Pharmacogenetic Testing: Why Is It So Disappointing?

J Psychosoc Nurs Ment Health Serv. 2019 Apr 01;57(4):9-12

Authors: Limandri BJ

Abstract
Pharmacogenetic testing to aid in making decisions about prescribing medications was approved by the U.S. Food and Drug Administration in 2005 and gradually became a common practice. However, an innovation that was thought to help individualize prescribing psychotropic medications with fewer trials and errors soon became a disappointment to clinicians. Current pharmacogenetic testing assesses how the liver metabolizes drugs through the cytochrome p 450 system; however, much of the variability in how a drug affects an individual also relies on the pharmacodynamics of the drug (i.e., the specific ways the drug changes the body). The current article discusses the advantages and disadvantages of pharmacogenetic testing to aid in prescribing psychotropic medications. [Journal of Psychosocial Nursing and Mental Health Services, 57(4), 9-12.].

PMID: 30933297 [PubMed - indexed for MEDLINE]

Drug-Drug Interactions With Oral Antineoplastic Agents.

JAMA Oncol. 2017 06 01;3(6):736-738

Authors: Parsad S, Ratain MJ

PMID: 27737450 [PubMed - indexed for MEDLINE]

AR-V7 and AR-FL expression is associated with clinical outcome: a translational study in patients with castrate resistant prostate cancer.

BJU Int. 2019 May 04;:

Authors: Del Re M, Crucitta S, Sbrana A, Rofi E, Paolieri F, Gianfilippo G, Galli L, Falcone A, Morganti R, Porta C, Efstathiou E, van Schaik R, Jenster G, Danesi R

Abstract
OBJECTIVES: To investigate if full-length androgen receptor (AR-FL) is associated with resistance to AR-directed therapy independently and/or combined with AR splice variant 7 (AR-V7).
PATIENTS AND METHODS: Plasma samples were prospectively collected from 73 patients with CRPC before first or second-line AR-directed therapy. mRNA was isolated from exosomes and AR-FL and AR-V7 were analyzed by ddPCR.
RESULTS: AR-FL was detected in all patients while 22% were AR-V7+ at baseline. AR-FL expression was significantly higher in AR-V7+ vs AR-V7- patients (p<0.0001). Stratifying patients by tertiles for AR-FL expression, PFS was 22 vs 18 vs 4 months for lower vs intermediate vs higher tertile, respectively (p=0.0003). Median PFS and OS were significantly longer in AR-V7- vs AR-V7+ patients (20 vs 4 months, p<0.0001; not reached vs 9 months, p<0.0001, respectively).
CONCLUSIONS: Resistance to AR-directed therapy is associated with the presence of AR-V7; however, AR-FL expression may help better refine response and survival of patients to AR-directed therapy. Both biomarkers, if validated in prospective trials, may be used to select the best treatment strategy. This article is protected by copyright. All rights reserved.

PMID: 31055861 [PubMed - as supplied by publisher]

Creatine based polymer for codelivery of bioengineered MicroRNA and chemodrugs against breast cancer lung metastasis.

Biomaterials. 2019 Apr 26;210:25-40

Authors: Xu J, Sun J, Ho PY, Luo Z, Ma W, Zhao W, Rathod SB, Fernandez CA, Venkataramanan R, Xie W, Yu AM, Li S

Abstract
Metastasis is the major cause for breast cancer related mortality. The combination of miRNA-based therapy and chemotherapy represents a promising approach against breast cancer lung metastasis. The goal of this study is to develop an improved therapy that co-delivers a novel bioengineered miRNA prodrug (tRNA-mir-34a) and doxorubicin (DOX) via a multifunctional nanomicellar carrier that is based on a conjugate of amphiphilic copolymer POEG-VBC backbone with creatine, a naturally occurring cationic molecule. Co-delivery of DOX leads to more effective processing of tRNA-mir-34a into mature miR-34a and down-regulation of target genes. DOX + tRNA-mir-34a/POEG-PCre exhibits potent synergistic anti-tumor and anti-metastasis activity in vitro and in vivo. Interestingly, the enhanced immune response contributes to the overall antitumor efficacy. POEG-PCre may represent a safe and effective delivery system for an optimal chemo-gene combination therapy.

PMID: 31054369 [PubMed - as supplied by publisher]

DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report.

Pharmaceutics. 2019 May 01;11(5):

Authors: Wigle TJ, Tsvetkova EV, Welch SA, Kim RB

Abstract
5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas.

PMID: 31052357 [PubMed]

Pharmacogenetic Tests in Reducing Accesses to Emergency Services and Days of Hospitalization in Bipolar Disorder: A 2-Year Mirror Analysis.

J Pers Med. 2019 Apr 30;9(2):

Authors: Callegari C, Isella C, Caselli I, Poloni N, Ielmini M

Abstract
Despite the enormous costs associated to mood disorders', few studies evaluate potential cost saving from the use of pharmacogenetic tests (PGT). This study compares 12 months before the execution of the PGT versus 12 months after, in terms of number and days of hospitalization and accesses to emergency services, in a sample of 30 patients affected by bipolar disorder. Secondarily, the study gives an economic value to the data based on the diagnosis-related group (DRG). Patients included in the study were required to be aged ≥18 years, sign an informed consent, have a score of Clinical Global Impression item Severity (CGIs) ≥3, and have a discordant therapy compared to the PGT in the 12 months preceding it and a therapy consistent with it for the following 12 months. Cost saving has been evaluated by paired t-tests in a mirror analysis. Statistically significant differences in all the comparisons (p < 0.0001) emerged. Important cost saving emerged after the use of PGT (€148,920 the first year versus €39,048 the following year). Despite the small sample size and lack of a control group in this study, the potential role of PGT in cost saving for the treatment of bipolar disorder treatment emerged. To confirm this result, larger and clinical trials are needed.

PMID: 31052247 [PubMed]

Pharmacogenomics in dermatology: tools for understanding gene-drug associations.

Semin Cutan Med Surg. 2019 Mar 01;38(1):E19-E24

Authors: Daneshjou R, Huddart R, Klein TE, Altman RB

Abstract
Pharmacogenomics aims to associate human genetic variability with differences in drug phenotypes in order to tailor drug treatment to individual patients. The massive amount of genetic data generated from large cohorts of patients with variable drug phenotypes have led to advances in this field. Understanding the application of pharmacogenomics in dermatology could inform clinical practice and provide insight for future research. The Pharmacogenomics Knowledge Base and the Clinical Pharmacogenetics Implementation Consortium are among the resources to help clinicians and researchers navigate the many gene-drug associations that have already been discovered. The implementation of clinical pharmacogenomics within health care systems remains an area of ongoing development. This review provides an introduction to the field of pharmacogenomics and to current pharmacogenomics resources using examples of gene-drug associations relevant to the field of dermatology.

PMID: 31051019 [PubMed - in process]

Developing Pharmacogenomic Reports: Insights from Patients and Clinicians.

Clin Transl Sci. 2018 05;11(3):289-295

Authors: Jones LK, Kulchak Rahm A, Gionfriddo MR, Williams JL, Fan AL, Pulk RA, Wright EA, Williams MS

Abstract
Increasingly, for a variety of indications, patients have their genomes sequenced and actionable results returned. A subset of returned results is pharmacogenomic (PGx) variants involved in the metabolism or action of medications. Although the impact of these variants on health is well-documented, little research exists on how to communicate these findings to patients and clinicians. We conducted semistructured interviews with end users to understand how best to communicate PGx results. Overall, patients and clinicians had similar opinions regarding report content, delivery, and application. Unique concerns specific to each stakeholder group were also expressed. Patients wanted an easy-to-understand individualized report that clinicians utilized to guide their care. Clinicians wanted reports that were easy-to-use, actionable, and integrated into their workflow. Implementation of these reports in a clinical setting will allow for broader user feedback and iterative improvement.

PMID: 29316365 [PubMed - indexed for MEDLINE]

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The increase in activating EGFR mutation in plasma is an early biomarker to monitor response to osimertinib: a case report.

BMC Cancer. 2019 Apr 30;19(1):410

Authors: Del Re M, Rofi E, Cappelli C, Puppo G, Crucitta S, Valeggi S, Chella A, Danesi R, Petrini I

Abstract
BACKGROUND: Systemic treatment of advanced non-small cell lung cancer (NSCLC) has changed dramatically since the introduction of targeted therapies. The analysis of circulating tumor DNA (ctDNA) is a valuable approach to monitor the clonal evolution of tumors during treatment with EGFR-tyrosine kinase inhibitors (TKIs) and to detect resistance mutations.
CASE PRESENTATION: A NSCLC patient with exon 19 deletion (ex19del) of EGFR was treated with osimertinib after multiple lines of treatment and obtained a partial response that lasted over 26 months. Blood was collected at each visit and ctDNA was extracted to monitor ex19del by digital droplet PCR. Within a few weeks from the beginning of osimertinib, ex19del disappeared from plasma but appeared again and steadily increased a few months later anticipating tumor progression. Interestingly, the change in ex19del was much more pronounced than other mutations, since T790M appeared 3 months after the increase of ex19del, and C797S was detectable a few weeks before clinical disease progression. Then the patient received cytotoxic chemotherapy, which was associated with a decrease in ex19del and disappearance of T790M and C797S; however, at disease progression, all EGFR mutations increased again in plasma together with MET amplification which was detected by NGS.
CONCLUSIONS: The measurement of ex19del changes in ctDNA is a simple and sensitive approach to monitor clinical outcome to osimertinib and, potentially, to other therapeutic interventions.

PMID: 31039766 [PubMed - in process]

Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in β-Thalassemia Intermedia: A Validation Cohort Study.

Hemoglobin. 2019 Apr 30;:1-7

Authors: Kolliopoulou A, Siamoglou S, John A, Sgourou A, Kourakli A, Symeonidis A, Vlachaki E, Chalkia P, Theodoridou S, Ali BR, Katsila T, Patrinos GP, Papachatzopoulou A

Abstract
Hemoglobinopathies exhibit a remarkable phenotypic diversity in terms of disease severity, while individual genetic background plays a key role in differential response to drug treatment. In the last decade, genomic variants in genes located within, as well as outside the human β-globin cluster have been shown to be significantly associated with Hb F increase, in relation to hydroxyurea (HU) therapy in patients with these diseases. Here, we aim to determine the effect of genomic variants located in genes, such as MAP3K5, ASS1, NOS2A, TOX, PDE7B, NOS1, FLT1 and ARG2, previously shown to modulate fetal hemoglobin (Hb F) levels in patients with β type hemoglobinopathies and reflecting disease severity and response to HU therapy in an independent cohort of Greek patients with these diseases. We recruited and genotyped 45 β-thalassemia patients (β-thal), either transfusion-dependent (TDT) or non transfusion-dependent (NTDT), 42 Hb S (HBB: c.20A>T)-β-thal compound heterozygotes, who were treated with HU, as well as 53 healthy individuals, all of Hellenic origin. Our study showed that genomic variants of the MAP3K5, NOS2A and ARG2 gene are associated with HU therapy efficacy in Hb S-β-thal compound heterozygotes. We have also shown that FLT1 and ARG2 genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that MAP3K5, NOS2A, ARG2 and FLT1 genomic variants could be considered as genomic biomarkers to predict HU therapy efficacy in Hb S-β-thal compound heterozygotes and also to describe disease severity in patients with β type hemoglobinopathies.

PMID: 31039620 [PubMed - as supplied by publisher]

Estradiol metabolites as biomarkers of endometrial cancer prognosis after surgery.

J Steroid Biochem Mol Biol. 2018 04;178:45-54

Authors: Audet-Delage Y, Grégoire J, Caron P, Turcotte V, Plante M, Ayotte P, Simonyan D, Villeneuve L, Guillemette C

Abstract
Endometrial cancer (EC) is the most common gynecologic malignancy prevailing after menopause. Defining steroid profiles may help predict the risk of recurrence after hysterectomy, which remains limited due to the lack of reliable markers. Adrenal precursors, androgens, parent estrogens and catechol estrogen metabolites were measured by mass spectrometry (MS) in preoperative serums and those collected one month after hysterectomy from 246 newly diagnosed postmenopausal EC cases. We also examined the associations between steroid hormones and EC status by including 110 healthy postmenopausal women. Steroid concentrations were analyzed in relation to clinicopathological features, recurrence and overall survival (OS). The mean follow-up time was 65.5 months and 26 patients experienced relapse after surgery for a recurrence incidence of 10.6% (6.4% Type I and 29.5% Type II). Recurrence and OS were related to a more aggressive disease but not linked to body mass index. Preoperative levels of estriol (E3) and estrone-sulfate (E1-S) were inversely associated with recurrence in a multivariate logistic regression analysis (Hazard ratios (HRs) of 0.31, P=0.039 and 3.01, P=0.024; respectively). All circulating steroids declined considerably after surgery almost reaching those of healthy women, except 4-methoxy-E2 (4MeO-E2) for which postoperative levels increased by 35% and were associated to a 68% decreased risk of recurrence (HR=0.32, P=0.015). Women diagnosed with both histological types of EC present significantly higher levels of steroids, in support of their mitogenic effects. The estrogen precursor E1-S, the anticancer metabolite 4MeO-E2, and E3 that exert mixed antagonist and agonist estrogenic activities and immunological effects, are potential independent prognostic factors.

PMID: 29092787 [PubMed - indexed for MEDLINE]

Sex modulates hepatic mitochondrial adaptations to high fat diet and physical activity.

Am J Physiol Endocrinol Metab. 2019 Apr 30;:

Authors: McCoin CS, Von Schulze A, Allen J, Fuller KN, Xia Q, Koestler DC, Houchen CJ, Maurer A, Dorn Ii GW, Shankar K, Morris EM, Thyfault JP

Abstract
The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific PGC-1a, a transcriptional co-activator of biogenesis, and BNIP3, a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2 production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild type (WT), liver-specific PGC-1a heterozygote (LPGC-1a) and BNIP3 null mice were thermoneutral housed (29-31°C) and divided into three groups: sedentary - low fat diet (LFD), 16 weeks of (HFD), or 16 weeks of HFD with VWR for the final 8 weeks (HFD+VWR) (n=5-7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group, however HFD+VWR significantly increased maximal respiratory capacity only in WT and PGC-1a females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling efficiency and reduced H2O2 production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1a and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD+VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1a or BNIP3.

PMID: 31039007 [PubMed - as supplied by publisher]

Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock Induced Liver Injury.

Hepatology. 2019 Apr 30;:

Authors: Xie Y, Xu M, Deng M, Li Z, Wang P, Ren S, Guo Y, Ma X, Fan J, Billiar TR, Xie W

Abstract
Hemorrhagic shock (HS) is a life-threatening condition associated with tissue hypoperfusion, and often leads to injury of multiple organs including the liver. Pregnane X receptor (PXR) is a species-specific xenobiotic receptor that regulates the expression of drug-metabolizing enzymes (DMEs) such as the cytochrome P450 3A (CYP3A). Many clinical drugs, including those often prescribed to trauma patients, are known to activate PXR and induce CYP3A. The goal of this study is to determine whether PXR plays a role in the regulation of DMEs in the setting of HS, and whether activation of PXR is beneficial or detrimental to HS-induced hepatic injury. PXR transgenic, knockout, and humanized mice were subject to HS, and the liver injury was assessed histologically and biochemically. The expression and/or activity of PXR and CYP3A were manipulated genetically or pharmacologically in order to determine their effects on HS-induced liver injury. Our results showed that genetic or pharmacological activation of PXR sensitized wild-type and hPXR/CYP3A4 humanized mice to HS-induced hepatic injury, whereas knockout of PXR protected mice from HS-induced liver injury. Mechanistically, the sensitizing effect of PXR activation was accounted for by PXR-responsive induction of CYP3A and increased oxidative stress in the liver. The sensitizing effect of PXR was attenuated by ablation or pharmacological inhibition of CYP3A, treatment with the antioxidant N-acetylcysteine amide (NACA), or treatment with a PXR antagonist. CONCLUSIONS: We have uncovered a novel function of PXR in HS-induced hepatic injury. Our results suggest that the unavoidable use of PXR-activating drugs in trauma patients has the potential to exacerbate HS-induced hepatic injury, which can be mitigated by the co-administration of anti-oxidative agents, CYP3A inhibitors, or PXR antagonists. This article is protected by copyright. All rights reserved.

PMID: 31038762 [PubMed - as supplied by publisher]

The advantages and challenges of diversity in Pharmacogenomics: Can minority populations bring us closer to implementation?

Clin Pharmacol Ther. 2019 Apr 30;:

Authors: Zhang H, De T, Zhong Y, Perera MA

Abstract
Health disparities exist among minorities in the United States, with differences seen in disease prevalence, mortality, and responses to medications. These differences are multifactorial with genetic variation explains a portion of this variability. Pharmacogenomics aims to find the effect of genetic variations on drug response, with the goal of optimizing drug therapy and development. Although genome-wide association studies have been useful in unbiasedly surveying the genome for genetic drivers of clinically relevant phenotypes, most of these studies have been conducted in mainly European and Asian descent participants, contributing to a growing health disparity in precision medicine. Diversity is important to pharmacogenomic studies, and there may be real advantages to the use of these complex genomes in pharmacogenomics. In this review we will outline some of the advantages and confounders of pharmacogenomics in minorities, the role of genetic variation in pharmacologic pathways and highlight a number of population-specific findings. This article is protected by copyright. All rights reserved.

PMID: 31038731 [PubMed - as supplied by publisher]

Development of the PGx-Passport: A Panel of Actionable Germline Genetic Variants for Pre-emptive Pharmacogenetic Testing.

Clin Pharmacol Ther. 2019 Apr 30;:

Authors: van der Wouden CH, van Rhenen MH, Jama WOM, Ingelman-Sundberg M, Lauschke VM, Konta L, Schwab M, Swen JJ, Guchelaar HJ

Abstract
Pre-emptive pharmacogenetic (PGx) testing of a panel of germline genetic variants represents a new model for personalised medicine. Clinical impact of PGx testing is maximized when all variant alleles for which actionable clinical guidelines are available, are included in the test panel. However, no such standardized method has been presented to date, impeding adoption, exchange and continuity of PGx testing. We, therefore, developed such a panel, hereafter called the PGx-Passport, based on the actionable Dutch Pharmacogenetics Working Group (DPWG) guidelines. Germline variant alleles were systematically selected using pre-defined criteria regarding allele population frequencies, effect on protein functionality and association with drug response. A PGx-Passport of 58 germline variant alleles, located within 14 genes (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, HLA-A, HLA-B, NUDT15, SLCO1B1, TPMT, UGT1A1 and VKORC1) was composed. This PGx-Passport can be used in combination with the DPWG guidelines to optimize drug prescribing for 49 commonly prescribed drugs. This article is protected by copyright. All rights reserved.

PMID: 31038729 [PubMed - as supplied by publisher]

Relationship between warfarin dosage and international normalized ratio: a dose-response analysis and evaluation based on multicenter data.

Eur J Clin Pharmacol. 2019 Apr 29;:

Authors: Xue L, Zhang Y, Xie C, Zhou L, Liu L, Zhang H, Xu L, Song H, Lin M, Qiu H, Zhu J, Zhu Y, Zou J, Zhuang W, Xuan B, Chen Y, Fan Y, Wu D, Shen Z, Miao L

Abstract
PURPOSE: The objectives of the study were to establish a dose-response model for warfarin based on the relationship between daily warfarin dose and international normalized ratio (INR) and to evaluate the stability and reliability of the established model using external data.
METHODS: Clinical data were recorded from 676 outpatients with a steady-state warfarin dosage. Demographic characteristics, concomitant medications, daily dosage of warfarin, CYP2C9 and VKORC1 genotypes, and INR were recorded. Data analysis based on the Michaelis-Menten equation to describe the relationship between daily warfarin dose and INR was performed using NONMEM. The reliability and stability of the final model were evaluated using goodness-of-fit plots, resampling techniques with a nonparametric bootstrap, and external data.
RESULTS: The daily warfarin dose and INR were described by a more pharmacologically expressive model than multivariate linear regression (MLR) model. The population standard value of Km was 3.56 mg, and the Hill coefficient was 0.512, with individual variabilities of 53.1% and 55.9%, respectively. CYP2C9 *1/*3, VKORC1 AA, concomitant amiodarone, and nonheart valve replacement reduced the warfarin Km by 30.4%, 74.3%, 34.5%, and 39.4%, respectively. The Km value decreased with age and increased with fat free mass (FFM). INR prediction error (73.0%) of the external datasets was within ± 20%.
CONCLUSION: A dose-response model of warfarin was established based on the relationship between daily warfarin dose and INR. Expected genotype effects on Km and demographic characteristics were confirmed. The model has the potential to be a powerful tool for individualized warfarin therapy for Chinese outpatients.

PMID: 31037455 [PubMed - as supplied by publisher]

Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39.

Ann Rheum Dis. 2019 Apr 29;:

Authors: Spiliopoulou A, Colombo M, Plant D, Nair N, Cui J, Coenen MJ, Ikari K, Yamanaka H, Saevarsdottir S, Padyukov L, Bridges SL, Kimberly RP, Okada Y, van Riel PLC, Wolbink G, van der Horst-Bruinsma IE, de Vries N, Tak PP, Ohmura K, Canhão H, Guchelaar HJ, Huizinga TW, Criswell LA, Raychaudhuri S, Weinblatt ME, Wilson AG, Mariette X, Isaacs JD, Morgan AW, Pitzalis C, Barton A, McKeigue P

Abstract
OBJECTIVES: We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response.
METHODS: We studied the relation of TNFi response, quantified by change in swollen joint counts (ΔSJC) and erythrocyte sedimentation rate (ΔESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation.
RESULTS: We detected a statistically significant association between ΔSJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between ΔSJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance.
CONCLUSIONS: The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.

PMID: 31036624 [PubMed - as supplied by publisher]

Genetic Predispositions of Glucocorticoid Resistance and Therapeutic Outcomes in Polymyalgia Rheumatica and Giant Cell Arteritis.

J Clin Med. 2019 Apr 27;8(5):

Authors: Smutny T, Barvik I, Veleta T, Pavek P, Soukup T

Abstract
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are closely related chronic inflammatory diseases. Glucocorticoids (GCs) are first-choice drugs for PMR and GCA, although some patients show poor responsiveness to the initial GC regimen or experience flares after GC tapering. To date, no valid biomarkers have been found to predict which patients are at most risk for developing GC resistance. In this review, we summarize PMR- and GCA-related gene polymorphisms and we associate these gene variants with GC resistance and therapeutic outcomes. A limited number of GC resistance associated-polymorphisms have been published so far, mostly related to HLA-DRB1*04 allele. Other genes such ICAM-1, TLR4 and 9, VEGF, and INFG may play a role, although discrepancies are often found among different populations. We conclude that more studies are required to identify reliable biomarkers of GC resistance. Such biomarkers could help distinguish non-responders from responders to GC treatment, with concomitant consequences for therapeutic strategy.

PMID: 31035618 [PubMed]

Melatonin Levels in Preterm and Term Infants and Their Mothers.

Int J Mol Sci. 2019 Apr 27;20(9):

Authors: Biran V, Decobert F, Bednarek N, Boizeau P, Benoist JF, Claustrat B, Barré J, Colella M, Frérot A, Garnotel R, Graesslin O, Haddad B, Launay JM, Schmitz T, Schroedt J, Virlouvet AL, Guilmin-Crépon S, Yacoubi A, Jacqz-Aigrain E, Gressens P, Alberti C, Baud O

Abstract
The prevention of perinatal brain damage following preterm birth remains a public health priority. Melatonin has been shown to be a promising neuroprotectant in neonatal preclinical models of brain damage, but few studies have investigated melatonin secretion in newborns. We hypothesized that melatonin circulating levels would be lower in preterm compared to term infants. We conducted a prospective, longitudinal, multicenter study to assess melatonin, and 6-sulfatoxy-melatonin (aMT6s) concentrations, measured by radioimmunoassay. Among 209 neonates recruited, 110 were born before 34 gestational weeks (GW) and 99 born after 34 GW. Plasma melatonin concentrations, measured at birth and on Day 3 were below detectable levels (≤7 pg/mL) in 78% and 81%, respectively, of infants born before 34 GW compared to 57% and 34%, respectively, of infants born after 34 GW. The distribution of plasma melatonin concentrations was found to be correlated with gestational age at both time-points (p < 0.001). Median urine aMT6s concentrations were significantly lower in infants born before 34 GW, both on Day 1 (230 ng/L vs. 533 ng/L, p < 0.0001) and on Day 3 (197 ng/L vs. 359 ng/L, p < 0.0001). In conclusion, melatonin secretion appears very low in preterm infants, providing the rationale for testing supplemental melatonin as a neuroprotectant in clinical trials.

PMID: 31035572 [PubMed - in process]