Correction: Integrated epigenetic and genetic analysis identifies markers of prognostic significance in pediatric acute myeloid leukemia.

Oncotarget. 2018 Jul 13;9(54):30473

Authors: Lamba JK, Cao X, Raimondi SC, Rafiee R, Downing JR, Shi L, Gruber T, Ribeiro RC, Rubnitz JE, Pounds SB

Abstract
[This corrects the article DOI: 10.18632/oncotarget.25475.].

PMID: 30101002 [PubMed - in process]

An African-specific profile of pharmacogene variants for rosuvastatin plasma variability: limited role for SLCO1B1 c.521T>C and ABCG2 c.421A>C.

Pharmacogenomics J. 2018 Aug 13;:

Authors: Soko ND, Chimusa E, Masimirembwa C, Dandara C

Abstract
Studies in Caucasian and Asian populations consistently associated interindividual and interethnic variability in rosuvastatin pharmacokinetics to the polymorphisms SLCO1B1 c.521T>C (rs4149056 p. Val174Ala) and ABCG2 c.421C>A (rs2231142, p. Gln141Lys). To investigate the pharmacogenetics of rosuvastatin in African populations, we first screened 785 individuals from nine ethnic African populations for the SLCO1B1 c.521C and ABCG2 c.421CA variants. This was followed by sequencing whole exomes from individuals of African Bantu descent, who participated in a 20 mg rosuvastatin pharmacokinetic trial in Harare Zimbabwe. Frequencies of SLCO1B1 c.521C ranged from 0.0% (San) to 7.0% (Maasai), while ABCG2 c.421A ranged from 0.0% (Shona) to 5.0% (Kikuyu). Variants showing significant association with rosuvastatin exposure were identified in SLCO1B1, ABCC2, SLC10A2, ABCB11, AHR, HNF4A, RXRA and FOXA3, and appear to be African specific. Interindividual differences in the pharmacokinetics of rosuvastatin in this African cohort cannot be explained by the polymorphisms SLCO1B1 c.521T>C and ABCG2 c.421C>A, but appear driven by a different set of variants.

PMID: 30100615 [PubMed - as supplied by publisher]

Promotor hypermethylated genes: Prospective diagnostic biomarkers in oral cancerogenesis.

J Craniomaxillofac Surg. 2018 Jul 29;:

Authors: Dvojakovska S, Popovic-Monevska D, Grcev A, Pancevski G, Benedetti A, Popovski V, Dimovski A, Stamatoski A

Abstract
The advancements in epigenetics of oral squamous cell carcinoma (OSCC), are made in regard to DNA hypermethylation of MGMT, DAPK, ECAD (E-cadherin) and p16, as an important component of oral carcinogenesis and new potential biomarkers in molecular diagnostic strategies. The objective of the study was to evaluate the methylation status of the proposed genes and their possible role in the tumor genesis and diagnosis of OSCC.
MATERIALS AND METHODS: From sixty surgically treated and molecularly analyzed patients, we obtained three groups of bioptical materials: tumor, normal contralateral and healthy tissues. Comparison of the frequencies of DNA methylation for all transcripts was utilized to validated their potential role in the cancerogenesis and detection of OSCC.
RESULTS: The most often methylated genes in the tumor samples were ECAD, MGMT, DAPK followed by p16 genes (90% vs 75% vs 75% vs 52,5%), respectively. We observed frequent methylated genes in contralateral mucosa and consistently unmethylated- 0% in healthy samples. ECAD methylated genes showed the highest sensitivity for diagnosing OSCC in tumor and contralateral tissues (90% and 89,7% respectively, with a specificity of 100%).
CONCLUSION: ECAD and MGMT have tumor-specific signatures and can be considered as potential noninvasive diagnostic biomarkers in OSCC.

PMID: 30100382 [PubMed - as supplied by publisher]

The Role of Racial/ethnic Factors in Global Clinical Trials.

Expert Rev Clin Pharmacol. 2018 Aug 13;:

Authors: Ferdinand KC, Igari M

PMID: 30099916 [PubMed - as supplied by publisher]

Genetic variation of the gene coding for microRNA-204 (miR-204) is a risk factor in acute myeloid leukaemia.

BMC Cancer. 2018 01 30;18(1):107

Authors: Butrym A, Łacina P, Kuliczkowski K, Bogunia-Kubik K, Mazur G

Abstract
BACKGROUND: MicroRNAs (miRNAs or miRs) are small molecules known to be involved in post-transcriptional gene expression. Many of them have been shown to influence risk for various diseases. Recent studies suggest that lower expression of miR-204, a gene coding for miRNA-204, is correlated with shorter survival in patients with acute myeloid leukaemia (AML). This observation prompted us to analyse the effect of two polymorphisms of the miR-204 gene, one in the upstream flanking region (rs718447 A > G) and the other inside the gene itself (rs112062096 A > G), both also in intron 3 of the TRPM3 gene.
METHODS: The study was conducted on DNA samples isolated from AML patients (n = 95) and healthy individuals (n = 148), who were genotyped using the Light SNiP assays.
RESULTS: The miR-204 rs718447 GG homozygosity was found to constitute a risk factor associated with susceptibility to AML (73/95 vs 92/148, AML patients vs healthy controls, OR = 2.020, p = 0.017). Additionally, this genotype was more frequent in patients with subtypes M0-M1 in the French-American-British (FAB) classification as compared to patients with subtypes M2-M7 (23/25 vs 39/57, p = 0.026). We also found that presence of allele A was linked to longer survival of AML patients.
CONCLUSIONS: Our results show that polymorphism in miR-204 flanking region may constitute a risk and prognostic factor in AML.

PMID: 29382303 [PubMed - indexed for MEDLINE]

Neuroinflammation - using big data to inform clinical practice.

Nat Rev Neurol. 2016 12;12(12):685-698

Authors: Dendrou CA, McVean G, Fugger L

Abstract
Neuroinflammation is emerging as a central process in many neurological conditions, either as a causative factor or as a secondary response to nervous system insult. Understanding the causes and consequences of neuroinflammation could, therefore, provide insight that is needed to improve therapeutic interventions across many diseases. However, the complexity of the pathways involved necessitates the use of high-throughput approaches to extensively interrogate the process, and appropriate strategies to translate the data generated into clinical benefit. Use of 'big data' aims to generate, integrate and analyse large, heterogeneous datasets to provide in-depth insights into complex processes, and has the potential to unravel the complexities of neuroinflammation. Limitations in data analysis approaches currently prevent the full potential of big data being reached, but some aspects of big data are already yielding results. The implementation of 'omics' analyses in particular is becoming routine practice in biomedical research, and neuroimaging is producing large sets of complex data. In this Review, we evaluate the impact of the drive to collect and analyse big data on our understanding of neuroinflammation in disease. We describe the breadth of big data that are leading to an evolution in our understanding of this field, exemplify how these data are beginning to be of use in a clinical setting, and consider possible future directions.

PMID: 27857124 [PubMed - indexed for MEDLINE]

Canon Fodder-A Case for Contrarian Science.

Circ Res. 2016 08 19;119(5):584-6

Authors: Dorn GW

PMID: 27539970 [PubMed - indexed for MEDLINE]

CRISPLD1 rs12115090 polymorphisms alters antiplatelet potency of clopidogrel in coronary artery disease patients in Chinese Han.

Gene. 2018 Aug 07;:

Authors: Wang JY, Zhang YJ, Li H, Hu XL, Li MP, Song PY, Ma QL, Peng LM, Chen XP

Abstract
BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is a recommended treatment for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) to reduce the rate of ischemic events and stent thrombosis. However, high on-treatment platelet reactivity (HTPR) during clopidogrel therapy for some patients may lead to outcome failure and occurrence of cardiovascular events. Amounts of studies have proved that genetic factors may contribute to HTPR. In our study, we explored the predictive value of 10 single nucleotide polymorphisms (SNPs) in 8 genes indicated by exome sequencing with clopidogrel efficacy.
METHODS: Two hundred and forty-one Han Chinese CAD patients (mean age: 61 ± 10 years) receiving dual antiplatelet therapy were recruited, among which 118 patients administered with 300 mg loading dose (LD) clopidogrel for 12-24 h and 123 subjects administered with 75 mg/day maintain dose (MD) clopidogrel for at least 5 days before discharge. The platelet reaction index (PRI) was determined to reflect clopidogrel response in the patients. Venous blood samples were drawn from all participants to extract genomic DNA. MassARRAY, Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to determine the genotypes of 10 SNPs.
RESULTS: Allelic tests showed significant differences in genotype distribution between HTPR and normal on-treatment platelet reactivity (NTPR) patients for 3 SNPs including CYP2C19 rs4244285 (CYP2C19*2) (co-dominant model: p = 0.003, dominant model: p = 0.004, recessive model: p = 0.012), CRISPLD1 rs12115090 (co-dominant model: p = 0.011, dominant model: p = 0.004), and LTA4H rs11108379 (dominant model: p = 0.041). After adjusting for covariates including clinical characteristics of patients, concomitant medications and complications, we confirmed that carriers of the CYP2C19*2 showed significantly increased risk of HTPR (*2/*2 vs *1/*1: OR = 12.266, 95% CI: 1.336-112.592, p = 0.027; *1/*2 + *2/*2 vs *1/*1: OR = 2.202, 95% CI: 1.083-4.480, p = 0.029). Contrarily, carriers of the CRISPLD1 rs12115090 C allele showed significantly reduced risk of HTPR (CC vs AA: OR = 0.242, 95% CI: 0.078-0.752, p = 0.014; CA + CC vs AA: OR = 0.457, 95% CI: 0.232-0.904, p = 0.024) in Chinese CAD patients. In addition, carriers of the CYP2C19*2 allele showed was significantly increased PRI (*1/*2 vs *1/*1: p = 0.008, 2/*2 vs 1/*1: p < 0.001, *2/*2 vs 1/*2: p = 0.011), while patients carrying the rs12115090 C allele showed significantly decreased PRI than the wild-type AA homozygotes (CA vs AA: p = 0.046, CA + CC vs AA: p = 0.023).
CONCLUSION: CYP2C19*2 reduced the antiplatelet potency of clopidogrel and increased the risk of HTPR, while CRISPLD1 rs12115090 A>C polymorphism increased the antiplatelet potency of clopidogrel. Genetic tests, especially for CYP2C19*2 are recommended in Han Chinese CAD patients before using of clopidogrel.

PMID: 30096456 [PubMed - as supplied by publisher]

Correction to: Clopidogrel Pharmacogenetics in Iranian Patients Undergoing Percutaneous Coronary Intervention.

Cardiovasc Toxicol. 2018 Aug 09;:

Authors: Mahdieh N, Rabbani A, Firouzi A, Zahedmehr A, Hoseinimoghaddam M, Saedi S, Sanati H, Basiri H, Noohi F, Rabbani B, Maleki M

Abstract
The original version of this article unfortunately contained a typo in the co-author name.

PMID: 30094619 [PubMed - as supplied by publisher]

Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer.

Breast Cancer Res Treat. 2018 Aug 09;:

Authors: Borrie AE, Rose RV, Choi YH, Perera FE, Read N, Sexton T, Lock M, Vandenberg TA, Hahn K, Dinniwell R, Younus J, Logan D, Potvin K, Yaremko B, Yu E, Lenehan J, Welch S, Tyndale RF, Teft WA, Kim RB

Abstract
PURPOSE: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia.
METHODS: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms.
RESULTS: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline.
CONCLUSIONS: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

PMID: 30094551 [PubMed - as supplied by publisher]

Clinical and molecular characteristics of colombian patients with mucopolysaccharidosis IVA, and description of a new galns gene mutation.

Mol Genet Metab Rep. 2018 Sep;16:53-56

Authors: Moreno Giraldo LJ, Escudero Rodríguez ÁM, Sánchez Gómez A, Satizabal Soto JM

Abstract
A study published in 2012 estimated incidence of MPS IVA, in 0.68 cases per 100, 000 live births in Colombia, and according to the Colombian Fund for High-Cost Diseases, in 2014 there were 15 people diagnosed with MPS IV. To enhance the knowledge of the disease in the country, we aimed to characterize clinical and molecular findings in 12 MPS IVA patients. Twelve patients were included in the study, with most patients of female gender (n = 7, 58,3%), age range 2 to 28 years, average weight 26 kg (17.6-43 kg), average height 97 cm (92-104 cm), average BMI 27.6 kg/m2 (19.92-47.65 kg/m2). Clinical findings were similar to those described in the literature. GALNS gene molecular analysis showed five homozygous missense mutations in exon 11 c.1156C > T or p.R386C, a single nonsense mutation in the heterozygous state c.974G > A p.W325, and heterozygous in exon 9 mutation of exon 3 c.280C > T p.R94C, missense variant reported by Ogawa in 1995 [17]. There was only one patient that presented a homozygous missense mutation in exon 9 c.901G > T p.G301C and four patients showed the heterozygous form. A heterozygous missense mutation in exon 5 c.425A > T p.H142L, which has not been previously reported, was found in a female patient, 2 years 11 months of age. The diagnosis algorithms that include molecular analysis, bioinformatic predictive tools, pharmacogenomics, and proteomics helps to improve the diagnosis, treatment, and prognosis of patients affected by MPS IVA.

PMID: 30094185 [PubMed]

Cross-ethnicity tagging SNPs for HLA alleles associated with adverse drug reaction.

Pharmacogenomics J. 2018 Aug 10;:

Authors: Erlichster M, Goudey B, Skafidas E, Kwan P

Abstract
Reduction of adverse drug reaction (ADR) incidence through screening of predisposing human leucocyte antigen (HLA) alleles is a promising approach for many widely used drugs. However, application of these associations has been limited by the cost burden of HLA genotyping. Use of single nucleotide polymorphisms (SNPs) that can approximate ('tag') HLA alleles of interest has been proposed as a cost-effective and simple alternative to conventional genotyping. However, most reported SNP tags have not been validated and there is concern regarding clinical utility of this approach due to tagging inconsistency across different populations. We assess the ability of 67 previously reported and 378 novel tagging SNPs, identified here in 5 HLA reference panels, to tag 15 ADR-associated HLA alleles in a panel of 955 ethnically diverse samples. Tags for 8 HLA alleles of interest were identified with 100% sensitivity and >95% specificity. These SNPs may act as a reliable genotyping approach for the routine screening of patients, without the need to account for patient ethnicity.

PMID: 30093715 [PubMed - as supplied by publisher]

Polymorphisms in CEP68 gene associated with risk of immediate selective reactions to non-steroidal anti-inflammatory drugs.

Pharmacogenomics J. 2018 Aug 10;:

Authors: Perkins JR, Acosta-Herrera M, Plaza-Serón MC, Jurado-Escobar R, Doña I, García-Martín E, Isidoro-García M, Bartra J, Ribas-Perez D, Mayorga C, Torres MJ, Flores C, Cornejo-García JA

Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions. Such reactions can be pharmacologically or immunologically mediated, but in both cases individual susceptibility can be influenced by genetic factors. Polymorphisms in centrosomal protein of 68 kDa (CEP68) have been associated with pharmacologically mediated NSAIDs reactions. Here, we evaluated this gene in immunologically mediated single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) by analyzing 52 single nucleotide polymorphisms in CEP68 in 176 patients and 363 NSAIDs-tolerant controls. Two intronic variants (rs2241160 and rs2241161) were significantly associated with an increased risk of SNIUAA, suggesting CEP68 to be a key player in both types of NSAIDs hypersensitivity. However, we found no overlap with genetic variants previously associated with pharmacologically mediated hypersensitivity, pointing to a complex role for this gene and its potential use in the development of biomarkers of clinical utility to diagnose patients at risk of these reactions and to differentiate entities.

PMID: 30093714 [PubMed - as supplied by publisher]

Frequency of vitamin K oxidoreductase complex subunit-1 (VKORC1) polymorphisms and warfarin dose management in patients with venous thromboembolism.

Pharmacogenomics J. 2018 Aug 10;:

Authors: Kabalak PA, Savaş İ, Akar N, Demir N, Eğin Y

Abstract
Warfarin works by inhibiting VKORC1, so polymorphisms of this gene modify the required drug dose. The aim of this study is to examine the relation between therapeutic weekly dose of warfarin and C1173T/G1639A polymorphism of VKORC1 in patients with VTE. Seventy-five patients with VTE were enrolled. Weekly warfarin doses and time (day) to reach therapeutic INR were evaluated retrospectively along with VKORC1-C1173T and G1639A alleles. The mean weekly warfarin dose was lower and time to reach therapeutic INR was shorter in homozygote alleles (AA and TT) (p < 0.05). The multivariate regression model was produced, R2 = 0.05% for age (p = 0.04), R2 = 6% for VKORC1 (p = 0.03), the model for estimating warfarin dose R2 = 17% (p > 0.05). In particular, patients who need overdose of warfarin or whose bleeding score is high, study of these polymorphisms can be considered.

PMID: 30093713 [PubMed - as supplied by publisher]

Systematic identification of non-coding pharmacogenomic landscape in cancer.

Nat Commun. 2018 Aug 09;9(1):3192

Authors: Wang Y, Wang Z, Xu J, Li J, Li S, Zhang M, Yang D

Abstract
Emerging evidence has shown long non-coding RNAs (lncRNAs) play important roles in cancer drug response. Here we report a lncRNA pharmacogenomic landscape by integrating multi-dimensional genomic data of 1005 cancer cell lines and drug response data of 265 anti-cancer compounds. Using Elastic Net (EN) regression, our analysis identifies 27,341 lncRNA-drug predictive pairs. We validate the robustness of the lncRNA EN-models using two independent cancer pharmacogenomic datasets. By applying lncRNA EN-models of 49 FDA approved drugs to the 5605 tumor samples from 21 cancer types, we show that cancer cell line based lncRNA EN-models can predict therapeutic outcome in cancer patients. Further lncRNA-pathway co-expression analysis suggests lncRNAs may regulate drug response through drug-metabolism or drug-target pathways. Finally, we experimentally validate that EPIC1, the top predictive lncRNA for the Bromodomain and Extra-Terminal motif (BET) inhibitors, strongly promotes iBET762 and JQ-1 resistance through activating MYC transcriptional activity.

PMID: 30093685 [PubMed - in process]

Correction to: Population-Based Analysis of Cluster Headache-Associated Genetic Polymorphisms.

J Mol Neurosci. 2018 Aug 09;:

Authors: Katsarou MS, Papasavva M, Latsi R, Toliza I, Gkaros AP, Papakonstantinou S, Gatzonis S, Mitsikostas DD, Kovatsi L, Izotov BN, Tsatsakis AM, Drakoulis N

Abstract
The original version of this article unfortunately contained mistakes in author group section.

PMID: 30091080 [PubMed - as supplied by publisher]

Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients.

Pharmacogenomics. 2018 Aug 08;:

Authors: Elsayed AH, Cao X, Crews KR, Gandhi V, Plunkett W, Rubnitz JE, Ribeiro RC, Pounds SB, Lamba JK

Abstract
AIM: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP.
METHOD:  We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68).
RESULTS:  Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP. A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groups based on ACSS: high-ACSS (score >0), intermediate-ACSS (score = 0) and low-ACSS (score <0). ACSS designation was significant predictor of intracellular ara-CTP levels (p = 0.00012), suggesting a cumulative or synergistic effect of the significant SNPs.
CONCLUSION: ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells, thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.

PMID: 30088438 [PubMed - as supplied by publisher]

A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening.

Front Oncol. 2018;8:279

Authors: Tong CC, Lam CW, Lam KO, Lee VHF, Luk MY

Abstract
Background: The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity. Patients and methods: A 49-year-old lady with resected stage III carcinoma of sigmoid colon was scheduled to have a course of 5-FU based adjuvant chemotherapy. She developed unexpected acute severe (grade 4) toxicity after the first cycle of chemotherapy. Genomic DNA was isolated from 3 ml peripheral blood cells for full sequencing of DPYD (the gene encoding DPD). Results: Exome sequencing confirmed that she is heterozygous for NM_000110.3: c.321+2T>C of the DPYD gene. To the best of our knowledge, this variant is a novel pathogenic splicing variant of the DPYD gene resulting in a non-functional allele. As she has a heterozygous genotype and considered having decreased DPD activity, we followed the international recommendation and restart chemotherapy with at least 50% reduction for 5-FU dose. We then titrated the 5-FU dose, and she tolerated the subsequent cycles of chemotherapy and completed the whole course of adjuvant chemotherapy. Conclusions: With a pre-emptive test on DPD deficiency before the administration of the fluoropyrimidine drugs, the aforementioned patient's life-threatening event could be avoided. This clinical utility has been confirmed by two recent large-scale studies and called for a drug label update.

PMID: 30087856 [PubMed]

Modeling Corticosteroid Pharmacogenomics and Proteomics in Rat Liver.

J Pharmacol Exp Ther. 2018 Aug 07;:

Authors: Ayyar VS, Sukumaran S, DuBois DC, Almon RR, Jusko WJ

Abstract
Corticosteroids (CS) regulate the expression of numerous genes at the mRNA and protein levels. The time-course of CS pharmacogenomics and proteomics were examined in livers obtained from adrenalectomized rats given a 50 mg/kg bolus dose of methylprednisolone. Microarrays and mass-spectrometry based proteomics were employed to quantify hepatic transcript and protein dynamics. A total of 163 differentially expressed mRNA and their corresponding proteins (163 genes) were clustered into two dominant groups. The temporal profiles of most proteins were delayed compared to its mRNA, attributable to synthesis delays and slower degradation kinetics. Based upon our fifth-generation model of CS, mathematical models were developed to simultaneously describe the emergent time-patterns for an array of steroid-responsive mRNA and proteins. The majority of genes showed time-dependent increases in mRNA and protein expression before returning to baseline. A model assuming direct, steroid-mediated stimulation of mRNA synthesis was applied. Some mRNAs and their proteins displayed down-regulation following CS. A model assuming receptor-mediated inhibition of mRNA synthesis was utilized. More complex patterns were observed for other genes (e.g. biphasic behaviors and opposite directionality in mRNA and protein). Models assuming either stimulation or inhibition of mRNA synthesis coupled with dual secondarily-induced regulatory mechanisms affecting mRNA or protein turnover were derived. These findings indicate that CS-regulated gene expression manifested at the mRNA and protein levels are controlled via mechanisms affecting key turnover processes. Our quantitative models of CS pharmacogenomics were expanded from mRNA to proteins and provide extended hypotheses for understanding the direct, secondary, and downstream mechanisms of CS actions.

PMID: 30087156 [PubMed - as supplied by publisher]

Clinical pharmacogenomics of carvedilol: the stereo-selective metabolism angle.

Pharmacogenomics. 2018 Aug 08;:

Authors: Parker BM, Rogers SL, Lymperopoulos A

PMID: 30086658 [PubMed - as supplied by publisher]