULTS: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250mg in both arms and thus selected for the cohort expansion. Dose-dense TMZ plus zotiraciclib (PSF4 40%) compared favorably with metronomic TMZ (PFS4 25%). Symptom burden worsened at Cycle 2 but stabilized by Cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. PK/PG analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value.

CONCLUSIONS: Zotiraciclib combined with TMZ is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

PMID:33785481 | DOI:10.1158/1078-0432.CCR-20-4730

BMC Bioinformatics. 2021 Mar 30;22(1):167. doi: 10.1186/s12859-021-04095-7.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC), derived from hepatocytes, is the main histological subtype of primary liver cancer and poses a serious threat to human health due to the high incidence and poor prognosis. This study aimed to establish a multigene prognostic model to predict the prognosis of patients with HCC.

RESULTS: Gene expression datasets (GSE121248, GSE40873, GSE62232) were used to identify differentially expressed genes (DEGs) between tumor and adjacent or normal tissues, and then hub genes were screened by protein-protein interaction (PPI) network and Cytoscape software. Seventeen genes among hub genes were significantly associated with prognosis and used to construct a prognostic model through COX hazard regression analysis. The predictive performance of this model was evaluated with TCGA data and was further validated with independent dataset GSE14520. Six genes (CDKN3, ZWINT, KIF20A, NUSAP1, HMMR, DLGAP5) were involved in the prognostic model, which separated HCC patients from TCGA dataset into high- and low-risk groups. Kaplan-Meier (KM) survival analysis and risk score analysis demonstrated that low-risk group represented a survival advantage. Univariate and multivariate regression analysis showed risk score could be an independent prognostic factor. The receiver operating characteristic (ROC) curve showed there was a better predictive power of the risk score than that of other clinical indicators. At last, the results from GSE14520 demonstrated the reliability of this prognostic model in some extent.

CONCLUSION: This prognostic model represented significance for prognosis of HCC, and the risk score according to this model may be a better prognostic factor than other traditional clinical indicators.

PMID:33784984 | DOI:10.1186/s12859-021-04095-7

World J Biol Psychiatry. 2021 Mar 30:1-19. doi: 10.1080/15622975.2021.1907711. Online ahead of print.

ABSTRACT

OBJECTIVE: Suicide is a major public health problem and it has a prominent genetic component. We performed a genome-wide association study (GWAS) of suicidal behaviour severity.

METHODS: Suicide behaviour severity was assessed within the Schedules for Clinical Assessment in Neuropsychiatry in our mood disorder sample (N = 3506) for the GWAS. We also performed polygenic risk score analyses to explore genetic sharing between suicidal behaviour severity and a number of phenotypes, including bipolar disorder, major depressive disorder, alcoholism, post-traumatic stress disorder, impulsivity, insomnia, educational attainment, loneliness, maltreatment, and amygdala volume.

RESULTS: We did not detect genome-wide significant findings at the single-marker or gene level. We report a number of suggestive single-marker and gene-based findings. Our polygenic risk score analyses did not yield significant findings with these phenotypes.

CONCLUSIONS: Larger sample sizes are required to detect moderate effects.

PMID:33783297 | DOI:10.1080/15622975.2021.1907711

Sci Rep. 2021 Mar 29;11(1):7117. doi: 10.1038/s41598-021-86514-6.

ABSTRACT

Inflammation is a natural defense process of the innate immune system, associated with the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-12 and TNFα; and enzymes including iNOS through the activation and nuclear translocation of NF-κB p65 due to the phosphorylation of IκBα. Regulation of intracellular Ca2+ is considered a promising strategy for the prevention of reactive oxygen species (ROS) production and accumulation of DNA double strand breaks (DSBs) that occurs in inflammatory-associated-diseases. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A (UA) has received an increasing attention as a novel candidate with anti-inflammatory and anti-oxidant effects. Here, we investigated the effect of UA on the suppression of pro-inflammatory molecules and NF-κB activation by targeting TLR4 signalling pathway. We also identified the influence of UA on Ca2+ entry, ROS production and DSBs availability in murine bone-marrow-derived macrophages challenged with lipopolysaccharides (LPS). We found that UA inhibits IκBα phosphorylation and supresses MAPK and PI3K activation. In addition, UA was able to reduce calcium entry, ROS production and DSBs availability. In conclusion, we suggest that urolithin A is a promising therapeutic agent for treating inflammatory diseases through suppression of NF-κB and preserving DNA through maintaining intracellular calcium and ROS homeostasis.

PMID:33782464 | DOI:10.1038/s41598-021-86514-6

Arch Med Res. 2021 Mar 26:S0188-4409(21)00046-1. doi: 10.1016/j.arcmed.2021.03.001. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Men develop gastric cancer more frequently than women, yet little is known about the mechanisms underlying this sex difference. Sex steroid hormones may influence gastric cancer risk. We therefore assessed whether major circulating adrenal precursors, androgens and estrogens were associated with gastric cancer in a high-risk Mexican population.

METHODS: Blood samples were collected at time of diagnosis from 50 noncardia gastric cancer patients and 50 histologically confirmed non-atrophic gastritis controls. Serum levels of estradiol, testosterone and dehydroepiandrosterone (DHEA) measured with a validated mass spectrometry method were categorized in tertiles as low (T1), middle (T2), and high (T3). Unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and education.

RESULTS: Levels of DHEA were inversely associated with gastric cancer (p-trend per tertile increase: <0.0001), with adjusted ORs (95% CI) of T2 and T3 (vs. T1) of 0.25 (0.09-0.70) and 0.10 (0.03-0.34), respectively. Levels of estradiol and testosterone were not significantly associated with gastric cancer.

CONCLUSIONS: Our study provides evidence that higher concentration of circulating DHEA may be associated with lower risk of noncardia gastric cancer. Longitudinal studies are needed to evaluate the temporality of this association and investigate mechanisms of disease pathogenesis.

PMID:33781580 | DOI:10.1016/j.arcmed.2021.03.001

Drug Metab Pers Ther. 2020 Dec 22. doi: 10.1515/dmdi-2020-0171. Online ahead of print.

ABSTRACT

OBJECTIVES: Warfarin use is limited by a low therapeutic index and significant interindividual variability of the daily dose. The most important factor predicting daily warfarin dose is individual genotype, polymorphisms of genes CYP2C9 (warfarin metabolism) and VKORC1 (sensitivity for warfarin). Algorithms using clinical and genetic variables could predict the daily dose before the initiation of therapy. The aim of this study was to develop and validate an algorithm for the prediction of warfarin daily dose in Czech patients.

METHODS: Detailed clinical data of patients with known and stable warfarin daily dose were collected. All patients were genotyped for polymorphisms in genes CYP2C9 and VKORC1.

RESULTS: Included patients were divided into derivation (n=175) and validation (n=223) cohorts. The final algorithm includes the following variables: Age, height, weight, treatment with amiodarone and presence of variant alleles of genes CYP2C9 and VKORC1. The adjusted coefficient of determination is 72.4% in the derivation and 62.3% in the validation cohort (p<0.001).

CONCLUSIONS: Our validated algorithm for warfarin daily dose prediction in our Czech cohort had higher precision than other currently published algorithms. Pharmacogenetics of warfarin has the potential in the clinical practice in specialized centers.

PMID:33780197 | DOI:10.1515/dmdi-2020-0171

Drug Metab Pers Ther. 2020 Dec 24. doi: 10.1515/dmdi-2020-0168. Online ahead of print.

ABSTRACT

OBJECTIVES: Hypoglycemia is the most common adverse effect of sulfonylureas (SUs) and a major concern when using these drugs. Transcription factor 7-like 2 (TCF7L2) rs7903146 C>T polymorphism is an established and well characterized genetic marker of type 2 diabetes (T2DM) risk. The aim of the present study was to analyze the potential association of TCF7L2 rs7903146 C>T polymorphism with SU-induced hypoglycemia in a well characterized cohort of SU-treated patients previously genotyped for cytochrome P450 2C9 (CYP2C9) and P450 oxidoreductase (POR).

METHODS: The study group consisted of 176 SU-treated T2DM patients of whom 92 had experienced at least one drug-associated hypoglycemic event. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for TCF7L2 rs7903146 genotyping.

RESULTS: TCF7L2 rs7903146 C>T genotype and allele frequency did not differ between cases and controls (p=0.745 and 0.671, respectively). In logistic regression analysis adjusted for other factors affecting hypoglycemia, including CYP2C9 and POR genotypes, TCF7L2 rs7903146 C>T polymorphism did not increase the risk of hypoglycemia (OR=1.238, 95% C.I.=0.750-2.044, p=0.405).

CONCLUSIONS: TCF7L2 rs7903146 C>T polymorphism is not associated with SU-induced hypoglycemia. Identifying additional gene polymorphisms associated with SU-induced hypoglycemia is crucial for improving T2DM patient therapy with SUs.

PMID:33780196 | DOI:10.1515/dmdi-2020-0168

Front Genet. 2021 Mar 12;12:626845. doi: 10.3389/fgene.2021.626845. eCollection 2021.

ABSTRACT

Genetic testing has the potential to revolutionize primary care, but few health systems have developed the infrastructure to support precision population medicine applications or attempted to evaluate its impact on patient and provider outcomes. In 2018, Sanford Health, the nation's largest rural nonprofit health care system, began offering genetic testing to its primary care patients. To date, more than 11,000 patients have participated in the Sanford Chip Program, over 90% of whom have been identified with at least one informative pharmacogenomic variant, and about 1.5% of whom have been identified with a medically actionable predisposition for disease. This manuscript describes the rationale for offering the Sanford Chip, the programs and infrastructure implemented to support it, and evolving plans for research to evaluate its real-world impact.

PMID:33777099 | PMC:PMC7994529 | DOI:10.3389/fgene.2021.626845