Human Genetics of Obesity and Type 2 Diabetes Mellitus: Past, Present, and Future.

Circ Genom Precis Med. 2018 Jun;11(6):e002090

Authors: Ingelsson E, McCarthy MI

Abstract
Type 2 diabetes mellitus (T2D) and obesity already represent 2 of the most prominent risk factors for cardiovascular disease, and are destined to increase in importance given the global changes in lifestyle. Ten years have passed since the first round of genome-wide association studies for T2D and obesity. During this decade, we have witnessed remarkable developments in human genetics. We have graduated from the despair of candidate gene-based studies that generated few consistently replicated genotype-phenotype associations, to the excitement of an exponential harvest of loci robustly associated with medical outcomes through ever larger genome-wide association study meta-analyses. As well as discovering hundreds of loci, genome-wide association studies have provided transformative insights into the genetic architecture of T2D and other complex traits, highlighting the extent of polygenicity and the tiny effect sizes of many common risk alleles. Genome-wide association studies have also provided a critical starting point for discovering new biology relevant to these traits. Expectations are high that these discoveries will foster development of more effective strategies for intervention, through optimization of precision medicine approaches. In this article, we review current knowledge and provide suggestions for the next steps in genetic research for T2D and obesity. We focus on four areas relevant to precision medicine: genetic architecture, pharmacogenetics and other gene-environment interactions, mechanistic inference, and drug development. As we describe, the genetic architecture of complex traits has major implications for the prospects of precision medicine, rendering some anticipated approaches decidedly unrealistic. We highlight obstacles to the translation of human genetic findings into mechanism inference but are optimistic that, as these are overcome, there is untapped potential for novel drugs and more effective strategies for treating and preventing T2D and obesity.

PMID: 29899044 [PubMed - in process]

Pharmacogenetic studies in Alzheimer disease.

Neurologia. 2018 Jun 10;:

Authors: Zúñiga Santamaría T, Yescas Gómez P, Fricke Galindo I, González González M, Ortega Vázquez A, López López M

Abstract
INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.
DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.
CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as aging.

PMID: 29898857 [PubMed - as supplied by publisher]

Evaluation of buccal swabs for pharmacogenetics.

BMC Res Notes. 2018 Jun 14;11(1):382

Authors: Ang JS, Aloise MN, Dawes D, Dempster MG, Fraser R, Paterson A, Stanley P, Suarez-Gonzalez A, Dawes M, Katzov-Eckert H

Abstract
OBJECTIVE: A simple, non-invasive sample collection method is key for the integration of pharmacogenetics into clinical practice. The aim of this study was to gain samples for pharmacogenetic testing and evaluate the variation between dry-flocked and sponge-tipped buccal swabs in yield and quality of DNA isolated.
RESULTS: Thirty-one participants collected samples using dry-flocked swabs and sponge-tipped swabs. Samples were assessed for DNA yield, quality and genotyping performance on a qPCR OpenArray platform of 28 pharmacogenetic SNPs and a CYP2D6 TaqMan copy number variant. DNA from sponge-tipped swabs had a significantly greater yield compared to DNA collected with dry-flocked swabs (p = 4.4 × 10-7). Moreover, highest genotyping call rates across all assays and highest CNV confidence scores were observed in DNA samples collected from sponge-tipped swabs (97% vs. 54% dry-flocked swabs; 0.99 vs. 0.88 dry-flocked swabs, respectively). Sample collection using sponge-tipped swabs provides a DNA source of sufficient quantity and quality for pharmacogenetic variant detection using qPCR.

PMID: 29898767 [PubMed - in process]

A cost effective RFLP method to genotype Solute carrier organic anion 1B1 (SLCO1B1) c.1929A>C (p.Leu643Phe, rs34671512); a variant with potential effect on rosuvastatin pharmacokinetics.

BMC Res Notes. 2018 Jun 14;11(1):384

Authors: Soko ND, Masimirembwa C, Dandara C

Abstract
OBJECTIVE: This study describes a restriction fragment polymorphism protocol for rapidly screening the polymorphism SLCO1B1 c.1929A>C in genomic DNA samples. The polymorphism SLCO1B1 c.1929A>C has been associated with increased activity resulting in increased hepatic uptake of drugs. Currently SLCO1B1 c.1929A>C is genotyped using direct sequencing techniques and 5' nuclease based assays which can be cost prohibiting in resource limited settings. The aim of this study therefore was to design and validate a cost effective RFLP for genotyping the SLCO1B1 c.1929A>C polymorphism. This study was designed to investigate the effect of the polymorphism SLCO1B1 c.1929A>C on interindividual variability in rosuvastatin pharmacokinetics in healthy volunteers of African descent.
RESULTS: We describe a restriction fragment length polymorphism method to genotype SLCO1B1 c.1929A>C polymorphism using the restriction enzyme Ase1. A student's t test with Welch correction was used to establish association between the SLCO1B1 c.1929A>C variant and rosuvastatin exposure. The frequency of the SLCO1B1 c.1929C allele amongst Zimbabweans was 6%. The SLCO1B1 c.1929C allele was associated with a 75% reduction (P < 0.001) in rosuvastatin exposure when compared to individuals carrying the wild type SLCO1B1 c.1929A allele. Polymorphism c.1929A>C may therefore play a significant role in rosuvastatin response. The RFLP method is quick and cost effective.

PMID: 29898760 [PubMed - in process]

Preventing the exacerbation of health disparities by iatrogenic pharmacogenomic applications: lessons from warfarin.

Pharmacogenomics. 2018 Jun 14;:

Authors: Duconge J, Ruaño G

PMID: 29898627 [PubMed - as supplied by publisher]

Carbamazepine adverse drug reactions.

Expert Rev Clin Pharmacol. 2018 Jun 14;:

Authors: Fricke-Galindo I, LLerena A, Jung-Cook H, López-López M

Abstract
INTRODUCTION: Carbamazepine (CBZ) is used for the treatment of epilepsy and other neurological and psychiatric disorders. The occurrence of adverse reactions (ADRs) to CBZ can negatively impact the quality of life of patients, as well as, increase health care costs. Thus, knowledge of CBZ-induced ADRs is important to achieve safer treatment outcomes. Areas covered. This review describes the clinical features, known mechanisms, and clinical management of the main CBZ-induced ADRs. In addition, pharmacogenetic studies focused on ADRs induced by CBZ are cited. Expert commentary. CBZ-induced ADRs are well known in the literature. The metabolite CBZ-10,11-epoxide plays an important role in the mechanism that underlies the ADRs induced by CBZ. Several factors should be considered for a safer use of CBZ such as monotherapy prescription when possible, an adequate dose titration, knowledge of previous ADRs in the patient, and routine monitoring of CBZ plasma concentrations in symptomatic patients. Pharmacogenetics is a potential tool for CBZ therapy improvement, and the design of multicenter studies focused on the identification of biomarkers for CBZ-induced ADRs could provide useful information for a safer CBZ therapy.

PMID: 29898616 [PubMed - as supplied by publisher]

Uridine 5'-diphospho-glucronosyltrasferase: Its role in pharmacogenomics and human disease.

Exp Ther Med. 2018 Jul;16(1):3-11

Authors: Sanchez-Dominguez CN, Gallardo-Blanco HL, Salinas-Santander MA, Ortiz-Lopez R

Abstract
Biotransformation is an enzyme-catalyzed process in which the body converts endogenous compounds, xenobiotics and toxic substances into harmless or easily excreted metabolites. The biotransformation reactions are classified as phase I and II reactions. Uridine 5'-diphospho (UDP)-glucuronosyltransferases (UGTs) are a superfamily of phase II enzymes which have roles in the conjugation of xenobiotics or endogenous compounds, including drugs and bilirubin, with glucuronic acid to make them easier to excrete. The method the human body uses to achieve glucuronidation may be affected by a large interindividual variation due to changes in the sequences of the genes encoding these enzymes. In the last five years, the study of the genetic variants of the UGTs at a molecular level has become important due to its association with several diseases and the ability to predict adverse events due to drug metabolism. In the present review, the structure and the prominent genetic variants of the UGT1A subfamily and their metabolic and clinical implications are described.

PMID: 29896223 [PubMed]

Clinical trials in neonates: How to optimise informed consent and decision making? A European Delphi survey of parent representatives and clinicians.

PLoS One. 2018;13(6):e0198097

Authors: Neyro V, Elie V, Thiele N, Jacqz-Aigrain E

Abstract
OBJECTIVES: Parental consent for the participation of their neonate in neonatal research is influenced by the quality of the information delivered and the interaction between parents and investigators. Failure to provide important information may lead to difficulties in the decision making process of parents. This Delphi survey aims to establish a consensus between parent representatives of neonatal associations and healthcare professionals concerning the information deemed essential by both parties in order to improve the recruitment of neonates into clinical trials.
METHOD: This study was conducted in Europe among parent representatives and healthcare professionals. In this 3-phase study, 96 items were defined by the Scientific Committee (CS), composed of 11 clinicians (from 8 countries) and 1 parent representative of the European network of neonatal associations. Then the Committee of Experts (CE) composed of 16 clinicians were matched by country with 16 national parent representatives and evaluated these items in two rounds. The importance of each item was evaluated by each member of the CE on a scale between 1 and 9 based on their personal experience.
RESULTS: Fifty eight items reached the second and final level of consensus. In contrast to clinicians, parent representatives preferred to be informed about the study by the physician in charge of their child. They also favoured additional support during the informed consent process and stated that both parents need to agree and sign.
CONCLUSION: The set of 58 items on which parents and clinicians reached consensus will be helpful to healthcare professionals seeking parental consent for the inclusion of a neonate in a clinical trial. Providing parents with information about the trial by the investigator in the presence of the patient's neonatologist, developing closer contacts with parents and informing them of the available support by parents associations may be helpful for parents.

PMID: 29897934 [PubMed - in process]

Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation.

Psychol Med. 2018 Jun 13;:1-10

Authors: Wolf EJ, Logue MW, Morrison FG, Wilcox ES, Stone A, Schichman SA, McGlinchey RE, Milberg WP, Miller MW

Abstract
BACKGROUND: Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock).
METHODS: Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments.
RESULTS: Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging.
CONCLUSIONS: This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.

PMID: 29897034 [PubMed - as supplied by publisher]

An investigation into the prediction of the plasma concentration-time profile and its inter-individual variability for a range of flavin-containing monooxygenase substrates using a mechanistic physiologically based pharmacokinetic modelling approach.

Drug Metab Dispos. 2018 Jun 12;:

Authors: Pilla Reddy V, Jones BC, Colclough N, Srivastava A, Wilson J, Li D

Abstract
Our recent paper (Jones et al., 2017) demonstrated the ability to predict in vivo clearance of Flavin-containing Monooxygenases (FMO) drug substrates, using in vitro human hepatocyte and human liver microsomal intrinsic clearance (CLint) with standard scaling approaches. In this paper, we apply physiologically based pharmacokinetic (PBPK) modelling & simulation approaches (M&S) to predict the clearance, AUC and Cmax together with the plasma profile of a range of drugs from the original study. The human physiological parameters for FMO, such as enzyme abundance in liver, kidney, gut were derived from in vitro data and clinical pharmacogenetics studies. The drugs investigated include itopride, benzydamine, tozasertib, tamoxifen, moclobemide, imipramine, clozapine, ranitidine, and olanzapine. The fraction metabolised (Fm) by FMO for these drugs ranged from 21 to 96%. The developed PBPK models were verified with data from multiple clinical studies. An attempt was made to estimate the scaling factor for recombinant FMO (rFMO) using a parameter estimation approach and an automated sensitivity analysis (ASA) within the PBPK platform. Simulated oral clearance (CLpo), using in vitro hepatocyte data and associated extrahepatic FMO data, predicts the observed in vivo plasma concentration profile reasonably well and predicts AUC for all of the FMO substrates within 2-fold of the observed clinical data, while, 7 out of 9 compounds fell within 2-fold when human liver microsomal data was used. rFMO over-predicted the AUC by approximately 2.5-fold for 3 out of 9 compounds. Applying a calculated inter-system extrapolation scalar or tissue specific scalar for rFMO data resulted in better prediction of clinical data. PBPK M&S results from this study demonstrate that human hepatocytes and human liver microsomes can be used along with our standard scaling approaches to predict human in vivo PK parameters for FMO substrates.

PMID: 29895591 [PubMed - as supplied by publisher]

Glucose elicits serine/threonine kinase VRK1 to phosphorylate nuclear pregnane X receptor as a novel hepatic gluconeogenic signal.

Cell Signal. 2017 Dec;40:200-209

Authors: Gotoh S, Miyauchi Y, Moore R, Negishi M

Abstract
Low glucose stimulated phosphorylation of pregnane X receptor (PXR) at Ser350 in correlation with an increased gluconeogenesis in human hepatoma-derived HepG2 cells. Only glucose, but neither insulin nor glucagon, stimulated this phosphorylation. Here, serine/threonine kinase, vaccinia related kinase 1 (VRK1)-mediated phosphorylation of PXR is now defined as this glucose-elicited novel signal. In low glucose conditions, VRK1 directly phosphorylates PXR at Ser350, enabling PO3-PXR to scaffold protein phosphatase PP2Cα. This PP2Cα dephosphorylates serine/threonine kinase 2 (SGK2) at Thr193. This dephosphorylation dissociates SGK2 from and actives the phosphoenolpyruvate carboxykinase 1 (PCK1) gene as phosphorylated SGK2 binds and represses the gene. Conversely, VRK1 self-represses its activity to phosphorylate PXR through cyclin-dependent kinase 2 (CDK2) in high glucose conditions, resulting in the repression of the PCK1 gene. This PXR phosphorylation was also observed in fasting mouse livers. Thus, the VRK1-CDK2-PXR-PP2Cα-SGK2 pathway can be a novel physiological cell signaling that regulates gluconeogenesis in response to glucose.

PMID: 28911860 [PubMed - indexed for MEDLINE]

Current and Future Molecular Testing in NSCLC, What Can We Expect from New Sequencing Technologies?

J Clin Med. 2018 Jun 09;7(6):

Authors: Garinet S, Laurent-Puig P, Blons H, Oudart JB

Abstract
Recent changes in lung cancer care, including new approvals in first line and the introduction of high-throughput molecular technologies in routine testing led us to question ourselves on how deeper molecular testing may be helpful for the optimal use of targeted drugs. In this article, we review recent results in the scope of personalized medicine in lung cancer. We discuss biomarkers that have a therapeutic predictive value in lung cancer with a focus on recent changes and on the clinical value of large scale sequencing strategies. We review the use of second- and third-generation EGFR and ALK inhibitors with a focus on secondary resistance alterations. We discuss anti-BRAF and anti-MEK combo, emerging biomarkers as NRG1 and NTRKs fusions and immunotherapy. Finally, we discuss the different technical issues of comprehensive molecular profiling and show how large screenings might refine the prediction value of individual markers. Based on a review of recent publications (2012⁻2018), we address promising approaches for the treatment of patients with lung cancers and the technical challenges associated with the identification of new predictive markers.

PMID: 29890761 [PubMed]

"No pain, No gain" still true with immunotherapy: When the finger shows the moon, look at the moon!

Crit Rev Oncol Hematol. 2018 Jul;127:1-5

Authors: Milano G, Innocenti F, Lacarelle B, Ciccolini J

Abstract
There is a rising evidence that the proverbial statement "No pain, No gain" first coined at the light of pioneering clinical experiences with canonical chemotherapy still holds true in the era of modern treatments of cancer. This close relationship between the occurrence of specific drug-related toxicity and treatment outcome has been confirmed since then with a large variety of treatments, ranging from cytotoxics, hormonotherapy, targeted therapy and much interestingly even with the latest immune checkpoint inhibitors. In the current context of precision medicine, and along with the constant quest for identifying predictive biomarkers, close monitoring of treatment-related toxicities could therefore be convenient to help predicting therapeutic response, but presents several caveats. The purpose of this review is to briefly describe these relationships across the different treatments, to comment on possible underlying mechanisms and to comment on possible strategies aiming at exploiting this relationship while keeping the maximal safety ensured in patients with cancer. In particular, this review will investigate on how drug exposure along with germinal and somatic genetic issues does impact on the "No Pain, No Gain" aphorism, and why the temptation to use treatment-related toxicities as a cheap and convenient way to predict clinical outcome or to adapt dosing should be resisted. We do advocate instead for developing comprehensive genomic support along with extensive biomathematical modeling to better customize dosing and shift towards a new "No Pain, Maximal Gain" paradigm.

PMID: 29891106 [PubMed - in process]

The Role of Genetic Polymorphisms in Chronic Pain Patients.

Int J Mol Sci. 2018 Jun 08;19(6):

Authors: Knezevic NN, Tverdohleb T, Knezevic I, Candido KD

Abstract
It is estimated that the total annual financial cost for pain management in the U.S. exceeds 100 billion dollars. However, when indirect costs are included, such as functional disability and reduction in working hours, the cost can reach more than 300 billion dollars. In chronic pain patients, the role of pharmacogenetics is determined by genetic effects on various pain types, as well as the genetic effect on drug safety and efficacy. In this review article, we discuss genetic polymorphisms present in different types of chronic pain, such as fibromyalgia, low back pain, migraine, painful peripheral diabetic neuropathy and trigeminal neuralgia. Furthermore, we discuss the role of CYP450 enzymes involved in metabolism of drugs, which have been used for treatment of chronic pain (amitriptyline, duloxetine, opioids, etc.). We also discuss how pharmacogenetics can be applied towards improving drug efficacy, shortening the time required to achieve therapeutic outcomes, reducing risks of side effects, and reducing medical costs and reliance upon polypharmacy.

PMID: 29890676 [PubMed - in process]

[Personalised pharmacotherapy in intensive care unit patients].

Med Klin Intensivmed Notfmed. 2017 May;112(4):289-294

Authors: Bellmann R

Abstract
Critically ill patients need fast, effective and safe pharmacotherapy. The pharmacokinetics and pharmacodynamics of the administered drugs are influenced by numerous individual conditions. Genetic factors mainly determines drug metabolism. However, therapeutic decisions are not yet guided by genetic analyses. In elderly patients, the volume of distribution can be altered and renal elimination may be delayed. Drug-drug interactions involving current medications can increase the incidence of adverse effects from treatment in the intensive care unit. In early severe sepsis, plasma levels of water-soluble drugs can be decreased because of enhanced volume of distribution and increased renal clearance. Later on, drug elimination can be impaired by deterioration of liver and renal function. Furthermore, the pharmacokinetic effects of continuous renal replacement therapy have to be considered. Plasma levels of critically ill patients show increased variability in comparison with healthy subjects or other patient groups. The therapeutic effect of antibiotics and of many other drugs cannot be assessed immediately. As dosage of these medications cannot be guided by their clinical efficacy, insufficient exposure or overdosage accompanied by toxic side effects may result. Standard dose recommendations that were developed in healthy volunteers or noncritically ill patients must be adapted to individual conditions and requirements of critically ill patients.

PMID: 28466289 [PubMed - indexed for MEDLINE]

Lethal cerebral hemorrhage after ticagrelor intoxication: a specific antidote is urgently needed.

Clin Toxicol (Phila). 2018 Jun 11;:1-4

Authors: Willeman T, Marlu R, Böhle H, Francony G, Jourdil JF, Fonrose X, Stanke-Labesque F

Abstract
BACKGROUND: Ticagrelor is a direct and reversible competitive antagonist of the P2Y12 receptor and inhibits platelet activation. Although adverse bleeding is common, fatal intoxication has never been documented.
CASE DESCRIPTION: A 47-year-old man died from a severe cerebral hemorrhage secondary to a fall and cranial trauma 4 d after the massive intake of ticagrelor. Iterative platelet transfusions did not improve his condition. Toxicological analyses by liquid chromatography tandem mass spectrometry (LC-MS/MS) revealed high plasma concentrations of ticagrelor (3343 µg/L) and its active metabolite AR-C124910XX (656 µg/L) 10 h after intake. The approximate ingested dose was extrapolated to 1677 mg. Assessment of ADP-induced platelet aggregation and platelet Vasodilator Stimulated Phosphoprotein phosphorylation (VASP), 2 and 3 d after admission, respectively, showed the persistence of platelet inhibition.
DISCUSSION: To the best of our knowledge, no prior fatal cases have been reported and documented with both ticagrelor and AR-C124910XX concentrations. Our findings highlight the need for a specific antidote to manage such complications resulting from ticagrelor overdose.

PMID: 29889575 [PubMed - as supplied by publisher]

Pharmacogenomic studies of hypertension: paving the way for personalized antihypertensive treatment.

Expert Rev Precis Med Drug Dev. 2018;3(1):33-47

Authors: Eadon MT, Kanuri SH, Chapman AB

Abstract
Introduction: Increasing clinical evidence supports the implementation of genotyping for anti-hypertensive drug dosing and selection. Despite robust evidence gleaned from clinical trials, the translation of genotype guided therapy into clinical practice faces significant challenges. Challenges to implementation include the small effect size of individual variants and the polygenetic nature of antihypertensive drug response, a lack of expert consensus on dosing guidelines even without genetic information, and proper definition of major antihypertensive drug toxicities. Balancing clinical benefit with cost, while overcoming these challenges, remains crucial.
Areas covered: This review presents the most impactful clinical trials and cohorts which continue to inform and guide future investigation. Variants were selected from among those identified in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR), the Genetic Epidemiology of Responses to Antihypertensives study (GERA), the Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study, the SOPHIA study, the Milan Hypertension Pharmacogenomics of hydro-chlorothiazide (MIHYPHCTZ), the Campania Salute Network, the International Verapamil SR Trandolapril Study (INVEST), the Nordic Diltiazem (NORDIL) Study, GenHAT, and others.
Expert Commentary: The polygenic nature of antihypertensive drug response is a major barrier to clinical implementation. Further studies examining clinical effectiveness are required to support broad-based implementation of genotype-based prescribing in medical practice.

PMID: 29888336 [PubMed]

Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder.

Int J Genomics. 2018;2018:8231547

Authors: Thongnak C, Hnoonual A, Tangviriyapaiboon D, Silvilairat S, Puangpetch A, Pasomsub E, Chantratita W, Limprasert P, Sukasem C

Abstract
Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.

PMID: 29888248 [PubMed]

CATCH-KB: Establishing a Pharmacogenomics Variant Repository for Chemotherapy-Induced Cardiotoxicity.

AMIA Jt Summits Transl Sci Proc. 2018;2017:168-177

Authors: Morash M, Mitchell H, Yu A, Campion T, Beltran H, Elemento O, Pathak J

Abstract
The Cardiotoxicity of Chemotherapy Knowledgebase (CATCH-KB) contains information extracted from articles investigating an association between germline genetic polymorphisms and the development of chemotherapy-induced cardiotoxicity (CIC) in cancer patients receiving antineoplastic treatments. CATCH-KB also contains integrated gene and drug information from open biomedical resources such as PharmGKB1 and SIDER2. Furthermore, the genetic polymorphisms, drugs, and cancer types detailed in CATCH-KB are standardized according to appropriate biomedical ontologies, such as SNOMED-CT3 and RxNorm4. CATCH-KB currently contains information on 49 research papers published between 2004 and 2017 investigating a total of 2,210 variants in over 280 genes for an association with CIC. By centralizing this information and linking it to external open-access biomedical resources, CATCH-KB will facilitate hypothesis generation and meta-analysis efforts and will ultimately accelerate the use of genetic screening in preventing CIC. CATCH-KB is publicly accessible via http://catchkb.org.

PMID: 29888066 [PubMed]

A single intraperitoneal injection of bovine fetuin-A attenuates bone resorption in a murine calvarial model of particle-induced osteolysis.

Bone. 2017 Dec;105:262-268

Authors: Jablonski H, Polan C, Wedemeyer C, Hilken G, Schlepper R, Bachmann HS, Grabellus F, Dudda M, Jäger M, Kauther MD

Abstract
Particle-induced osteolysis, which by definition is an aseptic inflammatory reaction to implant-derived wear debris eventually leading to local bone destruction, remains the major reason for long-term failure of orthopedic endoprostheses. Fetuin-A, a 66kDa glycoprotein with diverse functions, is found to be enriched in bone. Besides being an important inhibitor of ectopic calcification, it has been described to influence the production of mediators of inflammation. Furthermore, a regulatory role in bone metabolism has been assigned. In the present study, the influence of a single dose of bovine fetuin-A, intraperitoneally injected in mice subjected to particle-induced osteolysis of the calvaria, was analyzed. Twenty-eight male C57BL/6 mice, twelve weeks of age, were randomly divided into four groups. Groups 2 and 4 were subjected to ultra-high molecular weight polyethylene (UHMWPE) particles placed on their calvariae while groups 1 and 3 were sham-operated. Furthermore, groups 3 and 4 received a single intraperitoneal injection of 20mg bovine fetuin-A while groups 1 and 2 were treated with physiologic saline. After 14days calvarial bone was qualitatively and quantitatively assessed using microcomputed tomography (μCT) and histomorphometrical approaches. Application of fetuin-A led to a reduction of particle-induced osteolysis in terms of visible osteolytic lesions and eroded bone surface. The reduction of bone thickness and bone volume, as elicited by UHMWPE, was alleviated by fetuin-A. In conclusion, fetuin-A was found to exert an anti-resorptive effect on particle-induced osteolysis in-vivo. Thus, fetuin-A could play a potentially osteoprotective role in the treatment of bone metabolic disorders.

PMID: 28942123 [PubMed - indexed for MEDLINE]