J Dev Behav Pediatr. 2021 Apr 1;42(3):205-212. doi: 10.1097/DBP.0000000000000883.

ABSTRACT

OBJECTIVE: To determine the association between genetic variants reported to affect risperidone and adverse events (AEs) in children and adolescents.

METHODS: Individuals aged 18 years or younger with ≥4 weeks of risperidone exposure in a deidentified DNA biobank were included. The primary outcome was AE frequency as a function of genotype. Individuals were classified according to metabolizer status for CYP2D6, CYP3A4, and CYP3A5; wild type, heterozygote, or homozygote for specific single nucleotide variants for DRD2, DRD3, HTR2A, and HTR2C; and wild type versus nonwild type for multiple uncommon variants in ABCG2, ABCB1, and HTR2C. Tests of association of each classification to AEs were performed using a Fisher exact test and logistic regression, and statistically significant classifications were included in a final logistic regression.

RESULTS: The final cohort included 257 individuals. AEs were more common in CYP2D6 poor/intermediate metabolizers (PMs/IMs) than normal/rapid/ultrarapid metabolizers (NMs/RMs/UMs) in univariate and multivariate analysis. HTR2A-rs6311 heterozygotes and homozygotes had fewer AEs than wild types in logistic regression but not in univariate analysis. In the final multivariable model adjusting for age, race, sex, and risperidone dose, AEs were associated with CYP2D6 (adjusted odds ratio [AOR] 2.6, 95% CI 1.1-5.5, for PMs/IMs vs. NMs/RMs/UMs) and HTR2A-rs6311 (AOR 0.6, 95% CI 0.4-0.9, for each variant allele), both consistent with previous studies.

CONCLUSION: Children and adolescents who are CYP2D6 PMs/IMs may have an increased risk for risperidone AEs. Of the genes and variants studied, only CYP2D6 has consistent association and sufficient data for clinical use, whereas HTR2A-rs6311 has limited data and requires further study.

PMID:33759847 | DOI:10.1097/DBP.0000000000000883

Pharmacogenomics. 2021 Mar 24. doi: 10.2217/pgs-2020-0096. Online ahead of print.

ABSTRACT

Lopinavir and ritonavir are substrates of permeability glycoprotein encoded by ABCB1. The efficacy and safety of these drugs is unknown in coronavirus disease-2019 (COVID-19) patients affected by ABCB1 genetic variability. Patients carrying one or two copies of the ABCB1 C3435T were predictively considered as risk phenotypes. It was predicted that risk phenotypes due to carrying either one or two copies of ABCB1 C3435T were highly prevalent in Europe (76.8%; 95% CI: 75-78), followed by America (67%; 95% CI: 65-69), Asia (63.5%; 95% CI: 62-65) and Africa (41.4%; 95% CI: 37-46), respectively. It is hypothesized that a considerable proportion of COVID-19 patients treated with lopinavir/ritonavir inheriting ABCB1 C3435T genetic polymorphism may be predisposed to either therapeutic failure or toxicity.

PMID:33759544 | DOI:10.2217/pgs-2020-0096

Clin Pharmacol Ther. 2021 Mar 24. doi: 10.1002/cpt.2233. Online ahead of print.

ABSTRACT

Escitalopram is one of the most commonly used antidepressant drugs but exhibits a substantial interindividual variation in clinical response. A key factor underlying response differences is the polymorphic nature of the CYP2C19 gene encoding the major enzyme responsible for escitalopram metabolism. While pre-emptive CYP2C19 genotyping may improve escitalopram treatment outcome by dose individualisation, much of the interindividual variability cannot be assigned to the currently known CYP2C19 gene variants. The aim of the present study was to search for novel CYP2C-haplotypes for better genetic prediction of escitalopram metabolism. Firstly, the CYP2C18/CYP2C19 locus was sequenced from gDNA obtained from 24 patients previously genotyped as CYP2C19*1/*1 showing consistently low serum concentrations of escitalopram (<25 nM/10 mg). Three new haplotypes of the CYP2C locus (CYP2C:TG, CYP2C:TA and CYP2C:CG) were here identified, and their functional roles were evaluated using gDNA from 875 previously genotyped escitalopram-treated patients. The CYP2C:CG and CYP2C:TA haplotypes had no significant impact on escitalopram concentration. Based on the estimated effects of the novel CYP2C-haplotypes on escitalopram exposure, the predicted serum concentrations of escitalopram in homozygous CYP2C:TG and CYP2C19*17 carriers were 24.8% and 17.3% lower compared with the baseline (CYP2C:CG and CYP2C:TA), respectively. In conclusion, a novel CYP2C-haplotype defined by rs2860840T and rs11188059G associated with ultrarapid metabolism of escitalopram was identified. Further studies should clarify the genetic basis for the enhanced escitalopram metabolism and the impact of the CYP2C:TG haplotype on the metabolism of other CYP2C19 substrates like omeprazole, voriconazole and clopidogrel.

PMID:33759177 | DOI:10.1002/cpt.2233

Support Care Cancer. 2021 Mar 24. doi: 10.1007/s00520-021-06170-4. Online ahead of print.

ABSTRACT

PURPOSE: We estimated the prevalence of potentially actionable pharmacogenetic (PGx) variants related to symptom control medications (SCMs) based on institutional prescribing patterns and correlated presenting symptoms with SCM prescribing.

METHODS: This was a retrospective study of adult ambulatory cancer patients undergoing electronic distress screening (EDS) within 90 days of intake to the cancer hospital. We estimated the proportion prescribed SCM(s) with PGx evidence within 90 days of intake. Those with potentially actionable variants were estimated using population frequency data from 1000 genomes. The expected number at risk of altered drug response was estimated. The associations between symptom scores and SCM(s) were estimated with logistic regression and threshold analyses performed with receiver operating characteristic (ROC) curves.

RESULTS: Of 6985 patients, 3222 (46%) received ≥ one SCM. Of these, 2760 (86%) received SCM(s) with PGx evidence for CYP2B6, CYP2C19, CYP2D6, or SLC6A4; 2719 (84%) received a drug metabolized by CYP2D6, most commonly hydrocodone (40.4%), ondansetron (35.6%), oxycodone (24.2%), and/or tramadol (7.1%). Based on this, about one quarter were expected to have altered metabolism and/or drug response. One third were prescribed two or more SCMs with PGx evidence. About half reported at least one severe symptom, which significantly correlated with SCM prescribing (p < 0.001). Threshold scores were identified that highly correlated with SCM prescribing for anxiety, depression, nausea, neuropathy, pain, and sleep.

CONCLUSION: About half presented with significant symptom burden, which highly correlated with SCM prescribing. Most received SCMs with PGx evidence. Preemptive PGx testing for these variants should be evaluated in prospective trials to evaluate the impact on symptom control.

PMID:33758969 | DOI:10.1007/s00520-021-06170-4

Cardiol Rev. 2021 Mar 19. doi: 10.1097/CRD.0000000000000384. Online ahead of print.

ABSTRACT

Genetic testing for cardiovascular (CV) disease has had a profound impact on the diagnosis and evaluation of monogenic causes of CV disease, such as hypertrophic and familial cardiomyopathies, long QT syndrome, and familial hypercholesterolemia (FH). The success in genetic testing for monogenic diseases has prompted special interest in utilizing genetic information in the risk assessment of more common diseases such as atherosclerotic cardiovascular disease (ASCVD). Polygenic risk scores (PRS) have been developed to assess the risk of coronary artery disease (CAD) that now include millions of single-nucleotide polymorphisms (SNPs) that have been identified through genome-wide association studies (GWAS). While these PRS have demonstrated a strong association with CAD in large cross-sectional population studies, there remains intense debate regarding the added value that PRS contribute to existing clinical risk prediction models such as the pooled cohort equations (PCEs). In this review, we provide a brief background of genetic testing for monogenic drivers of CV disease and then focus on the recent developments in genetic risk assessment of ASCVD, including the use of PRS. We outline the genetic testing that is currently available to all cardiologists in the clinic and discuss the evolving sphere of specialized cardiovascular genetics programs (CVGPs) that integrate the expertise of cardiologists, geneticists, and genetic counselors. Finally, we review the possible implications that PRS and pharmacogenomic data may soon have on clinical practice in the care for patients with or at risk of developing ASCVD.

PMID:33758125 | DOI:10.1097/CRD.0000000000000384

J Pharmacol Exp Ther. 2021 Mar 23:JPET-AR-2020-000166. doi: 10.1124/jpet.120.000166. Online ahead of print.

ABSTRACT

Pulmonary hypertension (PH) is a disease of hyperplasia of pulmonary vascular cells. The pentose phosphate pathway (PPP) - a fundamental glucose metabolism pathway - is vital for cell growth. Because treatment for PH is inadequate, our goal was to determine whether inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, prevents maladaptive gene expression that promotes smooth muscle cell (SMC) growth, reduces pulmonary artery remodeling, and normalizes hemodynamics in experimental models of PH. PH was induced in mice by exposure to 10% oxygen (Hx) or weekly injection of vascular endothelial growth factor receptor blocker (Sugen5416 (SU); 20 mg.kg-1) during exposure to hypoxia (Hx+SU). A novel G6PD inhibitor (PDD4091;1.5 mg kg-1) was injected daily during exposure to Hx. We measured right ventricle (RV) pressure and left ventricle (LV) pressure-volume relationships, and gene expression in lungs of normoxic, Hx, and Hx+SU, and G6PD inhibitor-treated, mice. RV systolic and end-diastolic pressures were higher in Hx and Hx+SU than normoxic-control mice. Hx and Hx+SU decreased expression of epigenetic modifiers (writers and erasers), increased hypomethylation of the DNA, and induced aberrant gene expression in lungs. G6PD inhibition decreased maladaptive expression of genes and SMC growth, reduced pulmonary vascular remodeling, decreased RV pressures, and increased cardiac index, compared to untreated PH groups. Pharmacologic inhibition of G6PD activity, by normalizing activity of epigenetic modifiers and DNA methylation, efficaciously reduces RV pressure overload in Hx and Hx+SU mice, pre-clinical models of PH, appears to be a safe pharmacotherapeutic strategy. Significance Statement The results of this study demonstrated inhibition of a metabolic enzyme efficaciously reduces pulmonary hypertension. For first time, we show that a novel inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the fundamental pentose phosphate pathway, modulates DNA methylation and alleviates pulmonary artery remodeling and dilates pulmonary artery to reduce pulmonary hypertension.

PMID:33758056 | DOI:10.1124/jpet.120.000166

Cancer Chemother Pharmacol. 2021 Mar 23. doi: 10.1007/s00280-021-04264-8. Online ahead of print.

ABSTRACT

PURPOSE: Irinotecan (IR) displays significant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response).

METHODS: Eligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Affymetrix-DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250 MBq-99mTc-IDA, data derived for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS).

RESULTS: N = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P < 0.05) included: (1) PK: SN38-Metabolic Ratio with CLHNI, 1hRET, (2) Grade 3+ diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+ neutropenia with CLHNI, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T1/2-HNI, XDH (rs 207440), and ABCB11 (rs 4148777).

CONCLUSIONS: Exploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extensive pharmacogenomics. Further work is required to confirm and validate these findings in a larger cohort of patients.

AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY (ANZCTR) NUMBER: ACTRN12610000897066, Date registered: 21/10/2010.

PMID:33755789 | DOI:10.1007/s00280-021-04264-8

Pharmacogenomics. 2021 Mar 23. doi: 10.2217/pgs-2021-0002. Online ahead of print.

NO ABSTRACT

PMID:33754802 | DOI:10.2217/pgs-2021-0002

Gut. 2021 Mar 22:gutjnl-2021-324388. doi: 10.1136/gutjnl-2021-324388. Online ahead of print.

ABSTRACT

OBJECTIVE: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections.

DESIGN: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020.

RESULTS: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001).

CONCLUSIONS: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy.

TRIAL REGISTRATION NUMBER: ISRCTN45176516.

PMID:33753421 | DOI:10.1136/gutjnl-2021-324388

Clin Pharmacokinet. 2021 Mar 10. doi: 10.1007/s40262-020-00955-2. Online ahead of print.

ABSTRACT

OBJECTIVE: The aim of this systematic review and meta-analysis was to compare the clinical outcomes between genotype-guided and conventional tacrolimus doses in kidney transplantation patients.

MATERIALS AND METHODS: We performed a comprehensive literature search of the PubMed, EMBASE, and Cochrane databases from the date of inception to 26 February 2020. References of the retrieved articles were also reviewed and any further relevant studies were included. The search terms included 'tacrolimus', 'cytochrome P-450 CYP3A', 'polymorphism, genetic', 'genomics', 'genome', 'genotype', 'genes', 'alleles', and 'pharmacogenetics'.

RESULTS: Our study showed that the genotype-guided group included an increased proportion of patients with tacrolimus concentrations in the therapeutic range at steady state (risk ratio [RR] 1.40, 95% confidence interval [CI] 1.14-1.72, p = 0.001; high quality), with a trend for achieving therapeutic concentrations earlier compared with those in the conventional group. However, there was no statistical difference in the incidence of delayed graft function (RR 1.98, 95% CI 0.92-1.76, p = 0.12; moderate quality), incidence of acute rejection (RR 1.00, 95% CI 0.64-1.55, p = 1.00; moderate quality), incidence of graft survival censored for death (RR 1.02, 95% CI 0.98-1.06, p = 0.37; moderate quality), and incidence of adverse effects (AEs).

CONCLUSIONS: Although the genotype-guided group had a higher proportion of patients within the targeted concentration and less median time to achieve the therapeutic range, the clinical endpoints, including delayed graft function, acute rejection, graft survival censored for death, and AEs were similar in both groups. All in all, evidence suggested there was no utility in pharmacogenetics for tacrolimus based on the cytochrome P450 (CYP) 3A5 genotype. Studies with Chinese and African American populations are needed due to the frequency of genetic polymorphisms of CYP3A5. Furthermore, a dosing algorithm that includes demographic and clinical factors plus multiple genetic variants should be added for consideration, and may optimize early tacrolimus exposure.

PMID:33751414 | DOI:10.1007/s40262-020-00955-2

Pharmacogenomics J. 2021 Mar 9. doi: 10.1038/s41397-021-00226-8. Online ahead of print.

ABSTRACT

Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank linked to de-identified electronic health records, we studied 157 patients with a baseline pain score higher than 4 (0-10 scale) who received codeine. Based on CYP2D6 genotyping, 69 were classified as poor/intermediate and 88 as normal/ultrarapid CYP2D6 metabolizers. Pain response was defined as a score of 4 or lower while receiving codeine. In a propensity-score adjusted model, poor/intermediate metabolizers had lower odds (OR = 0.35, p = 0.02) of achieving a pain response than normal/ultrarapid metabolizers. To discriminate between codeine responders and nonresponders, a score including CYP2D6 phenotype and clinical variables was built. The response rate was 38.5% among patients in the high, 17.3% in the intermediate, and 9.4% in the low-score groups, respectively (p = 0.001).

PMID:33750887 | DOI:10.1038/s41397-021-00226-8

Sci Rep. 2021 Mar 9;11(1):5449. doi: 10.1038/s41598-021-84909-z.

ABSTRACT

Response to anti-TNF therapy is of pivotal importance in patients with Crohn's disease (CD). Here we integrated our and previously reported PBMC derived transcriptomic and genomic data for identification of biomarkers for discrimination between responders and non-responders to anti-TNF therapy. CD patients, who were naïve with respect to the treatment with biologicals, were enrolled in the study. DNA and RNA were extracted from peripheral blood mononuclear cells. RNA-seq was performed using BGISEQ-500. Genotyping was performed using Infinium Global Screening Array. Association regressions were carried out with 12 week response to adalimumab as an outcome variable. RNA-seq analysis confirmed 7 out of 65 previously suggested genes involved in anti-TNF response. Subsequently, analysis of single nucleotide variants in regions of confirmed genes identified 5 variants near MMD and two in ELOVL7 intronic regions associated with treatment response to anti-TNF. Functional analysis has shown that rs1465352, rs4422035 and rs78620886 are listed at H3K9ac_Pro histone modification epigenetic mark. The present study confirmed MMD and ELOVL7 involvement in anti-TNF response and revealed that the regulation of MMD and ELOVL7 gene regions in ADA response may be a part of a complex interplay extending from genetic to epigenetic and to transcriptomic level.

PMID:33750834 | DOI:10.1038/s41598-021-84909-z

Pharmacogenomics. 2021 Mar 22. doi: 10.2217/pgs-2020-0094. Online ahead of print.

ABSTRACT

Aim & methods: To review the existing literature concerning the relationship between venous thromboembolism (VTE) and prostate cancer (PC) and explore the putative biological and clinical implications of VTE genetic markers on PC patients by screening the PubMed database. Results: Considering the roles of VTE genome-wide association studies-identified genetic determinants in disease development in the general population, these variants might also underlie the susceptibility for PC-related VTE. Therefore, they could help to identify those with a positive benefit-to-harm ratio for thromboprophylaxis approaches during cancer therapy management, thereby improving patient's prognosis. Conclusion: Future studies are mandatory to explore the relationship between VTE and PC and dissect the predictive value of VTE genome-wide association studies-identified genetic determinants in PC patients, given their clinical implications.

PMID:33749329 | DOI:10.2217/pgs-2020-0094

Ann Pharmacother. 2021 Mar 22:10600280211002053. doi: 10.1177/10600280211002053. Online ahead of print.

ABSTRACT

BACKGROUND: Methotrexate (MTX) is an antirheumatic drug, transported by reduced folate carrier-1 (RFC1). The most common RFC1 gene variant, c.80 A>G (rs1051266) is ambiguously linked to adverse effects of MTX therapy in some rheumatoid arthritis (RA) patients.

OBJECTIVE: The purpose of meta-analysis was to summarize all major published studies on c.80 A>G SNP to clarify this ambiguity in MTX therapy.

METHODS: A total of 18 studies representing 3592 RA patients comprising 699 men and 2893 women were included. Both fixed and random effect models were applied to study the data.

RESULTS: The RFC1 80A-allele showed null association with MTX-mediated toxicity in both fixed (odds ratio [OR] = 0.91; 95% CI = 0.80-1.03) and random effects (OR = 0.89; 95% CI: 0.71-1.11) models. Because heterogeneity was observed in this association (P = 0.0006), data were segregated based on use of folate therapy. In 7 studies (n = 1191) where folate was used along with MTX, RFC1 AA patients showed reduced risk for MTX-mediated toxicity (OR = 0.67; 95% CI: 0.50-0.89; P = 0.0006). The RFC1 80A-allele was found to increase the efficacy of MTX therapy by 1.53-fold (95% CI: 1.24-1.88), whereas the 80AA-genotype increased the efficacy by 1.85-fold (95% CI: 1.41-2.42). No publication bias was observed in these associations.

CONCLUSION AND RELEVANCE: RFC1 c.80 A>G is an important pharmacogenetic determinant of MTX therapy in RA. The RFC1 80A-allele robustly increased therapeutic efficacy and safety when folate was used along with MTX. Findings are relevant to decision-making in the clinical use of MTX as a treatment for RA patients harboring the RFC1 gene variant.

PMID:33749319 | DOI:10.1177/10600280211002053

Front Mol Biosci. 2021 Mar 5;7:555630. doi: 10.3389/fmolb.2020.555630. eCollection 2020.

ABSTRACT

Background: Melanoma has a complex molecular background and multiple genes are involved in its development and progression. The advent of next generation sequencing platforms has enabled the evaluation of multiple genes at a time, thus unraveling new insights into the genetics of melanoma. We investigated a set of germline mutations able to discriminate the development of multiple primary melanomas (MPM) vs. single site primary melanomas (SPM) using a targeted next generation sequencing panel. Materials and Methods: A total of 39 patients, 20 with SPM and 19 with MPM, were enrolled in our study. Next generation analysis was carried out using a custom targeted sequencing panel that included 32 genes known to have a role in several carcinogenic pathways, such as those involved in DNA repair, pigmentation, regulation of kinases, cell cycle control and senescence. Results: We found a significant correlation between PIK3CA:p.I391M and MPMs, compared to SPMs, p = 0.031 and a trend for the association between CYP1B1: p.N453S and SPMs, compared to MPMs (p = 0.096). We also found that both subgroups shared a spectrum of 9 alterations in 8 genes (CYP1B1: p.N453S, BAP1: p.C39fs, PIK3CA: p.I391M, CDKAL1: c.1226_1227TG, POLE: p.V1161fs, OCA2: p.R419Q, OCA2: p.R305W, MC1R: p.V60L, MGMT: p.L115F), which suggested that these genes may play a role in melanoma development. Conclusions: In conclusion, despite the small cohort of patients, we found that germline mutations, such as those of PIK3CAand CYP1B1, might contribute to the differential development of SPM and MPM.

PMID:33748184 | PMC:PMC7973206 | DOI:10.3389/fmolb.2020.555630

Front Oncol. 2021 Feb 24;10:585046. doi: 10.3389/fonc.2020.585046. eCollection 2020.

ABSTRACT

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors of the head and neck, and it originates from the mucous epithelium of the nasopharynx. Because it is "hidden", the symptoms of NPC can easily be missed, and more than 70% of patients present with locally advanced disease at diagnosis. Concurrent radiation therapy with chemotherapy can significantly improve regional control of NPC. At present, distant metastasis is the main cause of treatment failure. At the end of the 20th century, clinical trial No. IG0099 in the United States confirmed the effectiveness of adjuvant chemotherapy (AC) for the first time. However, in the past 20 years, various clinical trials and meta-analyses conducted globally have yielded contradictory results regarding the effect of AC on locally advanced NPC. AC has changed from category 1 to the current category 2A in the National Comprehensive Cancer Network (NCCN) guidelines, and it remains controversial whether AC can significantly improve the survival of NPC patients. Here, we comprehensively analyzed the role of AC in locally advanced NPC by comparing some treatment methods. We conclude the role of AC in treating locally advanced NPC, based on the studies presented, remains undefined but is associated with increased toxicity.

PMID:33747895 | PMC:PMC7970762 | DOI:10.3389/fonc.2020.585046

Pharmgenomics Pers Med. 2021 Mar 12;14:319-326. doi: 10.2147/PGPM.S285444. eCollection 2021.

ABSTRACT

PURPOSE: CYP3A5 genotype is a significant contributor to inter-individual tacrolimus exposure and may impact the time required to achieve therapeutic concentrations and number of tacrolimus dose adjustments in transplant patients. Increased modifications to tacrolimus therapy may indicate a higher burden on healthcare resources. The purpose of this study was to evaluate whether CYP3A5 genotype was predictive of healthcare resource utilization in pediatric renal and heart transplant recipients.

PATIENTS AND METHODS: Patients <18 years of age with a renal or heart transplant between 6/1/2014-12/31/2018 and tacrolimus-based immunosuppression were included. Secondary use samples were obtained for CYP3A5 genotyping. Clinical data was retrospectively collected from the electronic medical record. Healthcare resource utilization measures included the number of dose changes, number of tacrolimus concentrations, length of stay, number of clinical encounters, and total charges within the first year post-transplant. Rejection and donor-specific antibody (DSA) formation within the first year were also collected. The impact of CYP3A5 genotype was evaluated via univariate analysis for the first year and multivariable analysis at 30, 90, 180, 270, and 365 days post-transplant.

RESULTS: Eighty-five subjects were included, 48 renal transplant recipients and 37 heart transplant recipients. CYP3A5 genotype was not associated with any outcomes in renal transplant, however, a CYP3A5 expresser phenotype was a predictor of more dose changes, more tacrolimus concentrations, longer length of stay, and higher total charges in heart transplant recipients. CYP3A5 genotype was not associated with rejection or DSA formation. Age and induction therapy were associated with higher total charges.

CONCLUSION: CYP3A5 genotype may predict healthcare resource utilization in the first year post-transplant, although this may be mitigated by differences in tacrolimus management. Future studies should evaluate the impact of genotype-guided dosing strategies for tacrolimus on healthcare utilization resources.

PMID:33746516 | PMC:PMC7967030 | DOI:10.2147/PGPM.S285444

BMC Genomics. 2021 Mar 20;22(1):197. doi: 10.1186/s12864-021-07508-2.

ABSTRACT

BACKGROUND: Low pass sequencing has been proposed as a cost-effective alternative to genotyping arrays to identify genetic variants that influence multifactorial traits in humans. For common diseases this typically has required both large sample sizes and comprehensive variant discovery. Genotyping arrays are also routinely used to perform pharmacogenetic (PGx) experiments where sample sizes are likely to be significantly smaller, but clinically relevant effect sizes likely to be larger.

RESULTS: To assess how low pass sequencing would compare to array based genotyping for PGx we compared a low-pass assay (in which 1x coverage or less of a target genome is sequenced) along with software for genotype imputation to standard approaches. We sequenced 79 individuals to 1x genome coverage and genotyped the same samples on the Affymetrix Axiom Biobank Precision Medicine Research Array (PMRA). We then down-sampled the sequencing data to 0.8x, 0.6x, and 0.4x coverage, and performed imputation. Both the genotype data and the sequencing data were further used to impute human leukocyte antigen (HLA) genotypes for all samples. We compared the sequencing data and the genotyping array data in terms of four metrics: overall concordance, concordance at single nucleotide polymorphisms in pharmacogenetics-related genes, concordance in imputed HLA genotypes, and imputation r2. Overall concordance between the two assays ranged from 98.2% (for 0.4x coverage sequencing) to 99.2% (for 1x coverage sequencing), with qualitatively similar numbers for the subsets of variants most important in pharmacogenetics. At common single nucleotide polymorphisms (SNPs), the mean imputation r2 from the genotyping array was 0.90, which was comparable to the imputation r2 from 0.4x coverage sequencing, while the mean imputation r2 from 1x sequencing data was 0.96.

CONCLUSIONS: These results indicate that low-pass sequencing to a depth above 0.4x coverage attains higher power for association studies when compared to the PMRA and should be considered as a competitive alternative to genotyping arrays for trait mapping in pharmacogenetics.

PMID:33743587 | DOI:10.1186/s12864-021-07508-2

Clin Transl Sci. 2021 Mar 20. doi: 10.1111/cts.13000. Online ahead of print.

ABSTRACT

The primary goal of precision medicine is to maximize the benefit-risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene-drug interactions (GDI) in clinical settings. The U.S. Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA-PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug-metabolizing enzymes and transporters (DMET), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate.

PMID:33742770 | DOI:10.1111/cts.13000

Basic Clin Pharmacol Toxicol. 2021 Mar 19. doi: 10.1111/bcpt.13581. Online ahead of print.

ABSTRACT

Cannabis is a complex plant including more than 400 chemicals compounds, of which more than 60 are cannabinoid compounds [1]. Cannabinoids are subjected to a significant first-pass metabolism in the liver involving the cytochrome P450 enzymes (CYP) 2C9, CYP2C19 and CYP3A4 [2];. Furthermore, CYP2J2 as the primary CYP of cardiomyocytes, is also directly involved in the metabolism of the phytocannabinoids [3]. The metabolism of tetrahydrocannabinol (THC) is predominantly hepatic catalyzed by microsomal hydroxylation and oxidation leading to delta 9-tetrahydrocannabidiol.

PMID:33740842 | DOI:10.1111/bcpt.13581