Sr Care Pharm. 2021 Jun 1;36(6):270-272. doi: 10.4140/TCP.n.2021.270.

ABSTRACT

The topic of phenoconversion was chosen for discussion in this editorial to add to the work presented by Cox and Marshall in this issue of The Senior Care Pharmacist. When considering the increased sensitivity that older patients have to medications, the inclusion of pharmacogenomics (PGx) information can be of great importance. Understanding the consequences of phenoconversion can further expand the role of PGx in patient care.

PMID:34016223 | DOI:10.4140/TCP.n.2021.270

Sr Care Pharm. 2021 Jun 1;36(6):268-269. doi: 10.4140/TCP.n.2021.268.

ABSTRACT

The prospects for the application of pharmacogenomic science for improving health care appear to be exciting, and it should be recognized rightly for its clinical applicability. Notwithstanding, the use of these techniques needs to be viewed in context. When people can reliably access safe and effective medicines at an affordable cost and with consistent support from pharmacists to ensure the outcomes are optimized and the prospect of iatrogenic disease is minimized, then there is no doubt that the wider adoption of these techniques needs to be embraced with enthusiasm.

PMID:34016222 | DOI:10.4140/TCP.n.2021.268

Immunol Lett. 2021 May 17:S0165-2478(21)00081-X. doi: 10.1016/j.imlet.2021.05.003. Online ahead of print.

ABSTRACT

Obesity has become a relevant problem in transplantation medicine with steadily increasing numbers of obese graft recipients. However, the effect of immunomodulatory drugs on transplant-related outcomes among obese patients are unknown. Therefore, we evaluated the impact of rapamycin on allograft rejection and alloimmune response in a murine model of diet-induced obesity and fully-mismatched skin transplantation. Rapamycin significantly delayed allograft rejection in obese recipient mice compared to treated lean mice (14.5 days vs. 10.7 days, p = 0.005). Treatment with rapamycin increased frequencies of monocytic myeloid-derived suppressor cells (M-MDSCs), augmented the immunosuppressive activity of M-MDSCs on T cells through indoleamine 2,3-dioxygenase pathway and shifted CD4+ T cells towards regulatory T cells in obese graft recipients. In summary, our results demonstrate that rapamycin delays allograft rejection in obese graft recipients by enhancing suppressive immune cell function and shifting immune cell subsets towards anti-inflammatory conditions.

PMID:34015361 | DOI:10.1016/j.imlet.2021.05.003

Pharmacogenomics. 2021 May 20. doi: 10.2217/pgs-2021-0021. Online ahead of print.

ABSTRACT

Aim: To perform a systematic review to determine the efficacy/safety of PGx-guided opioid therapy for chronic/postoperative pain. Materials & methods: We searched PubMed and other specialized databases. Articles were considered if they compared the efficacy/safety of PGx-guided opioid therapy versus usual care. The risk of bias assessment was performed using Cochrane tools. Results: A total of 3794 records were retrieved. Only five were included for data extraction. A lower requirement of analgesics during postoperative in the PGx-guided intervention arm was reported in two studies. Also, two studies reported significant pain improvement in favor of the PGx-guided therapy when analyzing the subgroup of patients with a high-risk CYP2D6 phenotype. Conclusion: Despite the findings described, information on the efficacy/safety of this intervention is scarce.

PMID:34013775 | DOI:10.2217/pgs-2021-0021

Heliyon. 2021 May 3;7(5):e06908. doi: 10.1016/j.heliyon.2021.e06908. eCollection 2021 May.

ABSTRACT

INTRODUCTION: Direct-acting antivirals (DAAs) represent a breakthrough in hepatitis C virus (HCV) treatment as they directly inhibit HCV nonstructural (NS) proteins (NS3/4A, NS5A, and NS5B). However, ongoing debates exist regarding their relationship with hepatocellular carcinoma (HCC) whose incidence is widely debated among investigators. This study was conducted to identify host pharmacogenetic factors that may influence HCC incidence upon using HCV DAAs.

MATERIALS AND METHODS: Details regarding 16 HCV DAAs were collected from literature and DrugBank database. Digital structures of these drugs were fed into the pharmacogenomics/pharmacovigilance in - silico pipeline (PHARMIP) to predict the genetic factors that may underpin HCC development.

RESULTS: We identified 184 unique genes and 40 unique variants that may have key answers for the DAA/HCC paradox. These findings could be used in different methods to aid in the precise application of HCV DAAs and minimize the proposed risk for HCC. All results could be accessed at: https://doi.org/10.17632/8ws8258hn3.2.

DISCUSSION: All the identified factors are evidence related to HCC and significantly predicted by PHARMIP as DAA targets. We discuss some examples of the methods of using these results to address the DAA/HCC controversy based on the following three primary levels: 1 - individual DAA drug, 2 - DAA subclass, and 3 - the entire DAA class. Further wet laboratory investigation is required to evaluate these results.

PMID:34013078 | PMC:PMC8113831 | DOI:10.1016/j.heliyon.2021.e06908

Oncogene. 2021 May 19. doi: 10.1038/s41388-021-01826-1. Online ahead of print.

ABSTRACT

Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.

PMID:34012098 | DOI:10.1038/s41388-021-01826-1

Pharmacogenomics J. 2021 May 19. doi: 10.1038/s41397-021-00233-9. Online ahead of print.

ABSTRACT

Steroid remains the keystone therapy for Idiopathic Nephrotic Syndrome (NS). Besides genetic factors and histological changes, pharmacogenomic factors also affect the steroid response. The upregulation of P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP-1) modulate the pharmacokinetics of steroids and may contribute to steroid resistance. Flow-cytometric analysis of P-gp, MRP-1 expression and functional activity on peripheral blood mononuclear cells (PBMCs) was carried out in steroid-sensitive nephrotic syndrome (SSNS) (n = 171, male 103, mean age = 8.54 ± 4.3); and steroid-resistant nephrotic syndrome (SRNS) (n = 83, male 43, mean age = 7.43 ± 4.6) patients. The genotypings of MDR-1 gene were carried out using PCR-RFLP. We observed that the percentage expression of P-gp (10.01 ± 2.09 and 3.79 ± 1.13, p < 0.001); and MRP-1 (15.91 ± 3.99 and 7.40 ± 2.33, p < 0.001) on lymphocyte gated population were significantly higher in SRNS than that of SSNS. The functional activity of P-gp and MRP-1 was also significantly escalated in SRNS as compared to SSNS (68.10 ± 13.35 and 28.93 ± 7.57, p < 0.001); (72.13 ± 8.34 and 31.56 ± 8.65, p < 0.001) respectively. AUC-ROC curve analysis revealed that P-gp and MRP-1 expression with a cut-off value of 7.13% and 9.62% predicted SRNS with the sensitivity of 90% and 80.7%; and specificity 90% and 80%, respectively. Moreover, MDR-1 homozygous mutant TT+AA for G2677T/A (rs2032582) was significantly associated with SRNS (p = 0.025, OR = 2.86 CI = 1.14-7.14). The expression of P-gp (9.68 ± 4.99 v/s 5.88 ± 3.38, p = 0.002) was significantly higher in the patients of homozygous mutant alleles compared to wildtype GG. The increased expression and functionality of P-gp and MRP-1 contribute to steroid resistance, and MDR-1 homozygous mutant G2677T/A promotes steroid resistance by inducing P-gp expression in NS.

PMID:34011975 | DOI:10.1038/s41397-021-00233-9

Endocr Connect. 2021 May 1:EC-21-0196. doi: 10.1530/EC-21-0196. Online ahead of print.

ABSTRACT

Most data on natural history of nonfunctioning adrenal incidentalomas (NFAI) are provided by follow-ups up to 5 years. We conducted a 10.5 (9.1-11.9)-year follow-up study of NFAI in 67 participants (20 (29.9%) males, 47 (70.1%) females) of mean age 57.9 (52.3-63.9) years and BMI 27.42 (24.07-30.56) kg/m2). We also evaluated the associations between baseline body mass index (BMI) and changes of NFAIs' characteristics at follow-up. Progression to mild autonomous cortisol excess (MACE) was observed in 15 (22 %) patients, with 14 of them having post overnight dexamethasone suppression test (ODST) cortisol between 50-138 nmol/L and only one >138 nmol/L. The progression rate was significantly higher in overweight and obese than in normal weighted subjects. Patients that developed MACE had significantly higher baseline mean cortisol after 1 mg ODST. Tumor enlargement ≥10 mm occurred in 8.9% of patients. All tumors had persistent radiological characteristics typical for adrenal adenoma. In comparison with reports of shorter observational periods, we observed higher growth rate ≥10 mm and higher progression rate from NFAI to MACE, particularly in overweight and obese subjects. We concluded that duration of the follow-up period is an important factor in characterizing the natural history of NFAI. Higher baseline BMI and higher baseline cortisol after ODST might predict the long-term likelihood of progression in hormonal activity. The magnitudes of observed progressions in growth or hormonal activity were clinical insignificant. Our long-term follow-up therefore clearly supports the general view that long term monitoring of patients with NFAI is not necessary.

PMID:34010150 | DOI:10.1530/EC-21-0196

J Psychiatry Neurosci. 2021 May 19;46(3):E358-E368. doi: 10.1503/jpn.200159.

ABSTRACT

BACKGROUND: The microbiota interacts with the brain through the gut-brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment.

METHODS: In this case-control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry.

RESULTS: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment.

LIMITATIONS: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results.

CONCLUSION: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode.

PMID:34008933 | DOI:10.1503/jpn.200159

Exp Dermatol. 2021 May 19. doi: 10.1111/exd.14392. Online ahead of print.

ABSTRACT

Atopic dermatitis (AD) is an inflammatory skin disorder affecting up to 20% of the pediatric population worldwide. AD patients commonly exhibit dry skin and pruritus and are at a higher risk for developing asthma as well as allergic rhinitis. Filaggrin loss-of-function variants are the most widely replicated genetic risk factor among >40 genes associated with AD susceptibility. The prevalence of AD has tripled in the past 30 years in industrial countries around the world. This urgent public health issue has prompted the field to more thoroughly investigate the mechanisms that underlie AD pathogenesis amidst environmental exposures. Epigenetics is the study of heritable, yet reversible, modifications to the genome that affect gene expression. The past decade has seen an emergence of exciting studies identifying a role for epigenetic regulation associated with AD and at the interface of environmental factors. Such epigenetics studies have been empowered by sequencing technologies and human genome variation and epigenome maps. miRNAs that post-transcriptionally modify gene expression and circRNAs have also been discovered to be associated with AD. Here we review our current understanding of epigenetics associated with atopic dermatitis. We discuss studies identifying distinct DNA methylation changes in keratinocytes and T cells, eQTLs as DNA methylation switches that impact gene expression, and histone modification changes associated with AD-related microbial dysbiosis. We further highlight the need for integrative and collaborative analyses to elucidate the impact of these epigenetic findings as potential drivers for AD pathogenesis and the translation of this new knowledge to develop newer targeted treatments.

PMID:34008901 | DOI:10.1111/exd.14392

Innov Pharm. 2020 Jul 31;11(3). doi: 10.24926/iip.v11i3.3203. eCollection 2020.

ABSTRACT

OBJECTIVE: To review available literature regarding pharmacogenomics (PGx) effects on the metabolism of irinotecan by the UGT1A1 gene and the resulting dose adjustments based on PGx genetic variant.

SUMMARY: Irinotecan is a chemotherapy agent commonly used in treatment of various cancers such as metastatic colorectal cancer (mCRC) and others. The extent of decreased function of UGT1A1 varies based on genotype so irinotecan dose adjustments may be needed. Those with UGT1A1 homozygous *28/*28 genotype may experience 70% reduction in activity, while heterozygous genotypes with *1/*28 may only experience 30% loss. UGT1A1*6 variants may also play a role in decreased function. The incidence of *28 and *6 alleles varies among ethnic populations resulting in the need for dosage adjustments to avoid toxicities.

CONCLUSION: These findings add to a growing body of literature that suggest patients with UGT1A1 *28 or *6 variant alleles benefit from lower doses of irinotecan. However, due to the heterogeneity of currently available studies, more evidence that investigates various regimens in different patient populations is needed to determine the most appropriate dosing strategies. Although other factors, as well as efficacy considerations will likely influence clinical decision making, genotype may be an important factor when determining dose.

PMID:34007623 | PMC:PMC8075136 | DOI:10.24926/iip.v11i3.3203

Innov Pharm. 2020 Apr 30;11(2). doi: 10.24926/iip.v11i2.3228. eCollection 2020.

ABSTRACT

OBJECTIVE: To demonstrate the types of clinical recommendations a pharmacogenomics pharmacist may make to medical clinicians with regard to medication management to improve therapeutic outcomes based on varied levels of medical literature evidence.

SUMMARY: This case demonstrates how a common type of patient seen in a pharmacist practice may present with a varied pharmacogenomic (PGx) profile, how they may benefit from PGx analysis, and how varying levels of medical literature evidence can be used with clinical decision making.

CONCLUSION: PGx testing can help avoid adverse drug reactions (ADRs) or medication inefficacy by assisting in the adjustment of current or future medication doses. It can also help predict the best medications to use or those to avoid in advance by eliminating much of the existing dosing or medication selection method of trial and error.

PMID:34007616 | PMC:PMC8051925 | DOI:10.24926/iip.v11i2.3228

South Afr J HIV Med. 2021 Apr 28;22(1):1206. doi: 10.4102/sajhivmed.v22i1.1206. eCollection 2021.

ABSTRACT

BACKGROUND: Blood-cerebrospinal fluid (CSF) barrier transporters affect the influx and efflux of drugs. The antiretrovirals tenofovir and emtricitabine may be substrates of blood-brain barrier (BBB) and blood-CSF barrier transporters, but data are limited regarding the pharmacogenetics and pharmacokinetics of their central nervous system (CNS) penetration.

OBJECTIVES: We investigated genetic polymorphisms associated with CSF disposition of tenofovir and emtricitabine.

METHOD: We collected paired plasma and CSF samples from 47 HIV-positive black South African adults who were virologically suppressed on efavirenz, tenofovir and emtricitabine. We considered 1846 single-nucleotide polymorphisms from seven relevant transporter genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, SLCO1B1 and ABCC4) and 782 met a linkage disequilibrium (LD)-pruning threshold.

RESULTS: The geometric mean (95% confidence interval [CI]) values for tenofovir and emtricitabine CSF-to-plasma concentration ratios were 0.023 (0.021-0.026) and 0.528 (0.460-0.605), respectively. In linear regression models, the lowest p-value for association with the tenofovir CSF-to-plasma ratio was ABCB1 rs1989830 (p = 1.2 × 10-3) and for emtricitabine, it was ABCC5 rs11921035 (p = 1.4 × 10-3). None withstood correction for multiple testing.

CONCLUSION: No genetic polymorphisms were associated with plasma, CSF concentrations or CSF-to-plasma ratios for either tenofovir or emtricitabine.

PMID:34007475 | PMC:PMC8111650 | DOI:10.4102/sajhivmed.v22i1.1206

Transl Psychiatry. 2021 May 18;11(1):294. doi: 10.1038/s41398-021-01417-4.

ABSTRACT

Pharmacogenetics aims to improve clinical care by studying the relationship between genetic variation and variable drug response. Large population-based datasets could improve our current understanding of pharmacogenetics from selected study populations. We provide real-world pharmacogenetic frequencies of genotypes and (combined) phenotypes of a large Danish population-based case-cohort sample (iPSYCH2012; data of the Integrative Psychiatric Research consortium). The genotyped sample consists of 77,684 individuals, of which 51,464 individuals had diagnoses of severe mental disorders (SMD case-cohort) and 26,220 were individuals randomly selected from the Danish population (population cohort). Array-based genotype data imputed to 8.4 million genetic variants was searched for a selected pharmacogenetic panel of 42 clinically relevant variants and a CYP2D6 gene deletion and duplication. We identified 19 of 42 variants. Minor allele frequencies (MAFs) were consistent with previously reported MAFs, and did not differ between SMD cases and population cohorts. Almost all individuals carried at least one genetic variant (> 99.9%) and 87% carried three or more genetic variants. When genotypes were translated into phenotypes, also > 99.9% of individuals had at least one divergent phenotype (i.e. divergent from the common phenotypes considered normal, e.g. extensive metabolizer). The high number of identified individuals with at least one pharmacogenetic variant or divergent phenotype indicates the importance of pharmacogenetic panel-based genotyping. Combined CYP2C19-CYP2D6 phenotypes revealed that 72.7% of individuals had divergent phenotypes for one or both enzymes. As CYP2D6 and CYP2C19 have an important role in the metabolism of psychotropic drugs, this indicates the relevance of pharmacogenetic testing specifically in individuals using psychotropic drugs.

PMID:34006849 | DOI:10.1038/s41398-021-01417-4

Mol Oncol. 2021 May 18. doi: 10.1002/1878-0261.13013. Online ahead of print.

ABSTRACT

Vitamin D is used to reduce cancer risk and improve the outcome of cancer patients, but the vitamin D receptor (VDR; also known as the calcitriol receptor) pathway needs to be functionally intact to ensure the biological effects of circulating calcitriol, the active form of vitamin D. Besides estrogen receptor alpha (ERα), estrogen-related receptor alpha (ERRα) has also been shown to interfere with the VDR pathway, but its role in the antitumor and transactivation activity of calcitriol is completely unknown in breast cancer (BC). We observed that ERRα functionally supported the proliferation of BC cell lines and acted as a calcitriol-induced regulator of VDR. As such, ERRα deregulated the calcitriol-VDR transcription by enhancing the expression of CYP24A1 as well as of both ERα and aromatase (CYP19A1) in calcitriol-treated cells. ERRα knockdown limited the effect of calcitriol by reducing calcitriol-induced G0/G1 phase cell cycle arrest and by affecting the expression of cyclin D1 and p21/Waf. The interactome analysis suggested that Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α (PGC-1α) and Proline-, glutamic acid-, and leucine-rich protein 1 (PELP-1) are key players in the genomic actions of the calcitriol-VDR-ERRα axis. Evaluation of patient outcomes in the The Cancer Genome Atlas (TCGA) dataset showed the translational significance of the biological effects of the VDR-ERRα axis, highlighting that VDR, CYP24A1 and ERRα overexpression correlates with poor prognosis in basal-like BC.

PMID:34003583 | DOI:10.1002/1878-0261.13013

Arch Toxicol. 2021 May 18. doi: 10.1007/s00204-021-03063-7. Online ahead of print.

ABSTRACT

Over the last decade, important clinical benefits have been achieved in cancer patients by using drug-targeting strategies. Nevertheless, drug resistance is still a major problem in most cancer therapies. Epithelial-mesenchymal plasticity (EMP) and tumour microenvironment have been described as limiting factors for effective treatment in many cancer types. Moreover, epithelial-to-mesenchymal transition (EMT) has also been associated with therapy resistance in many different preclinical models, although limited evidence has been obtained from clinical studies and clinical samples. In this review, we particularly deepen into the mechanisms of which intermediate epithelial/mesenchymal (E/M) states and its interconnection to microenvironment influence therapy resistance. We also describe how the use of bioinformatics and pharmacogenomics will help to figure out the biological impact of the EMT on drug resistance and to develop novel pharmacological approaches in the future.

PMID:34003341 | DOI:10.1007/s00204-021-03063-7

Pharmacogenomics. 2021 May 18. doi: 10.2217/pgs-2020-0128. Online ahead of print.

ABSTRACT

Aim: To evaluate the application of next-generation sequencing-based targeted protocol for full-length CYP3A4 gene sequencing analysis. Materials & methods: The developed sequencing protocol was applied to analyze human DNA samples (n = 7) obtained from tuberculosis patients admitted to the Riga East University Hospital, Center of Tuberculosis and Lung diseases. Results: The sequencing data quality was sufficient for the detection of already known genetic variants, as well as for identifying rare and novel variants dispersed throughout the CYP3A4 gene with a high degree of confidence. Conclusion: Developed protocol can be applied in subpopulation level association studies to determine whether specific genetic variants or variant combinations from multiple regions of the CYP3A4 gene are of clinical significance.

PMID:34003019 | DOI:10.2217/pgs-2020-0128

Nat Genet. 2021 May 17. doi: 10.1038/s41588-021-00857-4. Online ahead of print.

ABSTRACT

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

PMID:34002096 | DOI:10.1038/s41588-021-00857-4

Pharmacogenet Genomics. 2021 May 14. doi: 10.1097/FPC.0000000000000436. Online ahead of print.

ABSTRACT

OBJECTIVES: The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs. This could increase the susceptibility for SARS-CoV-2 infection and the severity of COVID-19.

PATIENTS AND METHODS: We performed genotyping of SNPs in the genes ACE2 and ACE in 297 SARS-CoV-2-positive and 253 SARS-CoV-2-negative tested patients. We analyzed the association of the SNPs with susceptibility for SARS-CoV-2 infection and the severity of COVID-19.

RESULTS: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics and clinical characteristics. For ACE2 rs2285666, the GG genotype or G-allele was significantly associated with an almost two-fold increased SARS-CoV-2 infection risk and a three-fold increased risk to develop serious disease or COVID-19 fatality. In contrast, the ACE polymorphism was not related to infection risk or severity of disease. In a multivariable analysis, the ACE2 rs2285666 G-allele remained as an independent risk factor for serious disease besides the known risk factors male gender and cardiovascular disease.

CONCLUSIONS: In summary, our report appears to be the first showing that a common ACE2 polymorphism impacts the risk for SARS-CoV-2 infection and the course of COVID-19 independently from previously described risk factors.

PMID:34001841 | DOI:10.1097/FPC.0000000000000436

Xenobiotica. 2021 May 18:1-22. doi: 10.1080/00498254.2021.1931554. Online ahead of print.

ABSTRACT

We explored the potential effects of genetic variations on the concentration to dose ratio (CDR) of VPA in pediatric epilepsy patients.Two hundred and twenty-nine epileptic children on VPA monotherapy were included, and the VPA trough concentrations at steady-state of all subjects were determined.Nineteen single nucleotide polymorphisms (SNPs) of seven selected genes related to the metabolizing enzymes and transporters of VPA were identified, and their influences on CDRVPA (a logarithmic transformation was performed if abnormally distributed) were evaluated.UGT2B7 rs7668258 (C > T) TT genotype was associated with a decrease in lnCDRVPA among epileptic children receiving VPA monotherapy (β = -0.191, p = 0.036). Significantly lower lnCDRVPA was also observed in pediatric patients with UGT1A6 rs2070959 (A > G) GG genotype compared to those AA genotype (β = -0.270, p = 0.021).This research indicated that UGT2B7 rs7668258 (C > T) and UGT1A6 rs2070959 (A > G) polymorphisms may be correlated to the normalized plasma concentrations of VPA in Chinese epileptic children. The associations could be abolished after Bonferroni's correction and our findings need to be validated in further and larger investigations.

PMID:34000957 | DOI:10.1080/00498254.2021.1931554