Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis.

Rheumatology (Oxford). 2019 Oct 10;:

Authors: Nair N, Plant D, Verstappen SM, Isaacs JD, Morgan AW, Hyrich KL, Barton A, Wilson AG

Abstract
OBJECTIVES: Identifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX.
METHODS: DNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study.
RESULTS: In the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study.
CONCLUSION: These data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks.

PMID: 31598719 [PubMed - as supplied by publisher]

Reporting of offspring data in diabetes, HIV infection and hypertension trials during pregnancy: a systematic review.

Arch Dis Child Fetal Neonatal Ed. 2019 Oct 09;:

Authors: Aurich B, Martin-Montoya T, Zhang D, Jacqz-Aigrain E

Abstract
BACKGROUND: Clinical trials are conducted during pregnancy to evaluate benefits and risks of medicines for mother and child. The safety of maternal treatments is a key issue for healthcare professionals and parents.
OBJECTIVE: To analyse offspring data reported in clinical trials in pregnant women with diabetes, HIV infection or hypertension (three of the most common diseases in women of childbearing potential) and either treated prior to pregnancy for these chronic diseases or diagnosed and treated during pregnancy.
METHODS: PubMed and Embase (1 January 1997 to 31 December 2017) were searched for drug trials in pregnant women with diabetes, HIV infection or hypertension. Titles and abstracts were screened, followed by a full-text review of eligible articles. Inclusion criteria were interventional clinical trials in pregnant women treated with medication and full text in English. Trial characteristics, maternal and offspring data were extracted. Data were summarised by disease and study. Twelve key items were considered for the offspring.
RESULTS: Overall, 196 articles reporting 132 clinical trials (diabetes n=55; HIV n=59; hypertension n=18) were included. Key offspring data were frequently not reported, for example, number of births (diabetes: 22/55, 40%; HIV: 14/59, 24%; hypertension: 10/18, 56%). Congenital malformations were often not reported with sufficient detail (diabetes: 40/55, 73%; HIV: 39/59, 66%; hypertension: 17/18, 94%). Similar observations were made for other key items (eg, fetal losses, neonatal deaths).
CONCLUSION: Under-reporting of key data for the offspring was frequent in publications of clinical trials in pregnant women with diabetes, HIV infection or hypertension making the assessment of the benefit-risk ratio of treatment options during pregnancy difficult.
TRIAL REGISTRATION NUMBER: CRD42017057024.

PMID: 31597728 [PubMed - as supplied by publisher]

Molecular basis for the sensitivity of TRP channels to polyunsaturated fatty acids.

Naunyn Schmiedebergs Arch Pharmacol. 2018 08;391(8):833-846

Authors: Riehle M, Tsvetkov D, Gohlke BO, Preissner R, Harteneck C, Gollasch M, Nürnberg B

Abstract
Transient receptor potential (TRP) channels represent a superfamily of unselective cation channels that are subdivided into seven subfamilies based on their sequence homology and differences in gating and functional properties. Little is known about the molecular mechanisms of TRP channel regulation, particularly of the "canonical" TRP (TRPC) subfamily and their activation by polyunsaturated fatty acids (PUFAs). Here, we analyzed the structure-function relationship of Drosophila fruit fly TRPC channels. The primary aim was to uncover the molecular basis of PUFA sensitivity of Drosophila TRP-like (TRPL) and TRPgamma channels. Amino acid (aa) sequence alignment of the three Drosophila TRPC channels revealed 50 aa residues highly conserved in PUFA-sensitive TRPL and TRPgamma channels but not in the PUFA-insensitive TRP channel. Substitution of respective aa in TRPL by corresponding aa of TRP identified 18 residues that are necessary for PUFA-mediated activation of TRPL. Most aa positions are located within a stretch comprising transmembrane domains S2-S4, whereas six aa positions have been assigned to the proximal cytosolic C-terminus. Interestingly, residues I465 and S471 are required for activation by 5,8,11,14-eicosatetraynoic acid (ETYA) but not 5,8,11-eicosatriynoic acid (ETI). As proof of concept, we generated a PUFA-sensitive TRP channel by exchanging the corresponding aa from TRPL to TRP. Our study demonstrates a specific aa pattern in the transmembrane domains S2-S4 and the proximal C-terminus essential for TRP channel activation by PUFAs.

PMID: 29736621 [PubMed - indexed for MEDLINE]

Obviously Nine Believers: Actionable Germline Genetic Variants for Pre-Emptive Pharmacogenetic Testing.

Basic Clin Pharmacol Toxicol. 2019 Oct 09;:

Authors: Damkier P

Abstract
A recent publication in Clinical Pharmacology and Therapeutics (CPT) by van der Wouden and colleagues on the preemptive pharmacogenomic PGx Passport, intended to optimize drug prescribing, caught my attention. 1 I believe that the overall narrative of the paper is disproportional to the supporting evidence. The Editors of CPT did not find that my comment and reflections on this paper could be prioritized. I hope that BCPT will endorse a discussion of how we, as a research community, frame and disseminate our findings.

PMID: 31597220 [PubMed - as supplied by publisher]

Use of circulating tumoral DNA to guide treatment for metastatic melanoma.

Pharmacogenomics. 2019 Oct 09;:

Authors: Herbreteau G, Charpentier S, Vallée A, Denis MG

Abstract
The management of metastatic cutaneous melanoma is conditioned by the identification of BRAF-activating mutations in tumor DNA. Tumor genotyping is usually performed on DNA extracted from tissue samples. However, these invasive samples are rarely repeated during follow-up, and their analysis requires a sample pre-treatment which may take several weeks. Circulating tumor DNA (ctDNA), released into blood by cancer cells, is a good alternative to tissue sampling. ctDNA is not subject to tumor heterogeneity, and can be analyzed rapidly, making possible the detection of mutations in emergency or in patients whose tumor cannot be sampled. ctDNA can also be analyzed repeatedly during follow-up, for postresection minimal residual disease assessment, for therapeutic response monitoring and for early relapse detection.

PMID: 31596166 [PubMed - as supplied by publisher]

Tacrolimus in adult hematopoietic stem cell transplantation.

Expert Opin Drug Metab Toxicol. 2019 Oct 09;:1-9

Authors: Gao Y, Ma J

Abstract
Introduction: Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplantation (HSCT); therefore, the prevention of GVHD is important for a successful treatment. Tacrolimus (Tac), a calcineurin inhibitor, has been widely used for the prophylaxis of GVHD in HSCT recipients. Areas covered: This review introduces phase II/III of clinical trials related with Tac's roles in the prevention of GVHD in HSCT. Furthermore, we discuss the normal ranges of Tac concentrations, pharmacogenetics, and drug interactions of Tac, as well as its side effects in adult HSCT recipients. Expert opinion: A series of studies has established the efficacy and safety of Tac alone or in combination with other agents in HSCT. However, successful administration of Tac is complicated by its narrow therapeutic window, inter-patient pharmacokinetic variability, and a spectrum of undesirable side effects. It is necessary to maintain concentrations of Tac within the desired ranges for GVHD prophylaxis. Moreover, various factors contribute to significant variability in Tac pharmacokinetics, including drug interactions and genomic variation.

PMID: 31595800 [PubMed - as supplied by publisher]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/10/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/10/08

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Southeast Asian Pharmacogenomics Research Network (SEAPharm): Current Status and Perspectives.

Public Health Genomics. 2019 Oct 04;:1-8

Authors: Chumnumwat S, Lu ZH, Sukasem C, Winther MD, Capule FR, Abdul Hamid AAAT, Bhandari B, Chaikledkaew U, Chanhom N, Chantarangsu S, Charoenyingwattana A, Hang TT, Hlaing TM, Htun KS, Jittikoon J, Le L, Mahasirimongkol S, Mohamed Noor DA, Shrestha J, Suwannoi L, Tragulpiankit P, Turongkaravee S, Wattanapokayakit S, Xangsayarath P, Yuliwulandari R, Zain SM, Chantratita W

Abstract
Pharmacogenomics (PGx) is increasingly being recognized as a potential tool for improving the efficacy and safety of drug therapy. Therefore, several efforts have been undertaken globally to facilitate the implementation process of PGx into routine clinical practice. Part of these efforts include the formation of PGx working groups working on PGx research, synthesis, and dissemination of PGx data and creation of PGx implementation strategies. In Asia, the Southeast Asian Pharmacogenomics Research Network (SEAPharm) is established to enable and strengthen PGx research among the various PGx communities within but not limited to countries in SEA; with the ultimate goal to support PGx implementation in the region. From the perspective of SEAPharm member countries, there are several key elements essential for PGx implementation at the national level. They include pharmacovigilance database, PGx research, health economics research, dedicated laboratory to support PGx testing for both research and clinical use, structured PGx education, and supportive national health policy. The status of these essential elements is presented here to provide a broad picture of the readiness for PGx implementation among the SEAPharm member countries, and to strengthen the PGx research network and practice in this region.

PMID: 31587001 [PubMed - as supplied by publisher]

The impact of steroids on the injured podocytes in nephrotic syndrome.

J Steroid Biochem Mol Biol. 2019 Oct 03;:105490

Authors: Hosseiniyan Khatibi SM, Ardalan M, Abediazar S, Vahed SZ

Abstract
Nephrotic syndrome (NS), a common chronic kidney disease, embraces a variety of kidney disorders. Though Glucocorticoids (GCs) are generally used in the treatment of NS, their mechanism of action is poorly understood. A plethora of evidence indicates that podocytes are considered as the main target cells for the therapeutic strategies to prevent NS. GCs regulate the transactivation and transrepression of genes in podocytes that affect their morphological and cytoskeletal features, motility, apoptosis, and survival rate. Moreover, they prevent protein leakage through the glomerular barrier membrane by affecting the synthesis, trafficking, and posttranslational modifications of slit diaphragms components, podocytes' intercellular junctions. The response to the treatment is variable among different ethnics and populations and resistance to the steroids is detected in almost 50% of adult patients. Not only do pharmacokinetics and pharmacogenetics of steroids play a role in GC resistance but also the genetic variations in one or more podocyte related genes are connected with the steroid resistance in cases with NS. The focus of this review is to explain the underlying cellular and molecular mechanisms of GCs in podocytes. Understanding the mechanisms by which the GCs and GCs receptors in podocytes regulate the gene expression network and crosstalk with other molecular pathways would guarantee an optimum therapeutic benefit of steroid treatment.

PMID: 31586640 [PubMed - as supplied by publisher]

Comparison of effects of UGT1A1*6 and UGT1A1*28 on irinotecan-induced adverse reactions in the Japanese population: analysis of the Biobank Japan Project.

J Hum Genet. 2019 Oct 04;:

Authors: Hikino K, Ozeki T, Koido M, Terao C, Kamatani Y, Murakami Y, Kubo M, Mushiroda T

Abstract
It has been reported that there are differences in effects on irinotecan-induced adverse reactions between UGT1A1*6 and UGT1A1*28. In order to compare those differences in the Japanese population, we examined the associations between UGT1A1 and irinotecan-induced adverse reactions using the BioBank Japan Project database. We genotyped UTG1A1*6 and UGT1A1*28 and conducted case-control analyses. A total of 651 patients (102 cases and 549 tolerant controls) were included in this study. The results showed that UGT1A1*6/*6 is a predictor of adverse drug reactions (ADRs) (p-value 0.00070, odds ratio 6.59, 95% confidence interval 2.33-18.6), whereas UGT1A1*6/*28 and UGT1A1*28/*28 were not. The subanalysis comprising only patients with UGT1A1*6/*6, UGT1A1*6/*28, and UGT1A1*28/*28 revealed a trend towards an increased risk of ADRs in patients with UGT1A1*6 (p-value 0.0092, odds ratio 4.39, 95% confidence interval 1.57-14.9). Multiple logistic regression analyses showed that use of platinum-based antineoplastic drugs and presence of UGT1A1*6/*6 were independent variables, significantly associated with ADRs. The diagnostic performance of a predictive model had a sensitivity of 49.0%, specificity of 70.1%, and a number needed to screen of 5.8. We concluded that UGT1A1 testing could be useful to predict irinotecan-induced ADRs, and that UTG1A1*6 rather than UGT1A1*28 contributed to ADR occurrence.

PMID: 31586129 [PubMed - as supplied by publisher]

The Future of Precision Medicine.

Clin Pharmacol Ther. 2019 Nov;106(5):903-906

Authors: Verstegen RHJ, Ito S

Abstract
Precision medicine is an emerging framework to maximize therapeutic benefit by modifying the treatment for individual patients based on their variations in demographic, genomic, and environmental factors. In particular, "Pharmacogenomics" and "Therapeutic Drug Monitoring" are key elements of individualized drug treatment, staging Clinical Pharmacology at the forefront of precision medicine.

PMID: 31584718 [PubMed - in process]

Is Pharmacogenetics Useful in Antidepressant Treatment?

Clin Pharmacol Ther. 2019 Nov;106(5):916-918

Authors: Fabbri C, Serretti A

PMID: 31584716 [PubMed - in process]

Development of an Inexpensive and Rapid Operation Device for High-Throughput Real-Time Quantitative PCR-Based CYP2D6 CNV Genotyping.

Biol Pharm Bull. 2019;42(10):1761-1765

Authors: Imai M, Kisoi M, Moritsugu M, Murata S, Ichikawa A, Kinoshita K

Abstract
The CYP2D6 gene is the most well characterized gene involved in drug metabolism and is known to have both gene duplication and deletion variants. We report an optimized method for the determination of copy number variation (CNV) in the CYP2D6 gene by a novel purification process for a real-time quantitative PCR. This high-throughput low-cost method accurately determines CNV in the CYP2D6 gene enabling reliable estimates of disease prediction in large epidemiological samples.

PMID: 31582664 [PubMed - in process]

[Development of Stratified and Personalized Medicine Based on Pharmacogenomic and Pharmacokinetic Analyses].

Yakugaku Zasshi. 2019;139(10):1253-1258

Authors: Hirai K

Abstract
To administer optimal and safe pharmacotherapy, development of stratified and personalized therapy is imperative. Pharmacogenomics (PGx) is useful in elucidating factors causing individual differences in drug efficacy and the emergence of adverse effects. It also helps design accurate drug administration methods by evaluating the effects of patient-related factors, such as genetic factors, that influence pharmacokinetics (PK) and pharmacodynamics (PD). In addition, selection of appropriate therapeutic agents requires the implementation of precision medicine allowing accurate disease diagnosis. To establish precision medicine, it is necessary to uncover the association of pathophysiological factors, which are represented as endotype or genotype, with the pathology of several phenotypes. This review describes two aspects related to realization of individualized medicine, namely the effectiveness of PK/PD/PGx studies and the stratification of pathological conditions. First, we conducted a PK/PD/PGx study with the aim to individualize warfarin treatment. In this study, we elucidated the effect of CYP4F2 polymorphisms associated with vitamin K metabolism by measuring the blood concentrations of warfarin and vitamin K. Then, to develop precision medicine for asthma and chronic obstructive pulmonary disease (COPD), we analyzed not only clinical symptoms but also pathological biomarkers and genes associated with inflammation. The findings may contribute toward better understanding of the pathological conditions of asthma, COPD, and asthma-COPD overlap.

PMID: 31582608 [PubMed - in process]

Pharmacogenomics: Prescribing Precisely.

Med Clin North Am. 2019 Nov;103(6):977-990

Authors: Wake DT, Ilbawi N, Dunnenberger HM, Hulick PJ

Abstract
Pharmacogenomics (PGx) is a powerful tool that can predict increased risks of adverse effects and sub-therapeutic response to medications. This article establishes the core principles necessary for a primary care provider to meaningfully and prudently use PGx testing. Key topics include in which patients PGx testing should be considered, how PGx tests are ordered, how the results are translated into clinical recommendations, and what further advancements are likely in the near future. This will provide clinicians with a foundational knowledge of PGx that can allow incorporation of this tool into their practice or support further personal investigation.

PMID: 31582008 [PubMed - in process]

Examining the role of precision medicine with oral baclofen in pediatric patients with cerebral palsy.

Curr Phys Med Rehabil Rep. 2019 Mar;7(1):40-45

Authors: McLaughlin MJ, Abdel-Rahman S, Leeder JS

Abstract
Purpose of review: a)Despite its widespread use, oral baclofen requires a critical review of the pharmacology to determine potential precision medicine applications to improve medication administration. Discussing the dose→exposure→response relationship of oral baclofen allows a conceptual framework in which designing clinical trials would become more successful. This paper seeks to examine some of the areas where variability in exposures can exist lead to undesired clinical responses.
Recent findings: b)Several factors are at play to implement precision medicine with oral baclofen in the pediatric patient with cerebral palsy. Variations in intestinal absorption, oral baclofen clearance, pharmacogenomic variants, and distribution of this medication into the cerebrospinal fluid cause differences in the amount of baclofen available at the GABA-B receptor site to cause a clinical response.
Summary: c)Oral baclofen has significant variability in disposition and clinical response. Research to determine the causes for this variability and controlling for these factors would allow improvement in clinical outcomes.

PMID: 31579558 [PubMed]

A Quarter Century of PCR-Applied Techniques and Their Still-Increasing Fields of Use.

Methods Mol Biol. 2020;2065:1-4

Authors: Raso A, Biassoni R

Abstract
Quantitative polymerase chain reaction (PCR) is the basis of a variety of scientific applications and publications in a broad range of interests. It also plays a fundamental role in nucleic acid sequencing applications, including Next Generation Sequencing (NGS)-based ones. The potential of PCR diagnostics is enormous, particularly for the early diagnosis of life-threatening infections. Some other fields of applications that use PCR on a regular basis include oncology, genetics, microbiology, biochemistry, immunogenetics, NGS, ecology, comparative genome evolution, ancestry DNA, pharmacogenomics, personalized medicine, and even general medicine.

PMID: 31578683 [PubMed - in process]

DTC pharmacogenomics testing under scrutiny.

Nat Biotechnol. 2019 Oct;37(10):1101

Authors:

PMID: 31578506 [PubMed - in process]

Towards precision medicine: interrogating the human genome to identify drug pathways associated with potentially functional, population-differentiated polymorphisms.

Pharmacogenomics J. 2019 Oct 03;:

Authors: Bachtiar M, Ooi BNS, Wang J, Jin Y, Tan TW, Chong SS, Lee CGL

Abstract
Drug response variations amongst different individuals/populations are influenced by several factors including allele frequency differences of single nucleotide polymorphisms (SNPs) that functionally affect drug-response genes. Here, we aim to identify drugs that potentially exhibit population differences in response using SNP data mining and analytics. Ninety-one pairwise-comparisons of >22,000,000 SNPs from the 1000 Genomes Project, across 14 different populations, were performed to identify 'population-differentiated' SNPs (pdSNPs). Potentially-functional pdSNPs (pf-pdSNPs) were then selected, mapped into genes, and integrated with drug-gene databases to identify 'population-differentiated' drugs enriched with genes carrying pf-pdSNPs. 1191 clinically-approved drugs were found to be significantly enriched (Z > 2.58) with genes carrying SNPs that were differentiated in one or more population-pair comparisons. Thirteen drugs were found to be enriched with such differentiated genes across all 91 population-pairs. Notably, 82% of drugs, which were previously reported in the literature to exhibit population differences in response were also found by this method to contain a significant enrichment of population specific differentiated SNPs. Furthermore, drugs with genetic testing labels, or those suspected to cause adverse reactions, contained a significantly larger number (P < 0.01) of population-pairs with enriched pf-pdSNPs compared with those without these labels. This pioneering effort at harnessing big-data pharmacogenomics to identify 'population differentiated' drugs could help to facilitate data-driven decision-making for a more personalized medicine.

PMID: 31578463 [PubMed - as supplied by publisher]