Drug Metab Dispos. 2021 Mar 3:DMD-AR-2020-000264. doi: 10.1124/dmd.120.000264. Online ahead of print.

ABSTRACT

SLCO1B1 is an important transmembrane hepatic uptake transporter. Genetic variants in the SLCO1B1 gene have been associated with altered protein folding, resulting in protein degradation and decreased transporter activity. Next-Generation Sequencing (NGS) of pharmacogenes is being applied increasingly to associate variation in drug response with genetic sequence variants. However, it is difficult to link variants of unknown significance with functional phenotypes using "one-at-a-time" functional systems. Deep mutational scanning (DMS) using a "landing pad cell-based system" is a high-throughput technique designed to analyze hundreds of gene open reading frame (ORF) missense variants in a parallel and scalable fashion. We have applied DMS to analyze 137 missense variants in the SLCO1B1 ORF obtained from the ExAC Project. ORFs containing these variants were fused to green fluorescent protein and were integrated into "landing pad" cells. Florescence-activated cell sorting was performed to separate the cells into four groups based on fluorescence readout indicating protein expression at the single cell level. NGS was then performed and SLCO1B1 variant frequencies were used to determine protein abundance. We found that six variants not previously characterized functionally displayed less than 25% and another twelve displayed approximately 50% of wild-type protein expression. These results were then functionally validated by transporter studies. Severely damaging variants identified by DMS may have clinical relevance for SLCO1B1-dependent drug transport but we need to exercise caution since the relatively small number of severely damaging variants identified raise questions with regard to the application of DMS to intrinsic membrane proteins such as OATP1B1 Significance Statement The functional implications of a large numbers of ORF "variants of unknown significance" (VUS) in transporter genes have not been characterized. This study applied deep mutational scanning to determine the functional effects of VUS that have been observed in the ORF of SLCO1B1 Several severely damaging variants were identified, studied and validated. These observations have implications for both the application of DMS to intrinsic membrane proteins and for the clinical effect of drugs and endogenous compounds transported by SLCO1B1.

PMID:33658230 | DOI:10.1124/dmd.120.000264

Pharmacogenomics. 2021 Mar 4. doi: 10.2217/pgs-2020-0112. Online ahead of print.

ABSTRACT

Aim: To assess providers' knowledge, attitudes, perceptions, and experiences related to pharmacogenomic (PGx) testing in pediatric patients. Materials & methods: An electronic survey was sent to multidisciplinary healthcare providers at a pediatric hospital. Results: Of 261 respondents, 71.3% were slightly or not at all familiar with PGx, despite 50.2% reporting prior PGx education or training. Most providers, apart from psychiatry, perceived PGx to be at least moderately useful to inform clinical decisions. However, only 26.4% of providers had recent PGx testing experience. Unfamiliarity with PGx and uncertainty about the clinical value of testing were common perceived challenges. Conclusion: Low PGx familiarity among pediatric providers suggests additional education and electronic resources are needed for PGx examples in which data support testing in children.

PMID:33657875 | DOI:10.2217/pgs-2020-0112

J Dermatolog Treat. 2021 Mar 3:1-23. doi: 10.1080/09546634.2021.1898526. Online ahead of print.

ABSTRACT

Psoriasis is a chronic disorder with increasing new treatments targeting the T-helper cell (Th)-1/Th17 axis. There remains a subset of patients who experience a primary or secondary failure to biologic treatments. We present ten patients with psoriasis who failed biologic therapy with measurement of serum drug levels and anti-drug antibody levels (ADAs) with review of the current literature. Our objective was to identify demographic factors, disease status, drug level and ADAs which might correlate with primary and secondary failure. There are a number of factors affecting drug levels in patients with psoriasis on biologics including the presence of ADAs, patient adherence to treatment regimes, pharmacogenetics and the pharmacokinetic properties of the drug following subcutaneous injection. Our results demonstrate that biologic failure is related to low serum drug levels subtherapeutic in 80% of our cohort. Primary failure may correlate with the presence of ADAs but not with serum drug levels. All patients were ANA negative and there remains considerable debate on the utility of routine ANA testing. The role of therapeutic drug monitoring in dermatology remains uncertain and requires further study. We aim to promote debate in the dermatology community as to the utility of therapeutic drug monitoring in routine practice.

PMID:33656955 | DOI:10.1080/09546634.2021.1898526

Sci Rep. 2021 Mar 2;11(1):4977. doi: 10.1038/s41598-021-83696-x.

ABSTRACT

Cytochrome P450 1A2 (CYP1A2) is one of the main hepatic CYPs involved in metabolism of carcinogens and clinically used drugs. Nonsynonymous single nucleotide polymorphisms (nsSNPs) of this enzyme could affect cancer susceptibility and drug efficiency. Hence, identification of human CYP1A2 pathogenic nsSNPs could be of great importance in personalized medicine and pharmacogenetics. Here, 176 nsSNPs of human CYP1A2 were evaluated using a variety of computational tools, of which 18 nsSNPs were found to be associated with pathogenicity. Further analysis suggested possible association of 9 nsSNPs (G73R, G73W, R108Q, R108W, E168K, E346K, R431W, F432S and R456H) with the risk of hepatocellular carcinoma. Molecular dynamics simulations revealed higher overall flexibility, decreased intramolecular hydrogen bonds and lower content of regular secondary structures for both cancer driver variants G73W and F432S when compared to the wild-type structure. In case of F432S, loss of the conserved hydrogen bond between Arg137 and heme propionate oxygen may affect heme stability and the observed significant rise in fluctuation of the CD loop could modify CYP1A2 interactions with its redox partners. Together, these findings propose CYP1A2 as a possible candidate for hepatocellular carcinoma and provide structural insights into how cancer driver nsSNPs could affect protein structure, heme stability and interaction network.

PMID:33654112 | DOI:10.1038/s41598-021-83696-x

Transl Psychiatry. 2021 Mar 2;11(1):153. doi: 10.1038/s41398-020-01097-6.

ABSTRACT

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.

PMID:33654056 | DOI:10.1038/s41398-020-01097-6

BMC Med Ethics. 2021 Mar 2;22(1):21. doi: 10.1186/s12910-021-00592-9.

ABSTRACT

BACKGROUND: In the context of translational research, researchers have increasingly been using biological samples and data in fundamental research phases. To explore informed consent practices, we conducted a retrospective study on informed consent documents that were used for CARPEM's translational research programs. This review focused on detailing their form, their informational content, and the adequacy of these documents with the international ethical principles and participants' rights.

METHODS: Informed consent forms (ICFs) were collected from CARPEM investigators. A content analysis focused on information related to biological samples and data treatment (context of sampling and collect, aims, reuse, consent renewal), including the type of consent. An automatic assessment of the readability of the ICFs were performed with the IT program "Flesch Score".

RESULTS: 29 ICFs from 25 of 49 studies were analyzed after selection criteria were applied. Three types of consent were identified: 11 broad consents, six specific consents, and two opt-out consents. The Flesch Scores showed that most of the documents were too complex to be fully understood by most of the potential research participants. Most of the biological samples were collected during the healthcare routine, but the information content about secondary use of biological samples varied between ICFs. All documents mentioned personal data treatment but information about their reuse was not standardized in the ICFs.

CONCLUSIONS: Our review of current IC procedures of CARPEM showed that practices could be improved considering new translational research methods. "Old fashion written ICFs" should be adapted to the translational research approach, to better respect individual rights and international research ethics principles. In this context, theoretically, a digital tool allowing dynamic information and consent of participants, through an electronic interactive platform may be a good way to promote more active participation in research. Nevertheless, its feasibility in the complex environment of biological samples and data research remains to prove. The way of a combination of a broad consent followed by dynamic information may be alternatively tested.

PMID:33653311 | DOI:10.1186/s12910-021-00592-9

J Asthma. 2021 Mar 2:1-26. doi: 10.1080/02770903.2021.1897836. Online ahead of print.

ABSTRACT

Objective: Nonadherence to asthma medications is prevalent among adolescents and young adults (AYAs) with asthma, leading to worsened control of asthma symptoms and more frequent exacerbations. AYAs have unique developmental transitional challenges that may alter medication adherence. We aimed to use a socio-ecological framework to explore the effect of transitional challenges from adolescence to young adulthood on asthma controller medication adherence and to identify possible strategies to promote medication adherence.Methods: We conducted qualitative semi-structured interviews by phone with 7 adolescents (14 to 17 years), their respective caregivers, and 7 young adults (18 to 30 years). Participants were recruited from a respiratory clinical trial network and pulmonary clinics in 4 states at 6 different sites through convenience sampling. Interviews were audio recorded, transcribed and coded using thematic analyses.Results: Participants identified personal challenges affecting adherence to asthma medications during the transition from adolescence to young adulthood including responsibility for asthma self-management, understanding of asthma condition and severity, embarrassment, and life demands. Health systems factors including medication cost, challenges with insurance, difficulties obtaining refills, and difficulty with access to medications at school also impacted asthma medication adherence. Participants recommended adherence strategies including improved access to inhalers, incorporating asthma medications into daily routines, and using reminders.Conclusions: Focusing on the transitional challenges of AYAs during the time period from adolescence to young adulthood is necessary for supporting their asthma medication adherence and creating future interventions. Socio-ecological and systems factors should also be targeted for improved asthma medication adherence.

PMID:33653199 | DOI:10.1080/02770903.2021.1897836

Diagnostics (Basel). 2021 Feb 26;11(3):398. doi: 10.3390/diagnostics11030398.

ABSTRACT

This prospective observational study aimed to evaluate whether women with SARS-CoV-2 infection during the first trimester of pregnancy are at higher risk of noninvasive prenatal screening test alterations and/or of congenital fetal anomalies at the second-trimester fetal anatomy scan. Maternal symptoms were secondly investigated. The study was carried out on 12-week pregnant women admitted for noninvasive prenatal testing (16 April and 22 June 2020). The cohort had seromolecular tests for SARS-CoV-2, after which they were divided into a positive case group and a negative control group. Both groups had 20-week ultrasound screening. Seventeen out of the 164 women tested positive for SARS-CoV-2 (10.3%). There were no significant differences in mean nuchal translucency thickness or biochemical markers (pregnancy-associated plasma protein A, alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol) between cases and controls (p = 0.77, 0.63, 0.30, 0.40, 0.28) or in the fetal incidence of structural anomalies at the second-trimester fetal anatomy scan (p = 0.21). No pneumonia or hospital admission due to COVID-19-related symptoms were observed. Asymptomatic or mildly symptomatic SARS-CoV-2 infection during the first trimester of pregnancy did not predispose affected women to more fetal anomalies than unaffected women. COVID-19 had a favorable maternal course at the beginning of pregnancy in our healthy cohort.

PMID:33652805 | DOI:10.3390/diagnostics11030398

Clin Transl Sci. 2021 Mar 1. doi: 10.1111/cts.13014. Online ahead of print.

ABSTRACT

To compare etonogestrel pharmacokinetic and pharmacodynamic outcomes by both self-reported race/ethnicity and genetically-determined ancestry among contraceptive implant users. We conducted a secondary analysis of our parent pharmacogenomic study of 350 implant users. We genotyped these reproductive-aged (18-45 years) women for 88 ancestry-informative single nucleotide polymorphisms. We then assigned each participant a proportion value for African (AFR), European (EUR), and Indigenous American (AMR) ancestry based on reference population data. We correlated genetic ancestry with self-reported race/ethnicity and utilized genetic ancestry proportion values as variables for previously-performed association analyses with serum etonogestrel concentrations and progestin-related side effects (e.g. bothersome bleeding, subjective weight gain). We successfully estimated genetically-determined ancestry for 332 participants. EUR, AFR, and AMR ancestry were each highly correlated with self-reported White/Non-Hispanic race (r=0.64, p=4.14x10-40 ), Black/African American race (r=0.88, p=1.36x10-107 ), and Hispanic/Latina ethnicity (r=0.68, p=4.03x10-47 ), respectively. Neither genetically-determined ancestry nor self-reported race/ethnicity were significantly associated with serum etonogestrel concentrations. AFR ancestry and self-reported Black race had similar associations with reporting monthly periods (OR 2.18, p=0.09 vs OR 2.22, p=0.02) and having received treatment for bothersome bleeding (OR 5.19, p=0.005 vs OR 4.73, p=2.0x10-4 ). In multivariable logistic regression for subjective weight gain, AMR ancestry dropped out of the model in preference for self-reported Hispanic/Latina ethnicity. We found no new associations between genetically-determined ancestry and contraceptive implant pharmacodynamics/pharmacokinetics. Self-reported race/ethnicity were strong surrogates for genetically-determined ancestry among this population of contraceptive implant users. Our data suggest that self-reported race/ethnicity, capturing societal and cultural aspects, remain important to the investigation of progestin-related side effects.

PMID:33650294 | DOI:10.1111/cts.13014

Diabetologia. 2021 Mar 2. doi: 10.1007/s00125-021-05410-w. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: Observational studies indicate that type 2 diabetes mellitus and fasting glucose levels are associated with a greater risk for hip fracture, smaller bone area and higher bone mineral density (BMD). However, these findings may be biased by residual confounding and reverse causation. Mendelian randomisation (MR) utilises genetic variants as instruments for exposures in an attempt to address these biases. Thus, we implemented MR to determine whether fasting glucose levels in individuals without diabetes are causally associated with bone area and BMD at the total hip.

METHODS: We selected 35 SNPs strongly associated with fasting glucose (p < 5 × 10-8) in a non-diabetic European-descent population from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 133,010). MR was used to assess the associations of genetically predicted fasting glucose concentrations with total hip bone area and BMD in 4966 men and women without diabetes from the Swedish Mammography Cohort, Prospective Investigation of Vasculature in Uppsala Seniors and Uppsala Longitudinal Study of Adult Men.

RESULTS: In a meta-analysis of the three cohorts, a genetically predicted 1 mmol/l increment of fasting glucose was associated with a 2% smaller total hip bone area (-0.67 cm2 [95% CI -1.30, -0.03; p = 0.039]), yet was also associated, albeit without reaching statistical significance, with a 4% higher total hip BMD (0.040 g/cm2 [95% CI -0.00, 0.07; p = 0.060]).

CONCLUSIONS/INTERPRETATION: Fasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings.

PMID:33650017 | DOI:10.1007/s00125-021-05410-w

Nat Methods. 2021 Mar 1. doi: 10.1038/s41592-021-01077-8. Online ahead of print.

ABSTRACT

The architecture of chromatin regulates eukaryotic cell states by controlling transcription factor access to sites of gene regulation. Here we describe a dual transposase-peroxidase approach, integrative DNA and protein tagging (iDAPT), which detects both DNA (iDAPT-seq) and protein (iDAPT-MS) associated with accessible regions of chromatin. In addition to direct identification of bound transcription factors, iDAPT enables the inference of their gene regulatory networks, protein interactors and regulation of chromatin accessibility. We applied iDAPT to profile the epigenomic consequences of granulocytic differentiation of acute promyelocytic leukemia, yielding previously undescribed mechanistic insights. Our findings demonstrate the power of iDAPT as a platform for studying the dynamic epigenomic landscapes and their transcription factor components associated with biological phenomena and disease.

PMID:33649590 | DOI:10.1038/s41592-021-01077-8

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00227-7. Online ahead of print.

ABSTRACT

Taxanes are used in the treatment of several solid tumours. Adverse events (AEs) might be influenced by single nucleotide polymorphisms (SNPs) in genes encoding proteins responsible for pharmacokinetic and pharmacodynamic. In this prospective, monocentric, observational study we explored the effect of SNPs in the main genes involved in taxanes metabolism and transport, on toxicity and efficacy in 125 patients (pts) treated with paclitaxel, nab-paclitaxel, or docetaxel for neoplasms. There was no statistically significant association between the investigated SNPs and AEs. The heterozygous genotype of CYP3A4*22 showed a trend of association with skin reactions in pts treated with paclitaxel and nab-paclitaxel (RR = 6.92; 95% CI 0.47, 99.8; p = 0.0766). CYP2C8*3/*4 variant carriers showed a trend of association with overall AEs in pts treated with paclitaxel and nab-paclitaxel (RR = 1.28; 95% CI 0.96, 1.67; p = 0.0898). No statistically significant relationship with treatment efficacy was found. ABCB1 3435TT showed a trend of association with a higher treatment response (RR = 0.22; 95% CI 0.03, 1.51; p = 0.0876). Despite the population was heterogeneous, CYP3A4*22 and CYP2C8 SNPs may influence paclitaxel and nab-paclitaxel toxicity and ABCB1 c.3435 may affect taxanes effectiveness, even if any statistically significant was found.

PMID:33649523 | DOI:10.1038/s41397-021-00227-7

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00221-z. Online ahead of print.

ABSTRACT

We sought to perform a genomic evaluation of the risk of incident cancer in statin users, free of cancer at study entry. Patients who previously participated in two phase IV trials (TNT and IDEAL) with genetic data were used (npooled = 11,196). A GWAS meta-analysis using Cox modeling for the prediction of incident cancer was conducted in the pooled cohort and sex-stratified. rs13210472 (near HLA-DOA gene) was associated with higher risk of incident cancer amongst women with prevalent coronary artery disease (CAD) taking statins (hazard ratio [HR]: 2.66, 95% confidence interval [CI]: 1.88-3.76, P = 3.5 × 10-8). Using the UK Biobank and focusing exclusively on women statin users with CAD (nfemale = 2952), rs13210472 remained significantly associated with incident cancer (HR: 1.71, 95% CI: 1.14-2.56, P = 9.0 × 10-3). The association was not observed in non-statin users. In this genetic meta-analysis, we have identified a variant in women statin users with prevalent CAD that was associated with incident cancer, possibly implicating the human leukocyte antigen pathway.

PMID:33649522 | DOI:10.1038/s41397-021-00221-z

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00223-x. Online ahead of print.

ABSTRACT

This study aimed to develop a population pharmacokinetic model using full pharmacokinetic (PK) profiles of isoniazid (INH) taking into account demographic and genetic covariates and to develop Bayesian estimators for predicting INH area under the curve (AUC) in Tunisian tuberculosis patients. The INH concentrations in the building data set were fitted using a one- to three-compartment model. The impact of the different covariates was assessed on the PK parameters of the best model. The best limited sampling strategy (LSS) for estimating the INH AUC was selected by comparing the predicted values to an independent data set. INH PK was best described using a three-compartment model with lag-time absorption. The different studied covariates did not have any impact on the PK parameters of the building model. The Bayesian estimation using one-point concentrations gave the lowest values of prediction errors for the C3 LSS model. This model could be sufficient in routine activity for INH monitoring in this population.

PMID:33649521 | DOI:10.1038/s41397-021-00223-x

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00214-y. Online ahead of print.

ABSTRACT

We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10-11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6-19.0), P = 0.038 and 13.4 (25.4-2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10-11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.

PMID:33649520 | DOI:10.1038/s41397-021-00214-y

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00222-y. Online ahead of print.

ABSTRACT

BACKGROUND: Filamin A and filamin B were involved in vascular development and remodeling. Herein, it is important to explore the associations of FLNA and FLNB variants with hypertension and stroke.

METHODS: The associations of two single-nucleotide polymorphisms (SNPs) at FLNA and five SNPs at FLNB with hypertension and stroke were examined in two case-control studies and a cohort study in Chinese Han population. Risks were estimated as odds ratio (OR) and hazard ratio (HR) by Logistic and Cox regression analysis respectively. In addition, filamin B, FLNA and FLNB mRNA expression were measured.

RESULTS: In the case-control study of hypertension, FLNA rs2070816 (CT + TT vs. CC) and rs2070829 (CG + GG vs. CC) were significantly associated with hypertension in <55 years group (OR = 1.338, P = 0.018; OR = 1.615, P = 0.005) and FLNB rs839240 (AG + GG vs. AA) was significantly associated with hypertension in females (OR = 0.828, P = 0.041) and nonsmokers (OR = 0.829, P = 0.020). In the follow-up study, rs2070829 GG genotype carriers presented a higher risk of hypertension than CC/CG in males (HR = 1.737, P = 0.014) and smokers (HR = 1.949, P = 0.012). In the case-control study of stroke, FLNB rs1131356 variation was significantly associated with ischemic stroke (IS) and intracerebral hemorrhage (ICH), ORs of additive model were 1.342 and 1.451, with P values of 0.001 and 0.007. The FLNA transcript 2, FLNB transcript 3, transcript 4 mRNA, and filamin B expression levels were significantly different between IS cases and hypertension controls and among the genotypes of rs839240 in hypertensive individuals (P < 0.05).

CONCLUSIONS: Our findings support the genetic contribution of FLNA and FLNB to hypertension, and stroke with differentially mRNA expression.

PMID:33649519 | DOI:10.1038/s41397-021-00222-y

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00215-x. Online ahead of print.

ABSTRACT

Sodium valproate (VPA) is a histone deacetylase (HDAC) inhibitor, widely prescribed in the treatment of bipolar disorder, and yet the precise modes of therapeutic action for this drug are not fully understood. After exposure of the rat serotonergic cell line RN46A to VPA, RNA-sequencing (RNA-Seq) analysis showed widespread changes in gene expression. Analysis by four bioinformatic pipelines revealed as many as 230 genes were significantly upregulated and 72 genes were significantly downregulated. A subset of 23 differentially expressed genes was selected for validation using the nCounter® platform, and of these we obtained robust validation for ADAM23, LSP1, MAOB, MMP13, PAK3, SERPINB2, SNAP91, WNT6, and ZCCHC12. We investigated the effect of lithium on this subset and found four genes, CDKN1C, LSP1, SERPINB2, and WNT6 co-regulated by lithium and VPA. We also explored the effects of other HDAC inhibitors and the VPA analogue valpromide on the subset of 23 selected genes. Expression of eight of these genes, CDKN1C, MAOB, MMP13, NGFR, SHANK3, VGF, WNT6 and ZCCHC12, was modified by HDAC inhibition, whereas others did not appear to respond to several HDAC inhibitors tested. These results suggest VPA may regulate genes through both HDAC-dependent and independent mechanisms. Understanding the broader gene regulatory effects of VPA in this serotonergic cell model should provide insights into how this drug works and whether other HDAC inhibitor compounds may have similar gene regulatory effects, as well as highlighting molecular processes that may underlie regulation of mood.

PMID:33649518 | DOI:10.1038/s41397-021-00215-x

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00213-z. Online ahead of print.

ABSTRACT

The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of the tested CYP3A, ABCB1, ABCC2, and SLCO1B3 genotypes and diplotypes showed a significant relation with an altered bioavailability or clearance of either docetaxel or ritonavir. Similarly, no clear effect of CYP1B1 genotype on clinical outcomes was observed in a subgroup of non-small cell lung cancer (NSCLC) patients. Our post hoc power analysis indicated that our pharmacogenetic-pharmacokinetic analysis was only powered for relatively high effect sizes, which were to be expected given the high interpatient variability. This makes it unlikely that future studies will explain the high observed interpatient variability in oral docetaxel pharmacokinetics as a result of any of these separate polymorphisms and diplotypes.

PMID:33649517 | DOI:10.1038/s41397-021-00213-z

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00220-0. Online ahead of print.

ABSTRACT

Missense polymorphism in HSD3B1, encoding 3β-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. Other androgen-metabolizing enzymes may be involved in therapeutic effect in abiraterone. In this study, we investigated the significance of polymorphisms in genes involved in androgen and abiraterone metabolisms in prostate cancer patients treated with abiraterone. A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349), CYP17A1 (rs743572), CYP17A1 (rs2486758), and AKR1C3 (rs12529) was performed by PCR-based technique. Among the 99 patients, 32 (32.3%), 49 (49.5%), and 18 patients (18.2%) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95% confidence interval, 0.20-0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles. In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95% confidence interval, 0.17-0.62; P = 0.0003) on multivariate analyses. This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.

PMID:33649516 | DOI:10.1038/s41397-021-00220-0

Pharmacogenomics J. 2021 Mar 1. doi: 10.1038/s41397-021-00216-w. Online ahead of print.

ABSTRACT

The aim of this study was to identify novel genetic variants affecting tacrolimus trough blood concentrations. We analyzed the association between 58 single nucleotide polymorphisms (SNPs) across the CYP3A gene cluster and the log-transformed tacrolimus concentration/dose ratio (log (C0/D)) in 819 renal transplant recipients (Discovery cohort). Multivariate linear regression was used to test for associations between tacrolimus log (C0/D) and clinical factors. Luciferase reporter gene assays were used to evaluate the functions of select SNPs. Associations of putative functional SNPs with log (C0/D) were further tested in 631 renal transplant recipients (Replication cohort). Nine SNPs were significantly associated with tacrolimus log (C0/D) after adjustment for CYP3A5*3 and clinical factors. Dual luciferase reporter assays indicated that the rs4646450 G allele and rs3823812 T allele were significantly associated with increased normalized luciferase activity ratios (p < 0.01). Moreover, CYP3A7*2 was associated with higher TAC log(C0/D) in the group of CYP3A5 expressers. Age, serum creatinine and hematocrit were significantly associated with tacrolimus log (C0/D). CYP3A7*2, rs4646450, and rs3823812 are proposed as functional SNPs affecting tacrolimus trough blood concentrations in Chinese renal transplant recipients. Clinical factors also significantly affect tacrolimus metabolism.

PMID:33649515 | DOI:10.1038/s41397-021-00216-w