Epigenetic predictive biomarkers for response or outcome to platinum-based chemotherapy in non-small cell lung cancer, current state-of-art.

Pharmacogenomics J. 2018 Sep 07;:

Authors: Szejniuk WM, Robles AI, McCulloch T, Falkmer UGI, Røe OD

Abstract
Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC). However, its efficacy is limited and no molecular biomarkers that predict response are available. In this review, we summarize current knowledge concerning potential epigenetic predictive markers for platinum-based chemotherapy response in NSCLC. A systematic search of PubMed and ClinicalTrials.gov using keywords "non-small cell lung cancer" combined with "chemotherapy predictive biomarkers", "chemotherapy epigenetics biomarkers", "chemotherapy microRNA biomarkers", "chemotherapy DNA methylation" and "chemotherapy miRNA biomarkers" revealed 1740 articles from PubMed and 36 clinical trials. Finally, 22 papers and no trials fulfilled the review criteria. Among miRNA, combination of miR-1290, miR-196b and miR-135a in tumor tissue, and miR-21, miR-25, miR27b, and miR-326 in plasma were predictive for response to platinum-based chemotherapy in advanced NSCLC. RASSF1A methylation measured in tumor or blood was predictive for response to neoadjuvant chemotherapy. These biomarkers remain experimental and none have been tested in a prospective trial.

PMID: 30190521 [PubMed - as supplied by publisher]

An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity.

J Immunol Res. 2018;2018:6431694

Authors: Chen CB, Abe R, Pan RY, Wang CW, Hung SI, Tsai YG, Chung WH

Abstract
Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

PMID: 29651444 [PubMed - indexed for MEDLINE]

Paeonol Ameliorates Ovalbumin-Induced Asthma through the Inhibition of TLR4/NF-κB and MAPK Signaling.

Evid Based Complement Alternat Med. 2018;2018:3063145

Authors: Tang Y, Huang W, Song Q, Zheng X, He R, Liu J

Abstract
Asthma is a chronic inflammatory disease of the airways, with complex signaling pathways involved in its pathogenesis. It was reported that paeonol attenuated airway inflammation of ovalbumin (OVA)-induced mice. Therefore, it is of importance to further investigate the underlying mechanism. BALB/c mice were challenged with OVA for the asthma model, which was validated by the changed levels of IL-4, IFN-γ, and IgE. The elevation of IL-4 and the decreasing of IFN-γ were significantly in middle (p<0.05) or high (p<0.01) paeonol dose groups compared with OVA group. MIP-1β in bronchoalveolar lavage fluid (BALF) also decreased significantly in middle and high paeonol group compared with OVA group (p<0.01), which is similar to the change of its mRNA in lung tissues. Moreover, the inflammatory cells infiltration and collagen deposition were attenuated by paeonol and montelukast sodium via histology examination. At last the immune blot of the protein extracted from lung tissues demonstrated that paeonol decreased the expression of TLR4 and the nuclear translocation of NF-κB, as well as the phosphorylation levels of P38 and ERK in asthma model. In conclusion, paeonol ameliorated OVA-induced asthma through the TLR4/NF-κB and mitogen-activated protein kinase (MAPK) signaling.

PMID: 30186353 [PubMed]

Genetic variants in major depressive disorder: From pathophysiology to therapy.

Pharmacol Ther. 2018 Sep 03;:

Authors: Gonda X, Petschner P, Eszlari N, Baksa D, Edes A, Antal P, Juhasz G, Bagdy G

Abstract
In spite of promising preclinical results there is a decreasing number of new registered medications in major depression. The main reason behind this fact is the lack of confirmation in clinical studies for the assumed, and in animals confirmed, therapeutic results. This suggests low predictive value of animal studies for central nervous system disorders. One solution for identifying new possible targets is the application of genetics and genomics, which may pinpoint new targets based on the effect of genetic variants in humans. The present review summarizes such research focusing on depression and its therapy. The inconsistency between most genetic studies in depression suggests, first of all, a significant role of environmental stress. Furthermore, effect of individual genes and polymorphisms is weak, therefore gene x gene interactions or complete biochemical pathways should be analyzed. Even genes encoding target proteins of currently used antidepressants remain non-significant in genome-wide case control investigations suggesting no main effect in depression, but rather an interaction with stress. The few significant genes in GWASs are related to neurogenesis, neuronal synapse, cell contact and DNA transcription and as being nonspecific for depression are difficult to harvest pharmacologically. Most candidate genes in replicable GxE interactions, on the other hand, are connected to the regulation of stress and the HPA axis and thus could serve as drug targets for a depression subgroups characterized by stress-sensitivity and anxiety while other risk polymorphisms such as those related to prominent cognitive symptoms in depression may help to identify additional subgroups and their distinct treatment. Until these new targets find their way in the therapy, the optimization of current medications can be approached by pharmacogenomics, where metabolizing enzyme polymorphisms remain prominent determinants of therapeutic success.

PMID: 30189291 [PubMed - as supplied by publisher]

Pharmacogenetic and clinical predictors of response to clopidogrel plus aspirin after acute coronary syndrome in Egyptians.

Pharmacogenet Genomics. 2018 Sep 04;:

Authors: Fathy S, Shahin MH, Langaee T, Khalil BM, Saleh A, Sabry NA, Schaalan MF, El Wakeel LL, Cavallari LH

Abstract
OBJECTIVES: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the risk for recurrent cardiovascular events after acute coronary syndrome (ACS). However, there is significant variation in response to DAPT that may be influenced by both genetic and nongenetic factors. This study aimed to assess the effect of genetic polymorphisms in PON-1, PEAR-1, P2Y12, CES1, and CYP2C19, along with clinical, demographic, and social factors, on variation in response to DAPT in Egyptians.
PARTICIPANTS AND METHODS: This study included 230 Egyptians treated with clopidogrel 75 mg/day and aspirin 81 mg/day for at least 12 months following their first ACS. Simple and multivariable logistic regression analyses were carried out to identify factors associated with major adverse cardiovascular events (MACE), defined as the occurrence of recurrent ACS, ischemic stroke, stent-related revascularization, or death, in clopidogrel-treated participants.
RESULTS: Using multivariable logistic regression analysis, the CYP2C19*2 polymorphism was the only genetic predictor of MACE [odds ratio (OR): 2.23, 95% confidence interval (CI): 1.15-4.33, P=0.01]. In addition, proton pump inhibitor use (OR: 4.77, 95% CI: 1.47-15.54, P=0.009) and diabetes (OR: 1.83, 95% CI: 1.03-3.26, P=0.03) were associated with higher cardiovascular risk, whereas statin use was associated with lower risk (OR: 0.43, 95% CI: 0.25-0.76, P=0.003). The contribution of these four genetic and nongenetic factors explained 19% of the variability in risk for MACE in Egyptians treated with DAPT.
CONCLUSIONS: These results highlight that CYP2C19*2, along with diabetes, and use of proton pump inhibitor and statin are important factors jointly associated with variability in clinical response to DAPT following ACS in Egyptians.

PMID: 30188374 [PubMed - as supplied by publisher]

Bendamustine alone or with rituximab modifies expression of apoptosis-regulating genes and proteins of CLL cells, depending on IGVH mutational status.

Leuk Lymphoma. 2018 Sep 06;:1-11

Authors: Ziolkowska E, Wolowiec D, Karpinski P, Blonski JZ, Lech-Maranda E, Borowiec M, Balcerczak E, Sasiadek M, Robak T, Korycka-Wolowiec A

Abstract
We studied whether bendamustine (BENDA) alone or with rituximab (RIT) modifies in vitro expression of apoptosis-involved genes and proteins of chronic lymphocytic leukemia (CLL) cells depending on IGVH mutational status. Circulating lymphocytes from 34 untreated patients (18 IGVH-MUT and 16 IGVH-UNMUT) were incubated with above drugs to evaluate proteins expression. Microarray analysis of 93 genes was performed in 14 patients. BENDA and BENDA + RIT increased expression of BAX and BBC3 in IGVH-MUT and IGVH-UNMUT groups, and significant differences in expression of above genes after BENDA + RIT were observed between both groups. Additionally, BENDA + RIT decreased NFκB and BCL-2 genes in IGVH-UNMUT patients and increased expression of P53, BAX and PUMA proteins in IGVH-MUT and UNMUT subjects. However, no significant differences were found between these groups. In conclusion, BENDA + RIT modified gene expression profile in CLL cells and affected expression of some apoptosis-regulating proteins in vitro. Expression of BAX and BBC3 depends on action of drugs and IGVH mutational status.

PMID: 30187811 [PubMed - as supplied by publisher]

Management of adverse events associated with idelalisib treatment in chronic lymphocytic leukemia and follicular lymphoma: A multidisciplinary position paper.

Hematol Oncol. 2018 Sep 05;:

Authors: Cuneo A, Barosi G, Danesi R, Fagiuoli S, Ghia P, Marzano A, Montillo M, Poletti V, Viale P, Zinzani PL

Abstract
The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases. However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment. Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL. The present publication represents a consensus document from a series of meetings held during 2017. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications. Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.

PMID: 30187496 [PubMed - as supplied by publisher]

A comparison of genome cohort participants' genetic knowledge and preferences to receive genetic results before and after a genetics workshop.

J Hum Genet. 2018 Sep 05;:

Authors: Yamamoto K, Shimizu A, Aizawa F, Kawame H, Tokutomi T, Fukushima A

Abstract
Several biobanks have begun returning genetic results to individuals, making the development of public genetic literacy an urgent task for their effective use. No research exists regarding the effects of genetic education on biobank participants, so we conducted genetics workshops with specialists, and surveyed differences in the participants' (n = 112) preferences to receive their own genetic information by disease categories and their genetic knowledge using questionnaires before and after the workshops. Almost 90% of our participants were over 60 years old, which was similar to our previous preference research. The preference to receive five of the six categories of genetic information (lifestyle diseases, pharmacogenetics, adult-onset non-clinically actionable diseases, non-clinically actionable multifactorial diseases, and all genetic information) was slightly but significantly decreased after the genetics workshop. More participants preferred to receive genetic results regarding lifestyle diseases, pharmacogenetics, and adult-onset clinically actionable diseases after the workshop, while less participants preferred to receive information regarding adult-onset non-clinically actionable diseases, non-clinically actionable multifactorial diseases, and all genetic information. Total genetic knowledge scores significantly increased after the workshop (before: 11.89, after: 13.30, p < 0.001). Our findings suggest that genetics workshops are useful to improve the genetic literacy of genome cohort participants.

PMID: 30185949 [PubMed - as supplied by publisher]

Knowledge, perceptions and confidence of physicians and pharmacists towards pharmacogenetics practice in Kuwait.

PLoS One. 2018;13(9):e0203033

Authors: Albassam A, Alshammari S, Ouda G, Koshy S, Awad A

Abstract
BACKGROUND: Pharmacogenetics practice has been successfully implemented in many developed countries to enhance personalized medicine and improve clinical and economic outcomes. An understanding of healthcare providers' knowledge, perceptions, confidence towards pharmacogenetics, and their active enrollment with pharmacogenetic testing is essential for test acceptance and utilization. This study was designed to assess physicians' and pharmacists' knowledge, perceptions, and confidence towards pharmacogenetics, determine the preferred learning format for their future education in pharmacogenetics, and identify the barriers to its application in their practice settings.
METHODS: A cross-sectional survey was conducted using a pretested self-administered questionnaire on a sample of 629 randomly selected physicians and pharmacists. Descriptive and comparative analyses were used in data analysis.
RESULTS: The response rate was 98.1%. Less than one-tenth of respondents were exposed to pharmacogenetics education or training (8.9%), applied pharmacogenetics testing in their practice (9.4%), or provided patient counselling on the results of the pharmacogenetic testing (9.1%), and over 90% of them were physicians. The overall respondents' mean (SD) total knowledge score percentage was low [45.0% (24)] and there was no significant difference between the physicians and pharmacists scores (p>0.05). Only 16.0% of participants indicated that they felt confident in applying pharmacogenetics in their practice settings. Despite these low levels of knowledge and self-confidence, 70.2% of participants expressed overall positive perceptions towards pharmacogenetics and its clinical implications. These positive overall perceptions were found to be significantly more common among pharmacists compared to physicians (p<0.05). The top two perceived barriers facing the implementation of pharmacogenetics in Kuwait were lack of education or training and clinical guidelines.
CONCLUSIONS: These findings highlight important concerns and will aid in the assessment of current pharmacogenetics practice. Also, they will provide further insight in designing future targeted multifaceted interventions to promote the adoption and utilization of pharmacogenetics testing in Kuwait.

PMID: 30183746 [PubMed - in process]

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

OMICS. 2018 Sep 05;:

Authors: Naranjo MG, Rodrigues-Soares F, Peñas-Lledó EM, Tarazona-Santos E, Fariñas H, Rodeiro I, Terán E, Grazina M, Moya GE, López-López M, Sarmiento AP, Calzadilla LR, Ramírez-Roa R, Ortiz-López R, Estévez-Carrizo FE, Sosa-Macías M, Barrantes R, LLerena A

Abstract
Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.

PMID: 30183544 [PubMed - as supplied by publisher]

Challenges and Solutions for Future Pharmacy Practice in the Era of Precision Medicine.

Am J Pharm Educ. 2018 Aug;82(6):6652

Authors: Dong OM, Howard RM, Church R, Cottrell M, Forrest A, Innocenti F, Mosedale M, Kashuba A, Gonzalez D, Wiltshire T

Abstract
As precision medicine research and its clinical applications continue to advance, it is critical for pharmacists to be involved in these developments to deliver optimal, tailored drug therapies for patients. To ensure pharmacists remain leaders in the field, the annual Pharmaceutical Sciences Conference convened by the University of North Carolina at Chapel Hill Eshelman School of Pharmacy focused on the role of pharmacy within precision medicine. This is a summary of the conference, highlighting the major challenges and solutions that will help advance individualized pharmacological methods within practice and research.

PMID: 30181675 [PubMed - in process]

BDNF Val66Met polymorphism and clinical response to antipsychotic treatment in schizophrenia and schizoaffective disorder patients: a meta-analysis.

Pharmacogenomics J. 2018 Sep 05;:

Authors: Huang E, Hettige NC, Zai G, Tomasi J, Huang J, Zai CC, Pivac N, Nikolac Perkovic M, Tiwari AK, Kennedy JL

Abstract
Brain-derived neurotrophic factor (BDNF) plays an important role in dopaminergic and serotonergic neurotransmission by modulating dopaminergic neuron differentiation and establishment. Multiple studies have analyzed the functional BDNF Val66Met variant in relation to antipsychotic response in schizophrenia (SCZ) patients, yielding mixed results. A meta-analysis was thus performed to examine the relationship between this variant and symptom improvement during antipsychotic treatment. Searches using PubMed, Web of Science, and PsycInfo until October 2017 yielded 11 studies that met inclusion criteria (total n = 3774). These studies investigated the BDNF Val66Met variant and antipsychotic response in patients with SCZ or schizoaffective disorder. Responders to antipsychotics were defined using the original criteria applied in each study. Effect sizes were computed using odds ratios, which were pooled according to the Mantel-Haenszel method. The BDNF Val66Met variant was not associated with the total number of responders and non-responders (p > 0.05) under dominant, recessive, or allelic models. Secondary analyses stratifying for individuals of each ethnicity and drug type also revealed no significant associations. Our findings suggest that the BDNF Val66Met variant is not associated with response to antipsychotics in individuals with SCZ. However, considering the current sample size, small effects cannot be ruled out. Moreover, recent studies have suggested that Val66Met forms haplotypes with other BDNF variants. Future studies should examine the Val66Met variant in conjunction with these other variants in relation to antipsychotic response. Moreover, since illness duration appears to influence BDNF levels in SCZ patients, future studies should aim to control for this potential confounding factor in response analyses.

PMID: 30181602 [PubMed - as supplied by publisher]

Cystic fibrosis in the era of precision medicine.

Paediatr Respir Rev. 2018 Jan;25:64-72

Authors: Paranjape SM, Mogayzel PJ

Abstract
The treatment of people with cystic fibrosis (CF) has been transformed by the availability of drugs that target the basic chloride defect in the disease. The use of drugs that target specific molecular defects embodies the goals of precision medicine, which incorporate preventive and therapeutic strategies and takes into account differences among individuals. However, the entirety of CF care, from diagnosis to understanding the clinical phenotype and developing a therapeutic strategy, depends on taking into account individual characteristics to achieve optimal outcomes. Future therapies are likely to be even more individualized ushering in a new era of precision medicine.

PMID: 28372929 [PubMed - indexed for MEDLINE]

An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy.

Nat Commun. 2016 11 07;7:13443

Authors: Chen Y, Xia R, Huang Y, Zhao W, Li J, Zhang X, Wang P, Venkataramanan R, Fan J, Xie W, Ma X, Lu B, Li S

Abstract
Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG2k-Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast cancer and melanoma mouse models.

PMID: 27819653 [PubMed - indexed for MEDLINE]

A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC.

Nat Commun. 2016 06 15;7:11743

Authors: Schell MJ, Yang M, Teer JK, Lo FY, Madan A, Coppola D, Monteiro AN, Nebozhyn MV, Yue B, Loboda A, Bien-Willner GA, Greenawalt DM, Yeatman TJ

Abstract
Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinicopathologic staging for decades. There is a need to stratify subpopulations of CRC on a molecular basis to better predict outcome and assign therapies. Here we report targeted exome-sequencing of 1,321 cancer-related genes on 468 tumour specimens, which identified a subset of 17 genes that best classify CRC, with APC playing a central role in predicting overall survival. APC may assume 0, 1 or 2 truncating mutations, each with a striking differential impact on survival. Tumours lacking any APC mutation carry a worse prognosis than single APC mutation tumours; however, two APC mutation tumours with mutant KRAS and TP53 confer the poorest survival among all the subgroups examined. Our study demonstrates a prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC.

PMID: 27302369 [PubMed - indexed for MEDLINE]

Label-free toxicology screening of primary human mesenchymal cells and iPS-derived neurons.

PLoS One. 2018;13(9):e0201671

Authors: Piccinno MS, Petrachi T, Resca E, Strusi V, Bergamini V, Mulas GA, Mari G, Dominici M, Veronesi E

Abstract
The high-throughput, label-free Corning Epic assay has applications in drug discovery, pharmacogenomics, cell receptor signaling, cell migration, and viral titration. The utility of Epic technology for biocompatibility testing has not been well established. In manufacturing of medical devices, in vitro and in vivo biocompatibility assessments are mandatory, according to ISO 10993. The new medical device regulation MDR 745/2017 specifies that ex vivo assays that can closely recapitulate in vivo scenarios are needed to better evaluate biomedical devices. We propose herein that Epic technology-which enables detection of variations in cell mass distribution-is suitable for biocompatibility screening of compounds. In this study, we challenged primary human osteoblasts, endothelial cells, and neurons derived from induced pluripotent stem cells with specific concentrations of methyl methacrylate (MMA). Polymeric MMA has long been applied in cranioplasty, where it makes contact with multiple cell types. Application of Epic technology yielded real-time cytotoxicity profiles for all considered cell types. The results were compared with those from microscopic observation of the same culture plate used in the Epic analyses. The Epic assay should be further examined for its utility for cell biology, genomics, and proteomics companion assays. Our results suggest that Epic technology can be applied to biocompatibility evaluation of human cells in medical device development.

PMID: 30180158 [PubMed - in process]

Role of CYP1A1, ABCG2, CYP24A1 and VDR gene polymorphisms on the evaluation of cardiac iron overload in thalassaemia patients.

Pharmacogenet Genomics. 2018 Sep 01;:

Authors: Allegra S, Cusato J, De Francia S, Longo F, Pirro E, Massano D, Avataneo V, De Nicolò A, Piga A, D'Avolio A

Abstract
OBJECTIVES: Iron-burden-induced arrhythmia and heart failure are among the leading causes of morbidity and mortality in β-thalassaemia major patients. T2* cardiac magnetic resonance remains the only reliable noninvasive method for the heart iron excess assessment. We explored the role of single nucleotide polymorphisms involved in vitamin D metabolism, transport and activity and in deferasirox (DFX) metabolism on cardiac iron burden.
PATIENTS AND METHODS: One hundred and five β-thalassaemia patients, treated with DFX, were enrolled in the present study. Drug plasma Ctrough was measured by a high-performance liquid chromatography-ultraviolet method. Allelic discrimination was carried out using the real-time PCR.
RESULTS: CYP1A1*1189 CC, ABCG2 421 GA, CYP24A1 8620 GG and VDR TaqI CC single nucleotide polymorphisms influenced T2* values. Age, serum ferritin, ABCG2 421 GA, ABCG2 1194 +928 TC/CC, CYP24A1 22776 TT and VDR TaqI TC/CC were retained in linear regression model.
CONCLUSION: Our results suggested, for the first time, the role of DFX and vitamin D pharmacogenetics on cardiac iron overload.

PMID: 30179981 [PubMed - as supplied by publisher]

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

Acta Ophthalmol. 2018 Sep 04;:

Authors: Meng W, Shah KP, Pollack S, Toppila I, Hebert HL, McCarthy MI, Groop L, Ahlqvist E, Lyssenko V, Agardh E, Daniell M, Kaidonis G, Craig JE, Mitchell P, Liew G, Kifley A, Wang JJ, Christiansen MW, Jensen RA, Penman A, Hancock HA, Chen CJ, Correa A, Kuo JZ, Li X, Chen YI, Rotter JI, Klein R, Klein B, Wong TY, Morris AD, Doney ASF, Colhoun HM, Price AL, Burdon KP, Groop PH, Sandholm N, Grassi MA, Sobrin L, Palmer CNA, Wellcome Trust Case Control Consortium 2 (WTCCC2), Surrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) study group

Abstract
PURPOSE: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.
METHODS: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts.
RESULTS: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429).
CONCLUSION: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

PMID: 30178632 [PubMed - as supplied by publisher]

In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics.

Eur J Clin Pharmacol. 2018 Apr;74(4):455-464

Authors: Jin Y, Borell H, Gardin A, Ufer M, Huth F, Camenisch G

Abstract
PURPOSE: The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism.
METHODS: In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism. Primary PK parameters were generated using the SimCYP and WinNonlin software.
RESULTS: Correlation analysis suggested that CYP2C9 is the main enzyme responsible for siponimod metabolism in humans. Compared with the CYP2C9*1/*1 genotype, HLM incubations from CYP2C9*3/*3 and CYP2C9*2/*2 donors showed ~ 10- and 3-fold decrease in siponimod metabolism, respectively. Simulations of enzyme contribution predicted that in the CYP2C9*1/*1 genotype, CYP2C9 is predominantly responsible for siponimod metabolism (~ 81%), whereas in the CYP2C9*3/*3 genotype, its contribution is reduced to 11%. The predicted exposure increase of siponimod with fluconazole 200 mg was 2.0-2.4-fold for CYP2C9*1/*1 genotype. In context of single dosing, the predicted mean area under the curve (AUC) is 2.7-, 3.0- and 4.5-fold higher in the CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, respectively, compared with the CYP2C9*1/*1 genotype.
CONCLUSION: .Enzyme phenotyping with correlation analysis confirmed the predominant role of CYP2C9 in the biotransformation of siponimod and demonstrated the functional consequence of CYP2C9 genetic polymorphism on siponimod metabolism. Simulation of fluconazole inhibition closely predicted a 2-fold AUC change (ratio within ~ 20% deviation) to the observed value. In silico simulation predicted a significant reduction in siponimod clearance in the CYP2C9*2/*2 and CYP2C9*3/*3 genotypes based on the in vitro metabolism data; the predicted exposure was close (within 30%) to the observed results for the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes.

PMID: 29273968 [PubMed - indexed for MEDLINE]

Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China.

Eur J Clin Pharmacol. 2018 Apr;74(4):423-431

Authors: Zhong Z, Hou J, Zhang Q, Li B, Li C, Liu Z, Yang M, Zhong W, He X, Wu H, Zhong M, Zhao P

Abstract
BACKGROUND AND OBJECTIVES: The objective of this study is to evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on adverse cardiovascular events (MACE) in Hakka patients with acute coronary syndrome (ACS) receiving clopidogrel who had undergone coronary drug-eluting stent placement after percutaneous coronary intervention (PCI) in southern China.
METHODS: Genotyping of CYP2C19 and MACE of 934 ACS patients with PCI on clopidogrel maintenance therapy were analyzed. Patients who carried loss-of-function CYP2C19 were treated with a 150-mg maintenance dose of clopidogrel or 90 mg of ticagrelor antiplatelet therapy, and patients who were non-carriers received clopidogrel therapy daily at a maintenance dose of 75 mg and the patients were followed-up for at least 12 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, and target vessel revascularization and stroke.
RESULTS: The allelic frequency of CYP2C19*2 and CYP2C19*3 of Hakka patients in the current study was 31.64 and 5.19%, respectively. The CYP2C19 wild-type homozygotes (*1/*1) were the most predominant among the patients (40.36%), followed by the CYP2C19*2 heterozygotes (*1/*2) (40.26%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM; 40.36%), intermediate metabolizers (IM; 45.61%), and poor metabolizers (PM; 14.03%). Based on the genotype-guided antiplatelet therapy, there was no significant association between the carrier status and the clinical outcome at 1, 6, and 12 months. In addition, no significant difference in the rates of bleeding was found among the three groups. After logistic regression analysis, hypertension was the only independent predictor of cardiovascular events (relative risk, 1.501; 95% CI, 1.011 to 2.229; P = 0.044).
CONCLUSIONS: Our results shed new light on the important benefit of testing CYP2C19 polymorphisms before prescribing clopidogrel in patients treated with drug-eluting stent implantation after PCI. The testing may help to optimize pharmacotherapy effectiveness by providing individualized treatment to the Chinese population. Our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy in a Hakka population in southern China.

PMID: 29243114 [PubMed - indexed for MEDLINE]