Author Interviews, Genetic Research, JAMA, Schizophrenia / 26.03.2016 Interview with: S. Hong Lee, PhD Queensland Brain Institute, The University of Queensland, Brisbane School of Environmental and Rural Science, University of New England, Armidale Australia What is the background for this study? What are the main findings? Response: Previous studies reported increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for schizophrenia tend to have children at an earlier or later age. We found evidence for a significant overlap between genetic factors associated with risk of schizophrenia and genetic factors associated with Age at First Birth (AFB). We observed a U-shaped relationship between schizophrenia risk and maternal AFB, consistent with the previously reported relationship between schizophrenia risk in offspring and maternal age when not adjusted for age of the father. (more…)
Allergies, Author Interviews, Genetic Research / 26.03.2016 Interview with: Dr Gabrielle A. Lockett PhD Postdoctoral Research Fellow Asthma Genetics Laboratory, Faculty of Medicine, University of Southampton What is the background for this study? What are the main findings? Dr. Lockett: Season of birth has been known for decades to influence a huge range of traits, such as height and lifespan, as well as the risks of diseases such as allergy and schizophrenia. But until now the mechanism for season of birth effects was unknown. This study discovered that epigenetic marks (specifically DNA methylation) on the genome are associated with season of birth in 18-year-olds, suggesting that this could be a mechanism for such long-lasting birth season effects. Epigenetic marks on the genome are known to both influence gene expression and to change in association with environmental exposures. This study is the first to identify DNA methylation associated with season of birth. This discovery therefore extends our knowledge of environmental exposures that are able to affect the epigenome. The study also went on to further examine the genes identified to contain birth season-associated DNA methylation. Groups of these genes have functions related to development, cell death and the cell cycle, suggesting that season of birth alters the epigenetic regulation of these processes in particular. There was also suggestive evidence that season-associated DNA methylation could be on the functional pathway to allergic disease outcomes. (more…)
Alcohol, Author Interviews, Breast Cancer, Genetic Research, PLoS / 18.03.2016 Interview with: Chin-Yo Lin, Ph.D. University of Houston Center for Nuclear Receptors and Cell Signaling Department of Biology and Biochemistry Science and Engineering Research Center (SERC) Houston, TX 77204-5056 What is the background for this study? What are the main findings? Dr. Lin: Many studies have established that alcohol consumption is a risk factor for breast cancer. Breast cancers associated with drinking tend to be hormone receptor-positive, the type is commonly treated with the drug tamoxifen which blocks the actions of estrogen in driving tumor growth in pre-menopausal women. Alcohol consumption has also been shown to increase the risk of disease recurrence in patients. Our study shows that alcohol can enhance the effects of estrogen by increasing cancer cell division and also reduce the efficacy of tamoxifen. The key mechanistic insight from the study is that alcohol treatment of breast cancer cells increased the expression of BRAF, a cancer-causing gene that is commonly mutated and activated in other types of cancers. (more…)
Author Interviews, Genetic Research, Heart Disease / 18.03.2016 Interview with: Jonathan P. Davis , Ph.D. Associate ProfessorThe Ohio State University Medical Center Department of Physiology & Cell Biology. Columbus, OH 43210 What is the background for this study? What are the main findings? Dr. Davis: Myocardial infarction (MI) is a leading cause of heart failure and death in the US. Since the infarcted heart does not contract as well, therapeutics have been designed (i.e. positive inotropes) to help the heart contract better. While current positive inotropes help the patients in the short-term, they have detrimental long-term effects (“feel better but die sooner”). There is a dire need to be able to increase cardiac contraction without the deleterious side effects. We have achieved this goal by engineering the Ca2+-dependent switch in the heart, troponin C, to be able to better bind Ca2+. Combining gene therapy with our smartly formulated TnC, we demonstrated that our novel strategy not only protected the mouse from the negative consequences of an MI, but was also therapeutic when given after the MI. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease, Lipids / 18.03.2016 Interview with: Dr. Sarah de Ferranti MD MPH Boston Children’s Hospital Director, Preventive Cardiology Program Assistant Professor of Pediatrics Harvard Medical School  What are the main findings? Dr. de Ferranti: Familial hypercholesterolemia, or FH, is a genetic condition that causes severely elevated cholesterol levels from birth and is a leading cause of early heart attack. It is generally slowly progressive without symptoms until there is serious heart disease in the 3rd and 4th decade of life, making it important to look for it at a young age. Prior to this analysis it was thought that FH affected about 1 in 500 adults. The current study used data from 36,949 adults who took part in the 1999-2012 National Health and Nutrition Examination Survey (NHANES) and extrapolated to the 210 million U.S. adults aged 20 years and older. We identified cases of probably or definite Familial hypercholesterolemia in our analysis by using a combination of high levels of low-density-lipoprotein cholesterol (considered “bad” because it contributes to plaque buildup in arteries) and early heart disease in a person or close relative. (more…)
Author Interviews, Brain Injury, Genetic Research / 09.03.2016 Interview with: Dr. Jane McDevitt Temple University in Philadelphia What is the background for this study? Dr. McDevitt: During a head impact there is a mechanical load that causes acceleration and deceleration forces on the brain within the cranium. The acceleration and deceleration causes stress to the neurons and initiates a neurometabolic cascade, where excitatory neurotransmitters such as glutamate are released and depolarize the cell.  This triggers protein channels to open and allow ions into and out of the cell.  Increases in calcium persist longer and have greater magnitude of imbalance than any other ionic disturbance. One channel responsible for allowing calcium into the cell is r-type voltage-gated calcium channel.  One of the main proteins within this voltage-gated calcium channel is the CACNA1E protein produced by the CACNA1E gene. This protein forms the external pore and contains a pair of glutamate residues that are required for calcium selectivity.   It is also responsible for modulating neuronal firing patterns. A variation within this gene (i.e,CACNA1E ) that regulates expression levels of CACNA1E could be associated with how an athlete recovers following a concussion injury. Upwards of 20% of the concussed population fall into the prolonged recovery category, which puts these athletes at risk for returning to play quicker than they should. Variation in recovery depends on extrinsic factors like magnitude of impact, and sport, or intrinsic factors like age or sex. One intrinsic factor that has not been definitively parsed out is genetic variation. Recovery is likely to be influenced by genetics because genes determine the structure and function of proteins involved in the cell’s resistance and response to mechanical stress. Due to CACNA1E’s relationship to calcium influx regulation, a single nucleotide polymorphism (SNP) could modify the expression level of the protein responsible for regulating calcium. Altered protein levels could lead to athlete’s responding to concussive injuries differently. The main objective of this study was to examine the association between CACNA1E SNPs with concussion recovery in athletes. (more…)
Author Interviews, Biomarkers, Cleveland Clinic, Genetic Research, Personalized Medicine, Prostate, Prostate Cancer, Urology / 07.03.2016 Interview with: Eric A. Klein, MD Chairman, Glickman Urological and Kidney Institute Cleveland Clinic What is the background for this study? What are the main findings? Dr. Klein: Prostate cancer is an enigma. While this tumor is the second leading cause of cancer death among American men, most newly diagnosed disease detected by PSA screening is biologically indolent and does not require immediate therapy. Currently, the main clinical challenge in these men is to distinguish between those who can be managed by active surveillance from those who require curative intervention. Current clinical and pathological tools used for risk stratification are limited in accuracy for distinguishing between these scenarios. An abundance of research in the last decade has provided evidence that genomics can offer meaningful and clinically actionable biological information to help inform decision making, and current National Comprehensive Cancer Network (NCCN) guidelines on prostate cancer endorse the use of commercially available genomic tools for men considering active surveillance.[1] It has been previously shown that the 22-gene genomic classifier, Decipher, accurately predicts the likelihood of metastasis and prostate cancer specific mortality when measured on tissue from radical prostatectomy specimens.[2] In multiple validation studies, it performed with higher accuracy and discrimination compared to clinical risk factors alone. The current study[3] is the first to examine whether the use of Decipher might aid decision making when measured on biopsy tissue at the time of diagnosis. Men with available needle biopsy samples were identified from a study cohort that previously had Decipher performed on their matched radical prostatectomy tissue. In this cohort of mixed low, intermediate and high risk men, Biopsy Decipher predicted the risk of metastasis 10 years post RP with high accuracy, outperforming NCCN clinical risk categorization, biopsy Gleason score and pre-operative PSA. Furthermore, this study showed that Decipher reclassified 46% of patients into lower or higher risk classification compared to NCCN classification alone. The study also showed that Biopsy Decipher can identify men that are at high risk for adverse pathology as defined by the presence of primary Gleason pattern 4 or greater. (more…)
Author Interviews, Breast Cancer, Cancer Research, Genetic Research / 06.03.2016 Interview with: Rong Li, Ph.D., Professor Holder of the Tom C. & H. Frost Endowment Department of Molecular Medicine Institute of Biotechnology Co-Leader, Cancer Development and Progression Program Cancer Therapy & Research Center University of Texas Health Science Center at San Antonio What is the background for this study? What are the main findings? Dr. Li: The breast cancer susceptibility gene BRCA1 is well known for its function in double strand break DNA repair. However, the ubiquitous role of BRCA1 in DNA repair may not be sufficient to explain its tissue-specific tumor suppressor function in vivo. Using the “awesome power” of mouse genetics, we identified a previously unappreciated crosstalk between BRCA1 and a transcription regulator in mammary gland development. Importantly, we provide compelling evidence that this BRCA1 function is independent of its well-established DNA repair activity. What should clinicians and patients take away from your report? Dr. Li: The newly identified DNA repair-independent function of BRCA1 may provide new tools and targets for early prevention of BRCA1-associated breast cancer. (more…)
Author Interviews, Genetic Research, Heart Disease, JACC / 04.03.2016 Interview with: Silvia G Priori ,MD, PhD and Andrea Mazzanti, MD Medical Research: What is the background for this study? What are the main findings? Response: The study investigates a novel therapeutic approach for Long QT Syndrome type 3: a malignant varian of long QT Syndrome a disease in which the risk of arrhythmias is proportional to the prolongation of QT interval. LAQT3 is caused by gain of function mutations in the gene SCN5A that encode for the alpha subunit of the cardiac sodium channel. These mutations increase the late sodium current (INa late) that prolongs the QT interval and predisposes the heart to develop life-threatening ventricular arrhythmias. In 1996 we demonstrated in an animal model of Long QT Syndrome type 3 that administration of mexiletine was able to shorten QT interval and the same results were obtained in LQT3 patients treated with mexiletine : these data provided rational for the adoption in clinical practice guidelines to recommend the use of mexiletine to shorten QT interval in LQT3 patients with the expectation that shortening QT interval would reduce the risk of arrhythmic death. In this setting, our study is the first to provide data in support of the view that mexiletine shortens QT interval and reduces the probability to experience arrhythmic events. (more…)
ASCO, Author Interviews, Biomarkers, Breast Cancer, Chemotherapy, Genetic Research, Journal Clinical Oncology / 03.03.2016 Interview with: Oleg Gluz, MD West German Study Group Breast Center Niederrhein Evangelical Hospital Bethesda Moenchengladbach, Germany What is the background for this study? Dr. Gluz: PlanB trial is a Phase III chemotherapy study performed in patients with clinically high risk HER2 negative breast cancer. After early amendement, Recurrence Score (Oncotype Dx) as a selection criterion for or against chemotherapy together with central pathology review were included into the study. Patients with very low RS of below 12 and up to 3 positive lymph nodes were recommended to omit chemotherapy based on the low genomic recurrence risk. Chemotherapy was omitted in about 15% of all patients. For the first time we present prospective data comparing a genomical tool (Oncotype Dx) and an independent central pathology review for grade, ER, PR, and Ki-67 from a large phase III study combined with an exploratory analysis on early relapse risk. What are the main findings? Dr. Gluz: The study has two major findings: We have found a significant discordance in risk assessment between prognostic tools (grade by local and central lab, Oncotype Dx, Ki-67). Patients treated by endocrine therapy alone based on very low Recurrence Score had an excellent disease free survival of 97% after 3 years of follow up. (more…)
Author Interviews, Genetic Research, MD Anderson, Nature, Prostate Cancer / 01.03.2016 Interview with Dr. Dingxiao Zhang Ph.D Department of Epigenetics and Molecular Carcinogenesis University of Texas MD Anderson Cancer Center Smithville, TX 78957, USA What is the background for this study? What are the main findings? Dr. Zhang: Prostate cancer (PCa) is a heterogeneous malignancy harboring phenotypically and functionally diverse subpopulations of cancer cells. To better understand PCa cell heterogeneity, it is crucial to dissect the biology of normal prostate epithelial lineages. The background for the current study is to annotate the gene expression profiles of normal prostate epithelial cells, through which we hope to gain insight on Prostate cancer subtypes and the cellular heterogeneity in PCa. The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. In this study, we have performed a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. One of our major findings is that the differential gene expression profiles in basal versus luminal prostate epithelial cells account for their distinct functional properties. Specifically, basal cells preferentially express gene categories associated with stem cells, MYC-transcriptional program, neurogenesis, and ribosomal RNA (rRNA) biogenesis regulated by Pol I. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene expression profile is enriched in advanced, anaplastic, castration-resistant, and metastatic prostate cancers. Therefore, we link the cell-type specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features. (more…)
Author Interviews, Genetic Research, Sleep Disorders / 28.02.2016 Interview with: Alice Gregory PhD Department of Psychology Goldsmiths, University of London London, UK Medical Research: What is the background for this study? What are the main findings? Dr. Gregory: Sleep paralysis involves a total inability to move just as someone is falling asleep or waking up. This experience typically ends within seconds to minutes and is not usually a sign of any wider problem – yet it can be extremely frightening. This is in part because this experience is often accompanied by hallucinations. To understand what is happening during episode of sleep paralysis it is useful to understand that there are different stages of sleep. One distinction is between Rapid Eye Movement (REM) and Non-Rapid Eye Movement (NREM) sleep. During REM sleep the body is paralysed. Dreaming often occurs during REM sleep, so it has been proposed that this paralysis keeps us safe, by preventing us from ‘acting out our dreams’. During an episode of sleep paralysis, someone may have woken up but has retained certain features of REM sleep (specifically the paralysis and sometimes dream-related hallucinations). While sleep paralysis is rather common and the public seem incredibly interested in learning more about this, it is surprising that there is such little research on this topic. Certain risk factors for sleep paralysis have been proposed previously, such as experiencing stress. However, those suffering from this experience are keen for more information, which is currently unavailable. For this reason, we wanted to see whether we could identify other factors which were associated with sleep paralysis. Furthermore, in reviewing the literature, we were stunned that while it seems obvious that genetic differences between people are likely to be important in explaining why certain people experience sleep paralysis and others do not – there was almost no work on this topic. We decided to investigate this further as well. (more…)
Author Interviews, Genetic Research, UCLA / 26.02.2016 Interview with: April D. Pyle PhD Associate Professor, Microbiology, Immunology & Molecular Genetics Molecular Biology Institute Center for Duchenne Muscular Dystrophy Edythe Broad Center of Regenerative Medicine and Stem Cell Research University of California, Los Angeles, CA Medical Research: What is the background for this study? What are the main findings? Dr. Pyle: We have developed a CRISPR/Cas9 gene editing platform that is applicable for approximately 60 percent of Duchenne muscular dystrophy patients. Duchenne is a devastating muscle wasting disorder affecting approximately1 in 5000 boys worldwide. It is caused by lack of the dystrophin protein. In our study, we demonstrate that we can restore the dystrophin reading frame by deleting up to 725kb of the DMD gene between exons 45 and 55, the largest deletion shown to date in this gene, which results in a functional dystrophin protein being expressed. We demonstrated feasibility of this platform in Duchenne patient-derived human induced pluripotent stem cells differentiated to skeletal and cardiac muscle cells. (more…)
Author Interviews, Breast Cancer, Genetic Research, JAMA / 25.02.2016 Interview with: Dr. Shoshana Rosenberg ScD, MPH Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts Medical Research: Why would BRCA testing rates have increased among younger women with cancer?   Dr. Rosenberg: There has been increasing awareness surrounding genetic testing for breast cancer in more recent years, likely contributing to the trend that we saw over time  in our cohort. This has included more media attention, most notably Angelina Jolie’s sharing her story in 2013. Medical Research: Is this increase in testing a good thing? Dr. Rosenberg: Young women who are diagnosed with breast cancer should be getting tested so the fact that an increasing proportion of women have been undergoing BRCA testing in recent years indicates patients (and the physicians who treat them) are following recommendations. (more…)
Author Interviews, Clots - Coagulation, Genetic Research, Heart Disease, JACC / 23.02.2016 Interview with: Professor Keith AA Fox Duke of Edinburgh Professor of Cardiology University of Edinburgh Medical Research: What is the background for this study? Prof. Fox: From previous reports, certain alleles of CYP2C19 are associated with reduced enzymatic function and reduced conversion of clopidogrel to the active metabolite. Patients carrying these reduced function alleles (reduced metabolizers) exhibit higher platelet reactivity when treated with clopidogrel, compared with patients without reduced-function alleles (extensive metabolizers). However, the relationship of CYP2C19 genotype and outcomes in medically managed patients with acute coronary syndromes (ACS) is not known. Medical Research: What are the main findings? Prof. Fox: There was no association between CYP2C19 metabolizer status (EM vs. RM) and the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio [HR]: 0.86). EM and RM patients had similar rates of the primary endpoint whether treated with prasugrel (HR: 0.82) or clopidogrel (HR: 0.91; p for interaction non significant). (more…)
Author Interviews, Autism, Genetic Research / 23.02.2016 Interview with: Li ZENG, Ph.D. Principal Investigator Neural Stem Cell Research Lab National Neuroscience Institute Singapore Medical Research: What is the background for this study? What are the main findings? Dr. Zeng: Autism Spectrum Disorders (ASDs) are a group of highly inheritable behavioural disorders that pose major personal and public health concerns. Patients with ASDs have mild to severe communication difficulties, repetitive behaviour and social challenges. Such disorders significantly challenge an individual’s ability to conduct daily activities and function normally in society. Currently there are very few medication options that effectively treat ASDs. Therefore, there is a need to better understand the biology of that produces Autism Spectrum Disorder symptoms. In the study, we found how one brain-specific microRNA (miR-128) plays a key role in causing abnormal brain development. MicroRNAs are small molecules that regulate gene expression in the human body to ensure proper cellular functions. Although it was known that miR-128 is misregulated in some patients with autism, what that meant and how it functioned was not known. We showed that miR-128 targets a protein called PCM1 that is critical to the cell division of neural precursor cells (NPCs). NPCs during early brain development have two fates - they either stay as NPCs and undergo self-renewal or become neurons through differentiation. The dysfunctional regulation of PCM1 by misregulated miR-128 impairs brain development, which may underlie brain size changes in people with Autism Spectrum Disorders. (more…)
Author Interviews, Genetic Research, JNCI, Melanoma / 21.02.2016 Interview with: Nancy E. Thomas, MD PhD Department of Dermatology, University of North Carolina Chapel Hill, NC 27599 Medical Research: What is the background for this study? Dr. Thomas: Melanoma had been thought for some time to arise from at least two causal pathways, a ‘chronic sun exposure pathway’ and a ‘nevus pathway’. However, the role of inherited genetic variation in development of melanoma along these pathways had not previously been studied. Thus, we chose to examine the association of SNPs in putative low-penetrance melanoma susceptibility loci with histologic markers of divergent pathways. Medical Research: What are the main findings? Dr. Thomas: Within the large Genes, Environment and Melanoma Study, we investigated the relationship of germline variants in newly identified low-penetrance melanoma risk loci to histologic markers of divergent causal pathways in melanoma. We present strong evidence that the IRF4 rs12203592*T genotype is positively associated with chronic sun exposure-related melanoma and inversely associated with nevus-related melanoma. We also found that the IRF4 rs12203592 genotype is linked to the bi-model age distribution known to occur in melanoma and which is related to the divergent pathways. IRF4 rs12203592 is a functional variant known to affect IRF4 expression in human skin and melanoma cell lines. We conclude that IRF4rs12203592 is likely, at least in part, to determine pathway-specific risk for melanoma development. (more…)
Author Interviews, Cancer Research, Columbia, Genetic Research / 19.02.2016 Interview with: Jeanine D'Armiento, M.D., Ph.D. Associate Professor of Medicine in Anesthesiology Director of the Center for Molecular Pulmonary Disease in Anesthesiology and Physiology and Cellular Biophysics Director, Center for LAM and Rare Lung Disease New York, NY 10032 Medical Research: What is the background for this study? What are the main findings? Dr. D'Armiento: I am the Director of the Center for Lymphangiomyomatosis (LAM) and Rare Lung Disease at Columbia University; the Center focuses on this proliferative lung disease, which arises spontaneously or as the pulmonary manifestation of the Tuberous Sclerosis Complex (TSC). We have one of the largest cohorts of these patients in the country. Through an understanding of the pathogenesis of LAM our research aims to identify novel therapeutic targets of the disease to improve the care of these patients. Building on our previous research we demonstrated that the HMGA2 gene and its signaling pathway (the route of information which begins an action within cells), are required to produce tumors in the lung and kidneys in individuals with Tuberous Sclerosis Complex. (more…)
Author Interviews, Cannabis, Genetic Research, Memory / 17.02.2016 Interview with: Prof. Celia Morgan PhD Professor of Psychopharmacology University of Exeter  Medical Research: What is the background for this study? What are the main findings? Dr. Morgan: We know cannabis increases the risk of psychosis but it is unclear how we can predict who is vulnerable to these negative effects. This study suggested that cannabis may have stronger effects in people carrying a particular genetic variant. This might be related to their risk of developing psychosis. We also found that women are more susceptible to the short term memory impairing effects of cannabis. (more…)
Author Interviews, Genetic Research, Race/Ethnic Diversity, Science / 15.02.2016 Interview with: Michael Yudell, PhD, MPH Chair & Associate Professor Drexel University School of Public Health Community Health and Prevention Philadelphia, PA 19104 Medical Research: What is the background for this study? Dr. Yudell: We came together as a group of scholars from the natural sciences, social sciences, and humanities to address what we believe is a long-standing challenge: how to improve the study of human genetic diversity without recapitulating the controversial and problematic concept of race. We believe that the cross-disciplinary focus of our work—an examination of the historical, biological, and sociological aspects of the race concept—can shed new light on the long-standing debate about the use of the race concept in genetics research. We believe modern genetics remains stuck in a paradox: that on the one hand race is a tool to elucidate human genetic diversity, and on the other hand race is believedthree main concerns to be a poorly defined marker of that diversity and an imprecise proxy for the relationship between ancestry and genetics. This paradox is rooted in the nature of the field: it dates back to the evolutionary geneticist Theodosius Dozhansky, who in the 1930s redefined race in his work on what was known as biology’s evolutionary synthesis (the synthesis of population genetics with Darwinian thought). For much of his career, Dobzhansky believed race to be a useful tool to elucidate human genetic diversity. But by the end of his career he became worried that the study of human diversity had “floundered in confusion and misunderstanding” and was concerned over the nonscientific misuse of the term. He, like we and many others in genetics, anthropology, and the social sciences, have called on the field to devise better methods to improve the study of human genetic diversity. Can the race concept in genetics elucidate the relationship between humans and their evolutionary history, between humans and their health? In the wake of the human genome project the answer seemed to be a pretty resounding “no.” In 2004, for example, Francis Collins, then head of the National Human Genome Research Institute and now Director of the National Institutes of Health called race a “flawed” and “weak” concept and argued that science needed to move beyond race. Yet, as our paper highlights, the use of race persist in genetics, despite voices like Collins, like Craig Venter—leaders in the field of genomics-who have called on the field to move beyond it. They, of course, were not the first to do, but we hope they are among the last. We believe it is time to revisit this century-long debate and bring biologists, social scientists, and scholars from the humanities together in a to find better ways to study the ever-important subject of human diversity. (more…)
Author Interviews, Biomarkers, Genetic Research, Ophthalmology / 11.02.2016 Interview with: Dr Shi Song Rong PhD and Guy Li-Jia CHEN MBBS, MMed, MRCSEd (Ophth), PhD Assistant Professor Department of Ophthalmology & Visual SciencesPrince of Wales Hospital Faculty of Medicine The Chinese University of Hong Kong Medical Research: What is the background for this study? What are the main findings? Response: Glaucoma is a leading cause of irreversible blindness worldwide. Primary angle-closure glaucoma (PACG) as a major form of glaucoma accounts for about half of the cases blinded from the disease. So far, more than 50 genes/loci have been assessed for their associations with PACG and a wider spectrum of relevant conditions, primary angle-closure disease (PACD).  In the article, we summarize the statistical associations of individual genes varying across different study cohorts and conducted meta-analysis to evaluate the associations of 28 polymorphisms in 11 genes/loci with PACD and its subtypes, including PACG, primary angle-closure (PAC) and/or primary angle-closure suspect (PACS). Thus, we affirmed the association of PACG and combined PACS/PAC/PACG with 10 polymorphisms in 8 genes/loci as potential biomarkers. Among them 3 were identified in the genome-wide association study (COL11A1,PLEKHA7 and PCMTD1-ST18), and 5 (HGFHSP70MFRPMMP9 and NOS3) in candidate gene studies. (more…)
Author Interviews, Genetic Research, Kidney Disease / 10.02.2016 Interview with: Prof. Hirofumi Kai Kumamoto University Japan MedicalResearch: What is the background for this study? Dr. Kai: Alport Syndrome (AS) is a hereditary progressive kidney disease that affects 1 in 5000-10000 individuals in the US. Depending on the specific subtype and genetic mutation, the onset, symptoms and progression vary among patients. Some have earlier onset and severe phenotypes while others have slow progression towards end-stage renal disease (ESRD). The gene affected in  Alport Syndrome is type 4 collagen, which codes for a protein component of the glomerular basement membrane (GBM). This mutation leads to the dysregulated proliferation (or dysplasia) of the GBM, which has an important role in urine filtration. The pathophysiological process of dysplasia indicates a dysfunction of protein/s that control cellular homeostasis. Because the tumor suppressor p53 is critically involved in modulating cell proliferation, we focused our attention on this protein. (more…)
Author Interviews, Brain Cancer - Brain Tumors, Genetic Research, Pediatrics, University of Pennsylvania / 04.02.2016 Interview with: Dr. Adam C. Resnick, Ph.D Assistant Professor of Neurosurgery Faculty, Abramson Cancer Center Director of Children's Brain Tumor Tissue Consortium Division of Neurosurgery Director, CHOP/PENN Department of Neurosurgery Brain Tumor Tissue BiorepositoryDirector for Neurosurgical Translational Research, Division of Neurosurgery Children's Hospital of Philadelphia   Payal Jain, PhD Candidate Division of Neurosurgery, Children's Hospital of Philadelphia Department of Neurosurgery Cell and Molecular Biology Graduate Group Gene Therapy and Vaccines Program Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania   Medical Research: What is the background for this study? What are the main findings? Response: This study originates from our long-standing interest in studying pediatric low-grade gliomas (PLGGs), which are the most commonly diagnosed brain tumor in children. While several PLGGs have been found to harbor mutations/gene fusions driving the mitogen-associated protein kinase (MAPK) pathway leading to clinical trials testing MAPK inhibitors, these tumors remain poorly categorized and not enough is known about specific genetic mutations driving different tumor sub-types and the potential for specific targeted therapeutics. Our current study encompasses analysis of the largest combined genomic dataset of pediatric low-grade gliomas samples.  In doing this we, identified the MYB-QKI gene fusion, a non-MAPK related event, as the common genetic event driving a rare PLGG sub-type, called angiocentric gliomas. We have reported a novel tri-partite mechanism by which MYB-QKI mediates its oncogenic effect, this being the first report of a single gene rearrangement utilizing three different paths to cause cancer.
  • First, this gene rearrangement activates MYB, which is a proto-oncogene that is normally not expressed in the developed brain.
  • Second, we found that the rearrangement leads to translocation of QKI-related enhancers close to MYB’s promoters, thereby driving MYB-QKI expression in these tumors. Furthermore, MYB-QKI can also regulate its expression in a positive feedback loop.
  • Third, the tumor suppressor activities of QKI are disrupted in MYB-QKI. Such collaboration of genetic and epigenetic dysregulation in a single genetic rearrangement has previously not been reported.
Author Interviews, Genetic Research, JAMA, Schizophrenia / 04.02.2016 Interview with: Hannah J. Jones, PhD Centre for Academic Mental Health, School of Social and Community Medicine, Medical Research Council (MRC) Integrative Epidemiology Unit University of Bristol, Bristol, England MedicalResearch: What is the background for this study? What are the main findings? Dr. Jones: Schizophrenia is a highly heritable condition characterised by relatively diverse symptoms and frequent comorbid disorders. However, at present we don’t know how genetic risk for schizophrenia is expressed in children/adolescents in the general population. To investigate this, we studied data from individuals within the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort which consists of approximately 14,000 children born to women living in the former Avon Health Authority area in England with an expected delivery date from April 1, 1991, to December 31, 1992. We used genetic data from approximately 5,000 ALSPAC children and measures from adolescence relating to psychopathology to determine whether genetic risk for schizophrenia is associated with variation in psychotic experiences (e.g. delusions, hallucinations), negative symptoms (e.g. apathy, withdrawal), depressive disorder and anxiety disorder during this developmental period. We derived a score of genetic risk for schizophrenia in each individual within our study. This score is normally distributed such that most people have some genetic risk and a few people have very high or very low genetic risk. We found very weak evidence of an association between genetic risk for schizophrenia and psychotic experiences in adolescence and no evidence of an association with depressive disorder. However, we found strong evidence of association between genetic risk for schizophrenia and negative symptoms and anxiety disorder.  (more…)
Author Interviews, Genetic Research, JAMA, Pediatrics, Surgical Research / 03.02.2016 Interview with: Silje Steinsbekk PhD Associate Professor Dept. of Pschology Norwegian University of Science and Technology  Medical Research: What is the background for this study? Dr. Steinsbekk:  More than every third American child is overweight or obese. Childhood obesity is associated with multiple negative health outcomes such as metabolic syndrome and hypertension, as well as mental health problems, reduced self-esteem and impaired quality of life. Further, overweight and obesity tend to persist from childhood into adulthood, and the risk of adult overweight increases the longer a child has been overweight. Identifying modifiable factors contributing to the development and continuity of unhealthy weight is therefore needed. Genome-wide association studies (GWAS) have identified genetic risks for obesity and these genetic risks have shown to influence development of obesity partly by accelerating weight gain in childhood. Identification of mechanisms through which genetic risks for obesity accelerate weight gain in childhood can therefore provide insight into the developmental pathogenesis of obesity and thus inform intervention. Cross-sectional studies suggest appetite traits as a candidate mechanism. Appetite traits may therefore be targets of intervention to protect children against the effect of genetic predispositions to develop obesity. However, such a preventive approach presupposes that appetite traits indeed transmit the genetic effect upon later development of obesity. Notably, cross-sectional studies cannot establish whether appetite traits precede the development of obesity or are caused by it—a critical piece of information for clinicians seeking treatment targets to prevent childhood obesity. We therefore aimed to test whether genetic risk for obesity was associated with rapid childhood BMI growth and if this genetic effect was mediated by appetite traits, following a representative sample of Norwegian children from age 4 to 8. (more…)
Author Interviews, Genetic Research, JAMA, Pediatrics, Weight Research / 02.02.2016 Interview with: Profa. Patrícia Pelufo Silveira, MD, PhD Universidade Federal do Rio Grande do Sul Brazil Medical Research: What is the background for this study? What are the main findings? Response: Previous studies have shown that women who carry a certain gene variant (namely the 7-repeat allele of the dopamine type 4 receptor) have increased risk for obesity, especially if they also suffer from eating disorders. We have also demonstrated that girls who have this gene variant prefer to eat more fat when allowed to choose. However, for some neuropsychiatric conditions, this gene was shown to function as a “plasticity gene”. That is to say that being a carrier makes the individual more or less vulnerable to the disease, depending if the environment in which the person lives is bad (more risk) or good (less risk for the disease). This is called the “differential susceptibility” model. Therefore, in this paper, we wondered if the above described higher fat intake already reported in 7-repeat girls could be modified by the social environment in which they are raised. We saw that if a girl has the gene variant and is raised in a poorer environment, she is more likely to prefer to eat fat in her diet as we knew. However, if she has the gene variant but is raised in a better socioeconomic environment, she actually eats less fat in her regular diet compared to her counterparts who do not carry the gene variant. This is important because we change the focus from the gene (previously "blamed" for increasing fat preference and obesity as the years pass by) to the environment, as the genetic association will increase or decrease the risk according to the conditions in which the child is raised. (more…)
Author Interviews, Dermatology, Gastrointestinal Disease, Genetic Research / 01.02.2016 Interview with: Alexander Egeberg, MD PhD National Allergy Research Centre, Departments of Dermato-Allergology and Cardiology Herlev and Gentofte University Hospital University of Copenhagen Hellerup, Denmark Medical Research: What is the background for this study? What are the main findings? Dr. Egeberg: A recent genome-wide association study (GWAS) identified 90 shared genetic regions associated with celiac disease, type 1 diabetes mellitus, multiple sclerosis, and rheumatoid arthritis, respectively. Similarly, a newly published GWAS identified shared risk loci between rosacea, type 1 diabetes, and celiac disease. In the present study of 6,759 patients with rosacea and 33,795 control subjects, rosacea was associated with a 2 to 3-fold higher risk of these four conditions, particularly among women. (more…)
Author Interviews, Autism, Genetic Research, JAMA, Schizophrenia / 30.01.2016 Interview with: Andrea J. Gonzalez-Mantilla, M.D. Postdoctoral Fellow Andres Moreno-De-Luca, M.D. Investigator I Autism & Developmental Medicine Institute Department of Radiology Geisinger Health System Danville, PA 17822 Medical Research: What is the background for this study? What are the main findings? Response: Developmental brain disorders (DBD), such as autism, intellectual disability, and schizophrenia are a group of heterogeneous conditions characterized by deficits that affect multiple functional domains, such as cognition, behavior, communication, and motor skills. Previous studies provide strong evidence of common underlying molecular pathways and shared genetic causes among apparently different DBDs. Large-scale genomic studies of individuals with developmental brain disorders have found that identifying multiple, independent de novo pathogenic loss-of-function (pLOF) variants in the same gene among unrelated individuals is a powerful statistical approach to reliably identify disease-causing genes. However, genomic data from smaller cohorts and case reports are not routinely pooled with data from larger studies. Moreover, most previous studies have been restricted to cohorts of individuals ascertained based on a single diagnosis (e.g., a study will focus on only individuals with a diagnosis of autism and not consider other genomic data from individuals with a different diagnosis). Therefore, genomic data from individuals across DBD are not being jointly analyzed in search of pLOF variants in the same gene that may help build evidence for a causative role in developmental brain disorders. In this study, we carried out data mining of previously published data to identify genes related to the DBD phenotype. We expanded the aforementioned method and developed a multilevel data-integration approach, which capitalizes on three genotype-phenotype data sources: (1) genomic data from structural and sequence pLOF variants, (2) phenotype data from six apparently distinct DBD (autism, intellectual disability, epilepsy, schizophrenia, bipolar disorder and attention-deficit/hyperactivity disorder), and (3) data from large scale studies, smaller cohorts, and case reports. We identified 241 candidate genes for developmental brain disorders, including 17 genes that had not previously been associated with developmental brain disorders. (more…)
Author Interviews, Cancer Research, Genetic Research, PNAS / 28.01.2016 Interview with: Nina Bhardwaj, MD, PhD and Director of Immunotherapy and professor of Hematology and Medical Oncology Benjamin Greenbaum, PhD Assistant Professor The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai   Medical Research: How did the discovery of the group of non-coding RNA molecules in cancer cells that sets off an immune response come about? Dr. Greenbaum: Our work is a collaboration between my lab, which is computational, and the Bhardwaj lab, focused on cancer immunology. I had previously made the observation that certain RNA viruses were avoiding certain motifs, such as CpG dinucleotide containing motifs, and the Bhardwaj lab tested whether those motifs could set off an immune response. Recent work had shown that tumors transcribe unusual RNA with immunological consequences, so we investigated whether the same sort of approaches we had used for viral RNA worked here. Dr. Bhardwaj: It has recently become clear that, due to epigenetic alterations, tumors transcribe non-coding RNAs that are typically silenced. Often such RNA emanates from the “dark matter” genome. Many of these regions consist of repetitive elements and endogenous retroelements that are rarely transcribed in normal tissue. At the same time, due to immunotherapy, understanding the role of the immune system and immune activation in tumors has become critically important. The activation of specific elements of the innate immune system in a tumor may have either beneficial or detrimental effects for patients. Moreover, recent work has suggested that endogenous element activation can lead to improved immunotherapy outcomes. Therefore, it is critically important to understand the nature of innate immune activation in tumors and what triggers are responsible for these responses. We have been developing methods to detect abnormal patterns in viral RNA that may indicate activation of the innate immune system. We have found that patterns of motif usage avoided in the evolution of viruses, such as influenza, indicate RNA features that provoke an innate immune response. The innate immune system is capable of sensing motifs in viruses. We tested directly whether these avoided patterns are immunostimulatory. Medical Research: What are the main findings? Dr. Bhardwaj: We used a novel quantitative approach, derived from methods in statistical physics, to characterize all of the non-coding RNA transcribed by normal tissue and compared them to the non-coding RNA found in tumors. We found that while the non-coding RNA transcribed in normal tissue displays patterns of motif usage consisting with that of coding RNA, the RNA transcribed in tumors, yet rarely found in normal tissue, can have motif usage more typically associated with viral and bacterial genomes. We predicted a handful of such RNA are immunostimulatory and validated this prediction in antigen presenting cells. We then showed that this sensing may come from a subset of the innate immune system associated with pathogen RNA sensing. We called these RNA “i-ncRNA”, for immunostimulatory non-coding RNA. (more…)