Genetic Variants Linked to Life-threatening Cardiac Arrhythmias in Patients With Dilated Cardiomyopathy and Implanted Defibrillators

MedicalResearch.com Interview with:

Ben Cordon, PhD NIHR Post-doctoral Academic Clinical Fellow Specialist Registrar training in cardiology

Dr. Cordon

Ben Cordon, PhD
NIHR Post-doctoral Academic Clinical Fellow
Specialist Registrar training in cardiology 

James S. Ware, PhD, MRCP  Reader in Genomic Medicine Group head within the Cardiovascular Genetics & Genomics Unit Imperial College London

Dr. Ware

James SWarePhD, MRCP
 Reader in Genomic Medicine
Group head within the Cardiovascular Genetics & Genomics Unit
Imperial College London

 

 

MedicalResearch.com: What is the background for this study?  

Response: Non-ischaemic dilated cardiomyopathy is a common cause of heart failure and carries the risk of life-threatening ventricular arrhythmia. An implantable cardioverter defibrillator (ICD) can be life-saving in this condition. However, the decision to implant an ICD is not one that can be taken lightly – ICD insertion carries its own risks, such as infection or inappropriate shocks, and our ability to predict who will benefit from a device is currently far from perfect. Genetic sequencing is affordable and widely available and for DCM, like many diseases, it is hoped that genetic stratification may one day help deliver personalised management. In DCM, variants in the Lamin A/C gene for example are known to cause a phenotype with early and severe arrhythmias and, as a result, international guidelines advocate a lower threshold for ICD insertion in these patients. However, Lamin A/C is an infrequent cause of DCM. The commonest known genetic cause of DCM are protein-truncating variants in the gene encoding Titin (TTNtv), accounting for ~15% of DCM cases. We wanted to know if this group had a higher risk of arrhythmia than the general DCM population.

Earlier work from our group on this topic found that patients with TTNtv-associated DCM were more likely to have a clinical history of arrhythmia (composite of atrial and ventricular arrhythmia, including NSVT), at the time of their initial DCM diagnosis. But it was unclear if this was driven by ventricular arrhythmia, atrial arrhythmia, or both or if it would translate into a long-term risk of potentially dangerous ventricular arrhythmia of the sort for which an ICD can be life-saving. In another study we analysed a larger cohort of ambulant DCM patients but did not find an increased risk of ventricular arrhythmia – but this was a relatively low-risk group, with comparatively mild symptoms (NHYA I/II heart failure) and moderately impaired LV function. As a result, the overall arrhythmic event rate was low, meaning that the power to detect differences between the TTNtv and non-TTNtv groups was reduced.

Continue reading

Americans Support Gene Therapies Even If They Cost More

Dr. Winegarden
Dr. Winegarden

MedicalResearch.com Interview with:

Wayne Winegarden, Ph.D.
Director, Center for Medical Economics and Innovation
Pacific Research Institute

MedicalResearch.com:  What is the background for this poll? Would you tell us a little about the Center for Medical Economics and Innovation? 

Response: Recent press reports have focused on how extensive innovative gene therapies can be.  PRI was interested in learning where Americans stand on these cures of the future, and commission a new national opinion survey to find out.

The Center for Medical Economics and Innovation is a new center launched by PRI this spring to research and advance policies showing how a thriving biomedical and pharmaceutical sector benefits both patients and economic growth. Medical innovation is an important driver of economic growth, responsible for over $1.3 trillion in economic activity each year. As the Milken Institute has found, every job in the biomedical sphere supports another 3.3 jobs elsewhere in the economy.

Among the activities of the Center – which can be accessed at www.medecon.org – are providing free-market analysis to evaluate current policy proposals, producing easy-to-understand data and analysis on current trends in medical science, breaking down complex issues like pharmaceutical and biomedical pricing structures, and demonstrating the benefits that market-based reforms can offer patients and the U.S. health care system.  Continue reading

Children with Birth and Chromosomal Defects More Likely to Develop Cancer

MedicalResearch.com Interview with:

Philip J. Lupo, PhD, MPH Co-Director, Childhood Cancer Epidemiology and Prevention Program, Texas Children's Cancer Center Associate Professor, Department of Pediatrics Section of Hematology-Oncology, Member, Dan L. Duncan Comprehensive Cancer Center Baylor College of Medicine Adjunct Associate Professor, Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences University of Texas School of Public Health

Dr. Lupo

Philip J. Lupo, PhD, MPH
Co-Director, Childhood Cancer Epidemiology and Prevention Program, Texas Children’s Cancer Center
Associate Professor, Department of Pediatrics
Section of Hematology-Oncology,
Member, Dan L. Duncan Comprehensive Cancer Center
Baylor College of Medicine
Adjunct Associate Professor, Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences
University of Texas School of Public Health
 

MedicalResearch.com: What is the background for this study?  

Response: While cancer risk in children with certain chromosomal defects like Down syndrome is well established, much less is known for children with birth defects where there is no known genetic cause, sometimes called non-chromosomal defects. Non-chromosomal defects, as a group, affect more children, but one of the primary challenges of understanding risk among these children is that limited sample sizes make studying specific defects, like spina bifida, more difficult.

Because of that, we gathered data from birth, birth defect, and cancer registries across Texas, Arkansas, Michigan, and North Carolina to generate a birth cohort of more than 10 million children born between 1992 and 2013. We looked at diagnoses of cancer until 18 years of age to determine differences in cancer risk between those with and without birth defects.

Continue reading

World Trade Center 9/11 Dust: Altered Gene Expression Links Exposure to Prostate Cancer Risk

MedicalResearch.com Interview with:

Emanuela Taioli, MD, PhD, Director of the Institute for Translational Epidemiology Icahn School of Medicine at Mount Sinai Asociate director for Population Science Tisch Cancer Institute

Dr. Taioli

Emanuela Taioli, MD, PhD,
Director of the Institute for Translational Epidemiology
Icahn School of Medicine at Mount Sinai
Asociate director for Population Science
Tisch Cancer Institute 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: An excess incidence of prostate cancer has been identified among World Trade Center responders. We wanted to study if this excess was associated with exposure to WTC dust
The results suggest that respiratory exposure to WTC dust can induce inflammatory and immune responses in prostate tissue. Chronic inflammation could facilitate prostate cancer development

Taken together, our results suggest that World Trade Center prostate cancer cases have a distinct gene expression pattern that may be the result of exposure to specific carcinogens during the WTC attacks. WTC dust-exposed rat prostate displayed unique changes in gene expression and immune cell infiltrates after acute dust exposure, suggesting that the effect of exposure may be measured locally in target organs such as prostate. In addition, some of the genes overexpressed in rat normal prostates as a consequence of exposure are also overexpressed in human prostate cancer tissues, suggesting a link between exposure, local immune dysregulation, and prostate cancer development Continue reading

Metagenomic Sequencing Enhanced Diagnosis of Meningitis and Encephalitis Infections

MedicalResearch.com Interview with:

Dr. Charles Chiu, M.D./Ph.D. Professor, Laboratory Medicine and Medicine / Infectious Diseases Director, UCSF-Abbott Viral Diagnostics and Discovery Center Associate Director, UCSF Clinical Microbiology Laboratory UCSF School of Medicine

Dr. Chiu

Dr. Charles Chiu, M.D./Ph.D.
Professor, Laboratory Medicine and Medicine / Infectious Diseases
Director, UCSF-Abbott Viral Diagnostics and Discovery Center
Associate Director, UCSF Clinical Microbiology Laboratory
UCSF School of Medicine

MedicalResearch.com: What is the background for this study? Would you describe what is meant by metagenomic sequencing?

Response: Metagenomic next-generation sequencing (mNGS) is the use of technology to generate millions of sequence reads to diagnose infection sin patients by characterizing the full range of potential pathogens (bacteria, viruses, fungi, and parasites) in a single sample. Although shown to be a promising diagnostic tool for  infectious diseases in case reports and limited case series (Chiu and Miller Nature Reviews Genetics 20, 341-355 (2019)), to date the “real-life” utility of this approach for patient care has hitherto not been demonstrated.  This study is the first prospective, multi-center study of clinical mNGS testing for the diagnosis of neurological infections in acutely ill hospitalized patients presenting with meningitis and/or encephalitis.

Continue reading

Novartis Piqray® Approved for Patients with a PIK3CA Mutation in HR+/HER2- Advanced Breast Cancer

MedicalResearch.com Interview with:

Fabrice André, MD, PhD Research director and head of INSERM Unit U981 Professor in the Department of Medical Oncology Institut Gustave Roussy in Villejuif, France Global SOLAR-1 Principal Investigator.

Dr. Fabrice André

Fabrice André, MD, PhD
Research director and head of INSERM Unit U981
Professor in the Department of Medical Oncology
Institut Gustave Roussy in Villejuif, France
Global SOLAR-1 Principal Investigator.

MedicalResearch.com: What is the background for this study? How does Piqray®  differ from other treatments for this type of advanced breast cancer? 

  • The US Food and Drug Administration (FDA) approved Piqray® (alpelisib, formerly BYL719) in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-), PIK3CA-mutated, advanced or metastatic breast cancer, as detected by an FDA-approved test after disease progression following an endocrine-based regimen.
  • Piqray is the first and only combination treatment with fulvestrant specifically for postmenopausal women, and men, with HR+/HER2- advanced or metastatic breast cancer with a PIK3CA mutation following progression on or after an endocrine-based regimen, bringing a biomarker-driven therapy option to this population for the first time.
  • Advanced breast cancer is incurable, and patients with all types need more treatment options. With this approval, physicians can now use an FDA-approved test to determine if their patients’ HR+/HER2- advanced breast cancer has a PIK3CA mutation and may be eligible for treatment with Piqray plus fulvestrant combination therapy. 

Continue reading

Does Genetic Information Encourage Doctors to Switch Anticoagulation Medications?

MedicalResearch.com Interview with:

Thomas J. Povsic, MD, PhDInterventional CardiologistDuke Clinical Research InstituteDuke University School of MedicineDurham, North Carolina 

Dr. Povsic

Thomas J. Povsic, MD, PhD
Interventional Cardiologist
Duke Clinical Research Institute
Duke University School of Medicine
Durham, North Carolina 

MedicalResearch.com: What is the background for this study? 

Response: The background for this study is that it is unknown how mandatory reporting of CYP2C19 metabolizer status affects how doctors treat patients or to what degree provision of this information would affect choice of a P2Y12 inhibitor within a clinical trial.

As part of the GEMINI-ACS trial, all patients underwent CYP2C19 metabolizer testing.  This trial enrolled patients with a recent acute coronary syndrome and randomized them to aspirin or a low dose of rivaroxaban.  All patients were also to be treated with ticagrelor or clopidogrel, which was at the discretion of the investigator.  Investigators were given information regarding the CYP2C19 metabolizer status about a week after randomization.  Importantly prior to randomization, all investigators were asked how they expected to use this information, and then we followed what they actually did.

Continue reading

Why Do Some People Get a Dog?

MedicalResearch.com Interview with:
Tove Fall PhD
Senior author of the study
Associate Professor in Epidemiology
Department of Medical Sciences and the Science for Life Laboratory
Uppsala University 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Dog ownership is common in the Western society but little is known about what actually makes people get a dog.

We conducted a twin study to understand whether the genetic make-up has an influence on this choice. We found that more than 50% of the differences in dog ownership is explained by genetic variants.  Continue reading

Genes Determine Why We Don’t All Smell the Same

MedicalResearch.com Interview with:

Dr. Casey Trimmer, PhDGeneticist, was a post-doctoral fellow at the Monell Center when the research was conducted

Dr. Trimmer

Dr. Casey Trimmer, PhD
Geneticist, was a post-doctoral fellow at the
Monell Center when the research was conducted

MedicalResearch.com: What is the background for this study?  

Response: We detect odors using 400 different types of sensor proteins, called olfactory receptors, in our noses. An odor molecule activates a specific combination of these receptors, and this pattern of activation gives us information on what we’re smelling–whether its floral or smoky, intense or weak, and how much we like it. However, how the system translates receptor activation to these perceptual features is largely unknown. Here, we take advantage of the extensive genetic variation in the OR gene family to understand the contribution of individual ORs to odor perception. By studying cases where the function of a particular OR is lost, we can examine what kinds of perceptual alterations occur, allowing us to link receptor to odor and understand what kind of information the receptor is encoding.

Data linking genetic variation to perceptual changes exist for only 5 ORs. Here, we examined the perceived intensity and pleasantness of 68 odors in 332 participants. We used next-generation genome sequencing to identify variants in 418 OR genes and conducted a genetic association analysis to relate this variation to differences in odor perception. We then use a cell-based assay to examine receptor function and investigate the mechanisms underlying our associations. Finally, we examined the contribution of single OR genotype, genetic ancestry, age, and gender to variations in odor perception.

Continue reading

Machine Learning Can Analyze Entire Transcriptome To Improve Diagnosis of Difficult Cancers

MedicalResearch.com Interview with:

Steven J.M. Jones, Professor, FRSC, FCAHSCo-Director & Head, BioinformaticsGenome Sciences CentreBritish Columbia Cancer Research CentreVancouver, British Columbia, Canada

Dr. Jones

Steven J.M. Jones, Professor, FRSC, FCAHS
Co-Director & Head, Bioinformatics
Genome Sciences Centre
British Columbia Cancer Research Centre
Vancouver, British Columbia, Canada and

Jasleen Grewal, BSc.Genome Sciences CentreBritish Columbia Cancer Research CentreVancouver, British Columbia, CanadaJasleen Grewal, BSc.
Genome Sciences Centre
British Columbia Cancer Research Centre
Vancouver, British Columbia, Canada

MedicalResearch.com: What is the background for this study?

Response: Cancer diagnosis requires manual analysis of tissue appearance, histology, and protein expression. However, there are certain types of cancers, known as cancers of unknown primary, that are difficult to diagnose based purely on their appearance and a small set of proteins. In our precision medicine oncogenomics program, we needed an accurate approach to confirm diagnosis of biopsied samples and determine candidate tumour types for where the primary site of the cancer was uncertain.  We developed a machine learning approach, trained on the gene expression data of over 10,688 individual tumours and healthy tissues, that has been able to achieve this task with high accuracy.

Genome sequencing offers a high-resolution view of the biological landscape of cancers. RNA-Seq in particular quantifies how much each gene is expressed in a given sample. In this study, we used the entire transcriptome, spanning 17,688 genes in the human genome, to train a machine learning method for cancer diagnosis. The resultant method, SCOPE, takes in the entire transcriptome and outputs an interpretable confidence score from across a set of 40 different cancer types and 26 healthy tissues.  Continue reading

You May Have Inherited Your Sweet Tooth

MedicalResearch.com Interview with:

Dr Daniel Hwang PhDPostdoctoral Research FellowThe University of Queensland Diamantina Institute

Dr. Hwang

Dr Daniel Hwang PhD
Postdoctoral Research Fellow
The University of Queensland Diamantina Institute

MedicalResearch.com: What is the background for this study?  

Response: The aim of the this study is to understand the genetic basis of human taste perception. In this international collaboration project, we started by collecting sensory data from twins in the Australia and USA since 2003. Based on the difference in the genetic relatedness between identical and non-identical twins, our previous studies have quantified the amount of genetic influence on sweet taste perception (https://doi.org/10.1017/thg.2015.42) as well as the other sensory phenotypes (https://doi.org/10.1093/chemse/bjs070).  Continue reading

Nature vs Nurture? Environment Play a Bigger Role in Dental Cavities

MedicalResearch.com Interview with:

Katrina Scurrah MDMelbourne School of Population and Global Health

Dr. Scurrah

Katrina Scurrah PhD
Senior Research Fellow (Biostatistician), Twins Research Australia, and Melbourne School of Population and Global Health, The University of Melbourne and
Honorary Fellow, Murdoch Childrens Research Institute.

MedicalResearch.com: What is the background for this study?

Response: Oral health is an important component of general health and yet dental caries (decay) is still common in children (affecting up to one in three 5-6 year old children in Australia). Although we know that some genetic and lifestyle factors (such as diet) are important risk factors for caries, the relative importance of these is still unclear.  Risk factors from pregnancy and very early childhood (even before teeth appear) might also be important. This study is the first to include prospectively measured data on health and well-being from pregnancy, birth and early childhood in a study of twin children. We analysed data from a cohort of 172 pairs of twin children to assess the effects of genes and environment on susceptibility to dental caries at six years-of-age.

Continue reading

Genetic Studies Can Help Determine How Low LDL Should Go With Treatment

Florian Kronenberg

Dr. Kronenberg

MedicalResearch.com Interview with:
Florian Kronenberg, MD
Division of Genetic Epidemiology
Department of Medical Genetics, Molecular and Clinical Pharmacology
Medical University of Innsbruck, Innsbruck, Austria

MedicalResearch.com: What is the background for this study?

Response: Lp(a) is one of the most prevalent lipoprotein risk factors for cardiovascular disease. Roughly 20% of the general Caucasian population have concentrations above 50 mg/dL and the 10% with the highest concentrations have a 2 to 3-fold increased risk for myocardial infarction.

There is strong evidence from genetic studies that high Lp(a) concentrations are causally related to cardiovascular outcomes. Until recently there was no drug available which lowers Lp(a) without any effects on other lipoproteins. This has recently changed by the development of drugs that block the production of Lp(a) in an impressive way. These drugs have to be studied in randomized controlled trials whether they not only lower Lp(a) concentrations but also cardiovascular outcomes. For the planning of such studies it is crucial to estimate the amount of Lp(a) lowering required to show a clinical benefit.

Continue reading

Gene Linked to Colon Cancer in Younger Patients Identified

MedicalResearch.com Interview with:

Valentine N. Nfonsam, MD, MS, FACSAssociate Professor of SurgeryProgram Director, General Surgery ResidencyColon and Rectal SurgeryDivision of Surgical OncologyUniversity of Arizona, Tucson

Dr. Nfonsam

Valentine N. Nfonsam, MD, MS, FACS
Associate Professor of Surgery
Program Director, General Surgery Residency
Colon and Rectal Surgery
Division of Surgical Oncology
University of Arizona, Tucson 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The overall incidence of colon cancer in the United states has gone down in the last few decades. However, there has been a significant increase in the incidence of sporadic colon cancer is young patients (<50 years old). The etiology of this phenomenon is likely multi-factorial.

These young patients do present with more advanced disease and with aggressive features. We demonstrated in our study that the colon cancer tumor biology was different between young and older patients. We also singled out a particular gene, Cartilage oligomeric Matrix Protein (COMP) which was significantly over-expressed in young patients and demonstrated its role in cancer proliferation and metastasis and also its potential as a prognostic biomarker since we were able to detect it in plasma.

Continue reading

DNA Copy Number Variants Linked to Increased Risk of Depression

MedicalResearch.com Interview with:

Dr Kimberley Kendall MBBChWellcome Trust Clinical Research Fellow

Dr. Kendall

Dr Kimberley Kendall MBBCh
Wellcome Trust Clinical Research Fellow

Professor James WaltersMRC Centre for Neuropsychiatric Genetics and GenomicsProfessor, Division of Psychological Medicine and Clinical Neurosciences

Prof. Walters

Professor James Walters
MRC Centre for Neuropsychiatric Genetics and Genomics
Professor, Division of Psychological Medicine and Clinical Neurosciences

Cardiff University
 

MedicalResearch.com: What is the background for this study?

Response: Copy number variants (CNVs) are the deletion or duplication of large sections of DNA. Large, rare CNVs have been shown to increase the risk of neurodevelopmental disorders including autism spectrum disorder (ASD), intellectual disability (ID), attention deficit/hyperactivity disorder (ADHD) and schizophrenia. However, the impact of these CNVs on risk of depression was unclear from the existing literature. Continue reading

RNA Genetic Testing Improves Analysis of Hereditary Cancer Genes

MedicalResearch.com Interview with:
Rachid Karam, PhD

Director, Ambry Translational Genomics Lab
Ambry Genetics 

MedicalResearch.com: What is the background for this study?

Response: DNA genetic testing (DGT) for hereditary cancer genes is now a well accepted clinical practice; however, the interpretation of DNA variation remains a challenge to laboratories and medical providers.

RNA genetic testing (RGT) as a supplement to DGT is a means to clarify the clinical actionability of variants in hereditary cancer genes, improving our ability to accurately apply known strategies for cancer risk reduction.

Continue reading

Bacteria in Intestinal Microbiome Freely Transfer Genes To Each Other

MedicalResearch.com Interview with:
Kyung Mo Kim

Senior research scientist
Korea Polar Research Institute.
Professor Gustavo Caetano-Anollés
Carl R. Woese Institute for Genomic Biology
University of Illinois
Arshan Nasir
Distinguished Fellow
Los Alamos National Laboratory in New Mexico

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Horizontal gene transfer is the process by which unrelated microorganisms can exchange genes. The famous examples would be transfer of antibiotic resistance genes among bacteria that renders many commercially expensive antibiotics useless. From an evolutionary point of view, it complicates our understanding of how bacteria are related since even distantly-related bacteria can share genes and then cluster together on evolutionary trees. Thus better understanding horizontal evolution is important for both public health and our basic understanding of microbial taxonomy and evolution.

There are some excellent existing methods of HGT detection that compare DNA features (e.g. GC%, codon usage) or statistical similarity between genomes to identify foreign genes. However, these methods work better to identify recently transferred genes. Transfers that happened millions or billions of years ago cannot be reliably detected since DNA sequences evolve over time during which foreign DNA can become more host-like. That is why we focused our attention on utilizing approaches that are based on sound evolutionary principles.

If a gene is horizontally acquired, then a phylogenetic tree of that gene will be different from the reference or known tree of the organisms. The true phylogenetic tree of organisms describes how organisms have descended from a common ancestor through inheritance of genes. If a gene is acquired from a source outside the parents or from an unrelated organism, then there will be a conflict between gene tree and the reference/known species tree. This conflict can be indication of HGT. Continue reading

Epilepsy: Genetic Testing Should Include Parental Sampling

MedicalResearch.com Interview with:

Dr. Ahmad Abou Tayoun, PhDClinical Molecular GeneticistDirector of the Genetics LaboratoryAl Jalila Children’sUnited Arab Emirates

Dr. Abou Tayoun

Dr. Ahmad Abou Tayoun, PhD
Clinical Molecular Geneticist
Director of the Genetics Laboratory
Al Jalila Children’s
United Arab Emirates

MedicalResearch.com: What is the background for this study?  

Response: In this study, we provide data in favor of using an exome-based testing approach, where parental samples can be readily accessible, for early onset epilepsy patients. The exome test includes all coding genes in the human genome. Although we perform exome sequencing on those patients, we demonstrate that a first tier analysis should include targeted interpretation of ~100 genes strongly associated with the disease. This analysis provides diagnoses in ~11% of the patients. Follow up parental testing on a limited number of patients (n=15) that had inconclusive results, revealed de novo (new mutations) variant status, leading to upgrade to positive reports in 7 patients and adding ~5% to the overall diagnostic yield.

Continue reading

Tracing Extrachromosomal DNA Inheritance Patterns in Glioblastoma Using CRISPR

MedicalResearch.com Interview with:

Eunhee Yi, Ph.D.Postdoctoral AssociateThe Jackson Laboratory

Dr. Yi

Eunhee Yi, Ph.D.
Postdoctoral Associate
The Jackson Laboratory

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Recurrence after therapy for glioblastoma (GBM) is unavoidable. There are substantial differences among the cells of GBM tumors in the abundance and types of genetic materials. This heterogeneity is a major driver of therapy failure and disease progression. We previously reported that extrachromosomal DNA (ecDNA) elements, which reside outside the linear genome and represent a mechanism to amplify and activate oncogenes, is a potential cause of the increasing genetic diversity in GBM. Our current study is focused on the development of a novel cytogenetic tool to visualize ecDNA to visualize the behavior of these elements in live cells. We have leveraged the unique properties of ecDNA to develop a CRISPR-based “ecDNA tracing toolbox (EDTB)”.  Continue reading

Genes Linked to Alcohol Use Disorder Identified

MedicalResearch.com Interview with:

Henry R. Kranzler, MDProfessor of PsychiatryPerelman School of MedicineUniversity of Pennsylvania

Dr. Kranzler

Henry R. Kranzler, MD
Professor of Psychiatry
Perelman School of Medicine
University of Pennsylvania

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Alcohol consumption and alcohol use disorder (AUD) are moderately heritable traits.  To date, genome-wide association studies (GWAS) have not examined these traits in the same sample, which limits an assessment of the extent to which genetic variation is unique to one or the other or shared.

This GWAS examined a large sample (nearly 275,000 individuals) from the U.S. Veterans Affairs Million Veteran Program (MVP) for whom data on both alcohol consumption and alcohol use disorder diagnoses were available from an electronic health record.  We identified 18 genetic variants that were significantly associated with either alcohol consumption, AUD, or both. Five of the variants were associated with both traits, eight with consumption only, and five with alcohol use disorder only.  Continue reading

Insulin Resistance Characterizes a Subset of Schizophrenia Patients

MedicalResearch.com Interview with:

Prof Sabine Bahn MD PhD MRCPsych FRSBCambridge Centre for Neuropsychiatric Research

Prof. Bahn


Prof Sabine Bahn MD PhD MRCPsych FRSB

Cambridge Centre for Neuropsychiatric Research

Jakub Tomasik, PhDDepartment of Chemical Engineering and Biotechnology

Dr. Tomasik

Jakub Tomasik, PhD
Department of Chemical Engineering and Biotechnology
University of Cambridge

 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Schizophrenia patients are at increased risk of impaired glucose metabolism, yet the comorbidity between the two conditions cannot be fully explained by known risk factors such as obesity, smoking, stress or antipsychotic medication. Previous family and genome-wide studies have suggested that the co-occurrence between schizophrenia and impaired glucose metabolism might be due to shared genetic factors, as exemplified by increased risk of diabetes in first-degree relatives of schizophrenia patients, but the biological mechanisms underlying this association remain unknown.

We examined the association between insulin resistance, schizophrenia polygenic risk and response to treatment in 58 drug-naive schizophrenia patients and 58 matched healthy individuals while controlling for a range of demographic (age, gender, body mass index), lifestyle (smoking, alcohol and cannabis use) and clinical (psychopathology scores, treatment drug) factors.

We found that insulin resistance, a key feature contributing to the development of type 2 diabetes, significantly correlated with schizophrenia polygenic risk score in patients, with higher genetic risk of schizophrenia associated with increased insulin resistance. Furthermore, we found that patients with higher insulin resistance were more likely to switch medication during the first year of treatment, which implies lower clinical response.  Continue reading

Shorter Individuals at Greater Risk of Heart Disease

MedicalResearch.com Interview with:

Eirini MarouliWilliam Harvey Research InstituteBarts and The London School of Medicine and Dentistry, Queen Mary University of London, London

Eirini Marouli

Eirini Marouli
William Harvey Research Institute
Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London

MedicalResearch.com: What is the background for this study?  

Response: Epidemiological studies suggest that shorter stature is associated with increased risk of coronary artery disease (CAD) or type 2 diabetes (T2D). It is not clear though whether these associations are causal or there are other factors mediating these effects. When randomized trials are inappropriate or impossible, we can use Mendelian Randomisation as a good alternative to study the causal relationship between a trait and a disease. Here, we examined over 800 places in the human genome known to be associated with adult height and evaluated how genetically predicted height can affect the risk of CAD or T2D. Furthermore, we evaluated the role of several risk factors including, cholesterol, triglycerides, blood pressure, body mass index, fat percentage, socio-economic parameters including education and income as well as lung function. Lung function was assessed by spirometry measures including FEV1: forced expiratory volume in 1 second, FVC: forced vital capacity.

Continue reading

Pathogenic RET Variants Occur at Higher Prevalence Than Previously Recognized

MedicalResearch.com Interview with:

Emily J. Gallagher, MDAssistant Professor of MedicineEndocrinology, Diabetes and Bone DiseaseIcahn School of Medicine at Mount Sinai 

Dr. Gallagher

Emily J. Gallagher, MD
Assistant Professor of Medicine
Endocrinology, Diabetes and Bone Disease
Icahn School of Medicine at Mount Sinai 

MedicalResearch.com: What is the background for this study?

Response: Multiple Endocrine Neoplasia Syndrome Type 2 (MEN2) is an inherited endocrine disorder characterized by the development of pheochromocytoma, medullary thyroid carcinoma (MTC) and parathyroid tumors. It occurs due to activating missense variants in the RET gene.

The estimated prevalence of MEN2 is 1 per 30,000 in the general population. Through a collaboration between The Center for Genomic Health, the Charles Bronfman Institute for Personalized Medicine, and the Division of Endocrinology at Mount Sinai, our aim was to investigate the prevalence and clinical manifestations of pathogenic RET variants in the multi-ethnic BioMe Biobank.

The BioMe Biobank is an electronic health record-linked biobank with exome sequencing data available for more than 30,000 patients recruited across The Mount Sinai Health System.

Continue reading

Genetic Evidence Suggests New LDL-C Lowering Drug May Decrease Cardiovascular Events and Have Additive Effect with Statins

MedicalResearch.com Interview with:

Brian A Ference, MD, MPhil, MSc, FACC, FESCProfessor and Director of Research in Translational TherapeuticsExecutive Director, Centre for Naturally Randomized TrialsStrangeways Research LaboratoryUniversity of CambridgeCambridge, UK

Dr. Ference

Brian A Ference, MD, MPhil, MSc, FACC, FESC
Professor and Director of Research in Translational Therapeutics
Executive Director, Centre for Naturally Randomized Trials
Strangeways Research Laboratory
University of Cambridge
Cambridge, UK

MedicalResearch.com: What is the background for this study?

Response: Bempedoic acid is a novel therapy currently in development that lowers LDL-C by inhibiting ATP-citrate lyase, an enzyme in the same cholesterol biosynthesis pathway as HMG-CoA reductase (the target of stains).  However, whether lowering LDL-C by inhibiting ATP-citrate lyase will reduce the risk of cardiovascular events to the same extent as lowering LDL-C by inhibiting HMG-CoA reductase with a statin is unknown.

We conducted a “naturally randomized trial” using Mendelian randomization in more than 650,000 participants who experienced more than 100,000 cardiovascular events to evaluate the potential clinical benefit of lowering LDL-C by inhibiting ATP-citrate lyase as compared to lowering LDL-C by inhibiting HMG-CoA reductase.

Continue reading

Genetic Mutation May Predict Outcomes of Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone

MedicalResearch.com Interview with:

Masaki Shiota MD, PhD Department of Urology, Graduate School of Medical Sciences Kyushu University Fukuoka , Japan

Dr. Shiota

Masaki Shiota MD, PhD
Department of Urology
Graduate School of Medical Sciences
Kyushu University
Fukuoka , Japan

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  3β-hydroxysteroid dehydrogenase-1 encoded by HSD3B1 is a rate-limiting enzyme required for all pathways of dihydrotestosterone synthesis, as well as converts abiraterone into Δ4-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor.

A mutation (1245A>C) in HSD3B1 is shown to be resistant to proteasomal degradation, causing substantial accumulation of this enzyme and gain-of-function. Although the HSD3B1 (1245C) allele can be acquired by mutation, germ-line single nucleotide polymorphism (SNP; rs1047303) is also known to exist. Then, in this study, we investigated the significance of missense polymorphism in HSD3B1 gene among men treated with primary ADT or abiraterone.

The results showed men carrying variant allele showed higher risk of progression in primary androgen-deprivation therapy, but vulnerable to abiraterone treatment. Continue reading

Genetics Could Explain Smokers’ Preference for Menthol Cigarettes

MedicalResearch.com Interview with:

Dennis Drayna, PhD Chief of the Laboratory of Communication Disorders and the Section on Genetics of Communication Disorders National Institute on Deafness and Other Communication Disorders Part of the National Institutes of Health

DR. Drayna

Dennis Drayna, PhD
Chief of the Laboratory of Communication Disorders and the Section on Genetics of Communication Disorders
National Institute on Deafness and Other Communication Disorders
Part of the National Institutes of Health

MedicalResearch.com: What is the background for this study?

Response: In the United States, there are striking racial differences in the rate of menthol cigarette use.  Tobacco use is a major preventable source of morbidity and mortality in the population, and menthol cigarette use by African Americans represents an important issue for attempts to address minority health disparities.

There have been many studies that have documented the role of inherited factors that contribute to smoking or tobacco use.  However, no studies have examined the role of genetic factors specifically in menthol tobacco use.  The preference for menthol cigarettes among African Americans has previously been attributed to cultural factors or industry advertising practices directed at this group.

In our study, we asked whether genetic factors could explain why African-American smokers choose menthol cigarettes over non-menthol cigarettes. Our initial hypothesis was that variation in genes that encode the known menthol receptors was important in this difference, although we designed our study to look at all 21,000 protein-coding genes in the genome.

Continue reading

Ultrasensitive DNA Screening for Down Syndrome Offers Potential for Early Detection

MedicalResearch.com Interview with:

Zhiyong Zhang PhD Key Laboratory for the Physics and Chemistry of Nanodevices and  Department of Electronics Peking University Beijing China

Prof. Zhang

Zhiyong Zhang PhD
Key Laboratory for the Physics and Chemistry of Nanodevices
Department of Electronics
Peking University
Beijing China

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Down syndrome is caused by the presence of an extra 21st chromosome within the genome and is the most common birth defect (occurring in approximately 1 in 800 births). In the absence of a multiplexed quantitative diagnostic device, pregnant women have been examined with the ultrasound and the indirect biochemical markers (Alpha-fetoprotein, chorionic gonadotropin and free estriol) which are accompanied with a high misdiagnosis rate. And the diagnostic test (such as amniocentesis) following the wrong screening test results will bring harm to both the pregnant women and the fetuses.

Through PCR (polymerization chain reaction) amplification of the fetal DNA in the pregnant mother’s peripheral blood and fluorescence read-out, whole-genome sequencing (WGS)-based non-invasive prenatal testing (NIPT) sequences all the genomic DNA segments in parallel and quantitatively compares the percentage of different chromosomes, which increases the sensitivity for prenatal detection of Down syndrome. However, the complex instrumental setups and the resulted high processing cost present challenges for the large-scale application of WGS-based diagnosis at the point of care in the urban and rural areas of developing countries. Hence, beside the costly WGS method, there is an urgent need to develop a cost-effective NIPT biochip with simple instrumental setting, fast detection speed, high sensitivity, and programmable to multiple disease markers.

Taking advantages of we have developed a novel field effect transistor (FET) based biosensor that reveals a fast, ultra-sensitive, highly specific and cost-effective methods and someday can be used to detect fetal Down syndrome in NIPT.  Continue reading

12 Genetic Loci Associated with Human Healthspan

MedicalResearch.com Interview with:

Yurii Aulchenko Co-founder and Chief Scientist of PolyOmica

Yurii Aulchenko

Yurii Aulchenko Co-founder and Chief Scientist of PolyOmica
PolyOmica is a research & development company providing services and tools for quantitative genetics and functional genomics.

Peter Fedichev Founder and Chief Science Officer of Gero

Peter Fedichev

Peter Fedichev Founder and Chief Science Officer of Gero
Gero is a data-driven longevity company developing innovative therapies that will strongly extend the healthy period of life also known as healthspan

MedicalResearch.com: What is the background for this study? What are the main findings?

Peter Fedichev, Gero: Age is the most important risk factor behind age-related diseases and death. Lifespan has increased quite dramatically over the last 150-200 years mostly due to the eradication of early-life mortality. What we find, however, is that the healthspan, understood as the chronic diseases-free period, is also on the rise, but not so much. It appears that lifespan is modifiable by interventions, at least in lab animals. It is therefore crucial to understand if the biology behind human healthspan. Is it the same as that of lifespan? What are the molecular pathways and genetic factors controlling the healthspan? At the end, we would like to develop interventions that extend not only lifespan, but also the healthspan. Everyone wants to stay healthy!

Yurii Aulchenko, PolyOmica: We studied the incidence of the most prevalent age-related diseases in the large UK Biobank, one of the best repositories of biologically and medically relevant data from a very large cohort of aging individuals. We observed that the incidence (the chances of) all the major diseases increased exponentially with age. The diseases risk doubling time was about eight years, same as the mortality doubling time from the Gompertz mortality law, discovered as early as in 1825 and used in life insurance ever since. The similar patterns of age-dependent risk acceleration suggest a major common driver behind the diseases, that is most plausibly aging itself.

Peter Fedichev, Gero: The incidence of the diseases could, therefore, be used as a biomarker of aging process. We used the age at the onset of the first age-related disease (the end of healthspan) as the target for a genome-wide association study (GWAS) and identified as many as 12 genetic loci associated with human healthspan. Continue reading

Link Between Apolipoprotein E and Brain Hemorrhage Varies by Ethnicity

MedicalResearch.com Interview with:

Dr. Marini

Dr. Marini

Sandro Marini, MD
Research Fellow
Jonathan Rosand Laboratory
Massachusetts General Hospital
Boston, MA 02114

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The epsilon(ε) 4 allele of the Apolipoprotein E (APOE) gene increases risk for Alzheimer’s disease (AD) and intracerebral hemorrhage (ICH).

In both diseases, it is believed to increase risk through the deposition of beta-amyloid within the brain and blood vessels, respectively. The effect of APOE ε4 on both AD and ICH risk changes across populations, for unclear reasons.

In our study, we confirmed the role of APOE ε4 for ICH risk in whites and found that the risk-increasing effect of the 4 allele is demonstrable in Hispanics only when balancing out the effect of hypertension.
Continue reading

Polygenic Risk Scores Linked to Intelligence, ADHD and Brain Findings

MedicalResearch.com Interview with:

Silvia Alemany ,PhD first author Barcelona Institute for Global Health (ISGlobal), a centre supported by "la Caixa". In collaboration with co-authors:

Dr. Alemany

Silvia Alemany, PhD first author
Barcelona Institute for Global Health (ISGlobal), a centre supported by “la Caixa”.

In collaboration with co-authors:
Philip Jansen,MD, MSc and
Tonya White, MD, PhD
Erasmus University Medical Center, Rotterdam

MedicalResearch.com: What is the background for this study?

Response: Individuals affected by psychiatric disorders can demonstrate morphological brain abnormalities when compared to healthy controls. Although both genetic and environmental factors can account for these brain abnormalities, we expect that genetic susceptibility for psychiatric disorders has the greatest influence on the development of the brain.

Genetic susceptibility for psychiatric disorders can be estimated at the individual level by generating polygenic risk scores. Using this methodology, genetic susceptibility to psychiatric disorders and cognition has been associated with behavior problems in childhood. These findings suggest that heritable neurobiological mechanisms are at play in very early in the course of the illnesses.

Continue reading