Author Interviews, Genetic Research, Weight Research / 08.12.2017

MedicalResearch.com Interview with: David Meyre PhD Associate Professor, McMaster University, Dept. of Health Research Methods, Evidence, and Impact Hamilton, Ontario Canada Visiting Professor, University of Lorraine, Inserm Nutrition-Genetics-Environmental Risks MedicalResearch.com: What is the background for this study? What are the main findings? Response: While the average body mass index has reached a plateau in Western countries such as the United States, extreme forms of obesity are still on the rise. The origins of super obesity are still poorly understood. We studied the effects of 37 well-established obesity genes on body-mass index in 75,230 adults with European ancestry using innovative statistical methods (conditional quantile regression and meta-regression models). We found that nine of the 37 genes (24%) make individuals gain more weight if they already have a high body mass index. The effect of these genes is amplified by four times, if we compare the 10% of the population at the low end of the body mass index, compared to the 10% at the high end. The plausible explanation is that there are interactions between these snowball obesity genes and risk environmental factors. (more…)
Author Interviews, Genetic Research, Weight Research / 05.12.2017

MedicalResearch.com Interview with: “Scale model” by brett jordan is licensed under CC BY 2.0William Barrington, PhD lead author on the study Recently graduated PhD student from the Threadgill lab David Threadgill, PhD Texas A&M College of Medicine and College of Veterinary Medicine & Biomedical Sciences, senior author MedicalResearch.com: What is the background for this study? What are the main findings? Response: Obesity and diet-induced diseases, such as cardiovascular disease, have reached epidemic proportions. The United States has offered universal dietary recommendations for decades, but they have been largely unsuccessful in reducing diet-induced diseases. These recommendations are largely built upon population-level data, which examines a large number of individuals and determines the average response to a dietary intervention. However, if there is large variation in responses within a population, then population-level data may be inadequate to improve health across genetically diverse individuals. Our study used four genetically diverse types of mice to examine how one’s genetics interact with diet to influence obesity and risk factors for cardiometabolic disease. The study compared four popular human diets (American, Mediterranean, Japanese, and Maasai/ketogenic). While all mice suffered detrimental effects from the American diet, the severity of disease varied widely across the types of mice. In comparison, no single diet improved health across all strains, but there was one or more diets that improved health in each strain. (more…)
Author Interviews, Dermatology, Genetic Research / 04.12.2017

MedicalReseaerch.com Interview with: Alicia R. Martin PhD, Postdoc Department of Genetics Stanford University Department of Medicine, Massachusetts General Hospital and Harvard Medical School Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA and Brenna M. Henn, Phd, Assistant Professor Department of Ecology and Evolution SUNY Stony Brook, NY  MedicalResearch.com: What is the background for this study? What are the main findings? Response: Skin pigmentation varies more in Africa than in any other continent, and yet genetic studies of this and other traits are massively underrepresented there. Previous Eurasian study biases have instead focused on populations that vary less and have fewer variants contributing to baseline skin color. In our study, we compiled quantitative skin color measurements from a large, globally diverse set of individuals and populations to show that pigmentation varies more closer to the equator than in high latitude populations. We focused on the ‡Khomani San and Nama populations from South Africa, which diverged early along the modern human lineage from other populations and have lighter skin than equatorial Africans. We showed that skin pigmentation is roughly 100% heritable, but that previously identified genes make up a tiny fraction (~10%) of the variation present in these populations. We identified both known and new genes contributing to this variability. (more…)
Author Interviews, Genetic Research, Heart Disease, JAMA, Lipids / 15.11.2017

MedicalResearch.com Interview with: Hao Yu Chen, MSc Department of Medicine McGill University Montreal, Quebec, Canada Senior author: George Thanassoulis, MD, MSc MedicalResearch.com: What is the background for this study? Response: Aortic stenosis, a narrowing of the main valve of the heart, is the most common type of valve disease in the US. Present in more than 2.5 million individuals in North America, aortic stenosis can lead to heart failure and death. However, there is little known about the causes of aortic stenosis and how it should be treated. Previously, we have demonstrated that variants of the gene LPA are associated with the development of aortic stenosis. A better understanding of how this region contributes to aortic stenosis could identify higher-risk individuals and inform the development of new medical therapies for aortic stenosis.  (more…)
Author Interviews, Autism, Genetic Research, Nature / 12.11.2017

MedicalResearch.com Interview with: Woo-Yang Kim, Ph.D Associate Professor Department of Developmental Neuroscience Munroe-Meyer Institute University of Nebraska Medical Center Omaha, NE 68198-5960 MedicalResearch.com: What is the background for this study? What are the main findings? Response:  Autism impairs the ability of individuals to communicate and interact with others. About 75 percent of individuals with autism also have intellectual disability, which is characterized by significant limitations in cognitive functions and adaptive behaviors. While autism and intellectual disability are currently defined using behavioral criteria, little is known about the neuropathogenesis of these conditions. Recent genetic studies have reported that haploinsufficiency of ARID1B causes autism and intellectual disability. However, the neurobiological function of ARID1B during brain development is unknown. Our study investigated the neurobiological role of the gene in brain development. Using genetically-modified mice, we found that Arid1b haploinsufficiency leads to an excitation-inhibition imbalance by reducing the number of GABAergic interneurons in the cerebral cortex. Furthermore, we showed that treatment with a GABAA-receptor positive allosteric modulator rescues ASD-like behavior and cognitive dysfunction in Arid1b-haploinsufficient mice, suggesting an association between lower numbers of GABAergic interneurons and behavioral outcomes. Our findings suggest a pathogenic mechanism for Autism Spectrum Disorder and intellectual disability. (more…)
Abuse and Neglect, Author Interviews, Genetic Research, OBGYNE, Pediatrics / 10.11.2017

MedicalResearch.com Interview with: Professor Sir Nicholas Wald FRCP FRS Professor of Preventive Medicine Wolfson Institute of Preventive Medicine 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: Prenatal screening for Down’s syndrome (trisomy 21), Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) by maternal plasma DNA analysis has an improved screening performance compared with conventional screening but is too expensive to be performed routinely and has a technical failure rate. The aim of the study was to take advantage of the improved screening performance of the DNA analysis in conjunction with the existing methods thereby providing a seamless testing interface between the “old” and the “new” methods that would detect a larger proportion of affected pregnancies with a much lower false-positive rate, at a much reduced cost compared with universal DNA testing and with no failed tests. The novel approach was to conduct a conventional screening test using a screening cut-off level that identifies about 10% of women with the highest risks of having an affected pregnancy (much higher than in conventional screening) and then to perform a DNA test using a portion of the original blood sample collected for the conventional test. Progressing to the DNA test was automatic for these high risk women without their having to be recalled for counseling and a fresh blood sample (ie as a reflex response hence the term “reflex DNA screening”). (more…)
Author Interviews, Genetic Research, Ophthalmology / 07.11.2017

MedicalResearch.com Interview with: Dr. Stephen M. Rose, PhD Chief Research Officer Foundation Fighting BlindnessDr. Stephen M. Rose, PhD Chief Research Officer Foundation Fighting Blindness Dr. Rose discusses the FDA advisory panel unanimously recommended approval of Spark Therapeutics' Gene Therapy Luxturna  for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal dystrophies, a group of rare blinding conditions caused by one of more than 220 different genes. MedicalResearch.com: Would you tell us a little about IRD? Whom does it affect and how?  How common is this disorder? Response: The retina at the back of the eye is responsible for collecting light and turning it into signals that are transmitted to the brain and interpreted as vision. Think of the retina as the film in a camera, or more recently the sensor at the back of a digital camera. Inherited rare retinal degenerations are when the retina at the back of the eye deteriorates and loses its ability to capture light, thereby leading to blindness. iRDs can affect anyone, no matter race or ethnicity. These are inherited conditions that are passed down from parents to children, if a parent or both parents are either affected already or are carriers for a variant in any of the over 250 genes responsible for retinal degeneration. There are over 15 different types of iRDs, with retinitis pigmentosa being the most common with a US affected population around 100,000. The rest of the iRDs make up another approximately 100,000 affected individuals in the US, so there are about 200,000 total affected individuals in the US. Worldwide these iRDs affect somewhere around one to two million individuals. (more…)
Alzheimer's - Dementia, Author Interviews, Cognitive Issues, Genetic Research, Nature / 07.11.2017

MedicalResearch.com Interview with: Dr Miguel Chillon PhD Department of Biochemistry and Molecular Biology Universitat Autonoma Barcelona Spain MedicalResearch.com: What is the background for this study? What are the main findings? Response: Klotho is a protein with an anti-aging and neuroprotective role. Recent studies show it prevents the development of cognitive problems associated with aging and Alzheimer's disease. Klotho works mainly by inhibiting the insulin / IGF-1 signaling pathway and decreasing the damage caused by oxidative stress in the brain. One of the latest results revealed that the concentration of Klotho in cerebrospinal fluid is significantly lower in Alzheimer's patients than in human controls of the same age; and it is lower in the elderly with respect to young adults. Our study used a gene therapy strategy to introduce the Klotho gene into the Central Nervous System of adult animals. With just a single injection of the Klotho gene, young adult animals were protected over time from the cognitive decline associated with aging in old animals. These exciting results pave the way to further advances in research and the development of a neuroprotective therapy based on Klotho. (more…)
Author Interviews, Dental Research, Genetic Research / 07.11.2017

MedicalResearch.com Interview with: “Dental Mold_002” by Ano Lobb is licensed under CC BY 2.0Alexandre R. Vieira, DDS. MS, PhD Professor, Director of Clinical Research,  Director of Student Research Department of Oral Biology Center for Craniofacial and Dental Genetics Department of Pediatric Dentistry School of Dental Medicine Department of Human Genetics Graduate School of Public Health Clinical and Translational Sciences Institute University of Pittsburgh  MedicalResearch.com: What is the background for this study? What are the main findings? Response: One aspect is the dilemma between continuing to use dental amalgams and the perception that composite resins are not as durable. We show that composite resin restorations can perform similarly to dental amalgams for the first 5 years. But the most remarkable is that composite resin failures may be related to certain individual risk factors, such as genetic variation. (more…)
Aging, Author Interviews, Gender Differences, Genetic Research / 02.11.2017

MedicalResearch.com Interview with: Dr Mandy Peffers BSc MPhil PhD BVetMed FRCVS Wellcome Trust Clinical Intermediate Fellow Institute of Ageing & Chronic Disease Faculty of Health & Life Sciences University of Liverpool Liverpool UK MedicalResearch.com: What is the background for this study? Response: The project was an extension of Louise Pease’s MSc research project in bioinformatics which aimed to re-analyse existing RNA-seq data to determine age related changes in gene expression in musculoskeletal tissues that may lead to the development of degenerative diseases.  From existing literature we identified that degenerative diseases such as osteoarthritis and tendinitis were more prevalent in females and became more frequent following menopause.  We looked at the biology of the cohort we were trying to assess and discovered a gender imbalance, we hypothesised that this was why few results had been obtained from the original analysis. So we developed a research proposal that detailed extending the existing data to publicly available data and merging the experiments; to increase the number of replicates available and balance the experimental design.  We conducted multiple analyses and discovered that splitting samples by age and gender obtained the most significant results, and that whilst in a lot of cases the same genes were being differentially expressed, they were changing in opposite directions.  Louise remembered her statistics lecturer Gerard Cowburn (Ged) taught her about the assumptions of statistical tests, in particular covariance analysis (which has previously been used to show that age and gender do not affect gene expression) assumed that under the conditions being tested data points were not opposites.  Realising that this assumption had been violated by the data she began to think about what other assumptions we were working with and how to test their validity. (more…)
Author Interviews, Genetic Research, PLoS / 07.10.2017

MedicalResearch.com Interview with: Colin Sharpe School of Biology Institute of Biomolecular and Biomedical Science School of Biological Sciences University of Portsmouth Portsmouth, United Kingdom  MedicalResearch.com: What is the background for this study? What are the main findings? Response: We have long been fascinated by the question of what underpins the increasing complexity of multicellular animals. In a recent publication we looked at changes to the diversity of the NCoR family corepressors (NCoRs) across the Deuterostomes and found an increase in diversity from sea urchins to humans (1). This is due to gene duplication, an increase in alternative splicing and the encorporation of more protein motifs and domains. In this study we devised a measure of functional diversity based on these three factors and calculated this value for over 12000 genes involved in transcription in nine species from the nematode worm to humans. Orthologues whose increase in diversity correlated with the increase in complexity of these animals were then selected and we looked for common features and interactions between the selected genes. We found that proteins that regulate the dynamic organisation of chromatin were significantly enriched within the selection. (more…)
Author Interviews, Clots - Coagulation, Genetic Research, JAMA, Surgical Research / 04.10.2017

MedicalResearch.com Interview with: Anne R. Bass, MD Associate Professor of Clinical Medicine Weill Cornell Medical College Rheumatology Fellowship Program Director Hospital for Special Surgery New York, NY 10021 MedicalResearch.com: What is the background for this study? Response: Blood thinners are used after orthopedic surgery to prevent blood clots from forming in the legs and traveling to the lungs. They are also used in patients with certain heart diseases to prevent strokes. Blood thinners, like warfarin, are effective but can be associated with serious bleeding complications, especially if the wrong dose is given. Genetic testing can help doctors predict the right warfarin dose to use in an individual patient. In this trial, ≈1600 elderly patients undergoing hip or knee replacement were randomly assigned to receive warfarin dosing based on genetics plus clinical factors (like height, weight and gender), or based on clinical factors alone. The specific genes tested wereVKORC1, CYP2C9, and CYP4F2 which influence warfarin metabolism and the body’s ability to produce clotting factors. (more…)
Author Interviews, Columbia, Genetic Research / 29.09.2017

MedicalResearch.com Interview with: Carlos Eduardo G. Amorim PhD Columbia University Department of Systems Biology Irving Cancer Research Center  MedicalResearch.com: What is the background for this study? Response: More generally, we were interested in understanding the determinants of the frequencies of mutations that cause disease in humans. More specially, we wanted to test if a long-standing theory in population genetics (namely mutation-selection balance) was a good explanation for the observed frequencies of disease mutations in humans. (more…)
Author Interviews, Autism, Genetic Research, JAMA / 27.09.2017

MedicalResearch.com Interview with: Sven Sandin, PhD Assistant Professor Department of Psychiatry Icahn School of Medicine at Mount Sinai New York, NY 10029  MedicalResearch.com: What is the background for this study? What are the main findings? Response: In 2014, we estimated the heritability of autism to be approximately 50%. Motivating us then was the lack of studies in autism heritability using population based and the findings from a twin-study in California finding the heritability to be substantially lower than the 80-90% estimated in previous studies. Since then continued efforts working with the questions on heritability and environmental factors for autism we found differences between different methods and different samples. When we went back to our previous data we found the heritability of autism to be higher than previously estimated. We found that our previous result was due to a methodological artifact where the adjustment for differences in follow-up used in that manuscript underestimated the heritability. Using methods used in other heritability studies the heritability is now estimated to 84%. Importantly, as previously concluded, there is no support for any ‘shared environmental factors’ in the etiology of autism, e.g. environmental factors shared between two siblings. (more…)
Author Interviews, Gender Differences, Genetic Research, Sexual Health / 22.09.2017

MedicalResearch.com Interview with: Steven Arnocky PhD Faculty of Arts & Science-Psychology Nipissing University Canada  MedicalResearch.com: What is the background for this study? What are the main findings? Response:  - Previous research has linked the facial width-to-height ratio to a number of testosterone-mediated traits, primarily in men, such as aggression and achievement drive. Some research has also linked FWHR to testosterone directly, although this research is less consistent. If testosterone is linked to cranio-facial development then we hypothesized that facial masculinization should therefore correlate with other testosterone-linked traits. In both men and women, there is good evidence that testosterone increases sexual motivation. In two samples of young-adults from two Canadian cities, we found that  facial width-to-height ratio predicted sex-drive, regardless of whether participants were male or female. In the second study (the larger of the two) we also found that FWHR predicted a more unrestricted sociosexual orientation, in other words, attitudes and behavior consistent with more pluralistic mating, as well as more intended infidelity. (more…)
Author Interviews, Diabetes, Flu - Influenza, Genetic Research / 19.09.2017

MedicalResearch.com Interview with: Paz Lopez-Doriga Ruiz MD, PhD candidate Norwegian Institute of Public Health Department of Non Communicable Diseases OsloPaz Lopez-Doriga Ruiz MD, PhD candidate Norwegian Institute of Public Health Department of Non Communicable Diseases Oslo  MedicalResearch.com: What is the background for this study? What are the main findings? Response: Some case reports have linked pandemic influenza to the development of type 1 diabetes. Other studies have suggested that also respiratory infections may contribute to type 1 diabetes risk.  Our findings supports a suggested role of respiratory infections in the etiology of type 1 diabetes and influenza virus could be a contributing factor to the development of clinical diabetes, due to stress and inflammation in predisposed individuals. (more…)
AHA Journals, Author Interviews, Genetic Research / 11.09.2017

MedicalResearch.com Interview with: Bengt Zöller, MD, PhD Associate professor in Internal Medicine Specialist Physician in Clinical Chemistry Specialist Physician in Family Medicine Lund University/ Region Skåne Center for Primary Health Care Research University Hospital, Malmö, Sweden MedicalResearch.com: What is the background for this study? Response: Previous studies have suggested an association between height and venous thromboembolism but association might be confounded. We therefore permed a Nationwide study including a cohort of siblings -a co sibling analysis to adjust for familial confounders (genetic and shared familial environmental factors). (more…)
Author Interviews, Genetic Research, Melanoma / 08.09.2017

MedicalResearch.com Interview with: Rutao Cui, MD/PhD Professor Vice Chair for Laboratory Administration Director, Laboratory of Melanoma Biology Department of Pharmacology and Experimental Therapeutics Professor of Dermatology Boston University Boston, Mass 02118 MedicalResearch.com: What is the background for this study? Response: Red-headed people are making up to 1~2% of the world’s population. They carry “red hair color” variants of MC1R (MC1R-RHC) which are responsible for their characteristic features, including red hair, pale skin, freckles and poor tanning ability. MC1R-RHC also increases risk of melanoma, the deadliest form of skin cancer. People without red hair but with a single copy of MC1R-RHC also have an increased melanoma risk, who may make more than 50% of the northern European population. It is unknown why redheads are more prone to melanoma, and whether the activity of red hair color variants could be restored for therapeutic benefits. (more…)
Author Interviews, Genetic Research, PLoS / 07.09.2017

MedicalResearch.com Interview with: Hakhamanesh Mostafavi, MS PhD student Department of Biological Sciences Columbia University  MedicalResearch.com: What is the background for this study? Response: We know very little about the genetic variants that underlie adaptation in humans. This is in part because we have mostly been limited to methods that search for footprints of ancient selection (that has acted for over thousands to millions of years) in the genomes of present-day humans; so by design are indirect and make strong assumptions about the nature of selection. These days, thanks to advances in genomic technologies, genetic data for large numbers of people is being collected, mostly for biomedical purposes. Accompanied by information on survival and reproductive success of these individuals, such large datasets provide unprecedented opportunities for more direct ways to study adaptation in humans. In this work, we introduced an approach to directly observe natural selection ongoing in humans. The approach consists in searching for mutations that change in frequency with the age of the individuals that carry them, and so are associated with survival. We applied it to around 210,000 individuals from two large US and UK datasets. (more…)
Alzheimer's - Dementia, Author Interviews, Gender Differences, Genetic Research, JAMA / 29.08.2017

MedicalResearch.com Interview with: Arthur W. Toga PhD Provost Professor of Ophthalmology, Neurology, Psychiatry and The Behavioral Sciences, Radiology and Engineering Ghada Irani Chair in Neuroscience Director, USC Mark and Mary Stevens Neuroimaging and informatics institute USC Institute for Neuroimaging and Informatics Keck School of Medicine of USC University of Southern California Los Angeles, CA  90032  MedicalResearch.com: What is the background for this study? What are the main findings? Response: The ε4 allele of the Apolipoprotein E (APOE) gene is the main genetic risk factor for late-onset Alzheimer's disease.  This study reexamines and corrects the sex-dependent risks that white men and women with one copy of the ε4 allele face for developing Alzheimer's disease using a very large data set of 57,979 North Americans and Europeans from the Global Alzheimer's Association Interactive Network (GAAIN). The study results show that these men and women between the ages of 55 and 85 have the same odds of developing Alzheimer's disease, with the exception that women face significantly higher risks than men between the ages of 65 and 75.  Further, these women showed increased risk over men between the ages of 55 and 70 for mild cognitive impairment (MCI), which is often a transitional phase to dementia. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease, Lipids, UCLA / 28.08.2017

MedicalResearch.com Interview with: Tamer Sallam, MD PhD Assistant Professor of Medicine Co-Director UCLA Center for Lipid Management Lauren B. Leichtman and Arthur E. Levine CDF Investigator Assistant Director, STAR Program Division of Cardiology, Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California 90095-1679 MedicalResearch.com: What is the background for this study? What are the main findings? Response: This study is extension of our previous work published in Nature showing that a gene we named LeXis (Liver expressed LXR induced sequence) plays an important role in controlling cholesterol levels. What is unique about  LeXis is that it belongs to a group of newly recognized mediators known as long noncoding RNAs. These fascinating factors were largely thought to be unimportant and in fact referred to as “junk DNA” prior the human genome project but multiple lines of evidence suggest that they can be critical players in health and in disease. In this study we tested whether we can use  LeXis “gene therapy”  to lower cholesterol and  heart disease risk. This type of approach is currently approved or in testing for about 80 human diseases. Our finding was that a single injection of LeXis compared with control significantly  reduced heart disease burden in mouse subjects. Although the effect size was moderate we specifically used a model that mimics a very challenging to treat human condition known as familial hypercholesterolemia..Familial hypercholesterolemia is one of the most common genetic disorders affecting up to 2 million Americans and characterized by 20 fold  fold increase risk of early heart attacks and often suboptimal response to currently available treatments. (more…)
Author Interviews, Genetic Research, JAMA, Pancreatic, Surgical Research / 25.08.2017

MedicalResearch.com Interview with: Nancy You, MD, MHSc, FACS Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston  MedicalResearch.com: What is the background for this study? What are the main findings? Response: This study was motivated by the emerging promise of precision medicine and the emerging evidence that immunotherapy may have phenomenal efficacy in particular molecular subtypes of cancers.  This specific molecular subtype shows deficiency in DNA mismatch repair mechanisms and therefore is thought to be more immunogenic.  DNA mismatch repair deficiency can arise from germline defects such as in the case of patients with Lynch Syndrome, an inherited cancer syndrome, or from epigenetic inactivation DNA mismatch repair genes. Overall, pancreas cancer has seen limited success with conventional chemotherapy.  In our study, we demonstrated that there is a particular molecular subtype of pancreas cancer that is characterized by defect in DNA mismatch repair genes and by microsatelie instability that has a different prognosis than other pancreas cancers.  This subtype of pancreas cancer is suspected to also respond to immunotherapy. (more…)
Author Interviews, Genetic Research, Nature / 29.07.2017

MedicalResearch.com Interview with: Dr. Zoltán Kutalik, PhD Group Leader Swiss Institute of Bioinformatics Assistant professor at the Institute of Social and Preventive Medicine MedicalResearch.com: What is the background for this study? What are the main findings? Response: Why do some of us live longer than others? While the environment in which we live – including our socio-economic status or the food we eat – plays the biggest part, about 20 to 30% of the variation in human lifespan comes down to our genome. Changes in particular locations in our DNA sequence, such as single-nucleotide polymorphisms (SNPs), could therefore hold some of the keys to our longevity. Until now, the most comprehensive studies had found only two hits in the genome. (more…)
Author Interviews, Genetic Research, Lancet, Ophthalmology / 17.07.2017

MedicalResearch.com Interview with: Stephen R. Russell, MD Dina J Schrage Professor of Macular Degeneration Research Service Director, Vitreoretinal Diseases and Surgery Professor of Ophthalmology and Visual Sciences The University of Iowa MedicalResearch.com: What is the background for this study? What are the main findings? Response: This study examines the efficacy (and safety) of treating children and adults with a form of retinitis pigmentosa known as RPE65-associated Lebers congenital amaurosis, with an adeno-associated viral vector(AAV) delivered RPE65 construct.  Building on successful phase 1/2b trials from multiple centers, the AAV-hRPE65v2 agent now designated as voretigene neparvovec, contains a highly optimized enhancing sequence and promoter. The main findings were an improvement on a multiple light level mobility test (MLMT) and multiple additional supportive secondary endpoints which included improvements in full-field light sensitivity, Goldmann visual field, and others. (more…)
Author Interviews, Genetic Research, Ophthalmology, University Texas / 07.07.2017

MedicalResearch.com Interview with: Stephen P. Daiger, PhD Professor, Human Genetics Center Thomas Stull Matney, Ph.D. Professor in Environmental and Genetic Sciences Mary Farish Johnston Distinguished Chair in Ophthalmology The University of Texas Health Science Center at Houston   MedicalResearch.com: What is the background for this study? What are the main findings? Response: Thanks for your questions about our research.  My research group and I have a long-term interest in finding genes and mutations causing inherited retinal diseases.  Our main focus is on retinitis pigmentosa (RP) and, more specifically, the autosomal dominant form of RP. Inherited retinal diseases are progressive, degenerative diseases of the retina.  Onset can be very early in life, even at birth, or much later in life.  As the degeneration develops an affected person may first experienced limited loss of vision, progressing to severe loss of vision, ending, in many cases, in legal or complete blindness.  About 300,000 Americans are affected by inherited retinal disease and 50% of these have RP.  RP, like most hereditary conditions, can be inherited in an autosomal dominant, autosomal recessive or X-linked fashion. One of the surprising, and in some sense, disturbing findings in studying  retinitis pigmentosa is that mutations in many different genes can cause this disease.  We now know that mutations in more than 80 genes can cause RP and thousands of different mutations have been found in these genes.  With next-generations sequencing it is possible to find the cause of RP in from 50% to 80% of cases, depending on the underlying mode of inheritance.For example, in our research we can find the disease-causing mutation in about 75% of families with autosomal dominant RP.  Needless to say, a primary aim of our research is to find the cause in the remaining 25%. In looking for the cause of retinitis pigmentosa in the remaining 25%, that is, those in whom mutations were not detected by earlier methods, we found a potential dominant-acting mutation in the arrestin-1 gene (gene symbol “SAG”) using whole-genome sequencing.  Molecular modeling suggests this mutation is damaging.  This was unexpected because previously-reported mutations in this gene were associated with Oguchi disease, a recessive retinal disease with symptoms distinct from RP.  On further testing our cohort of patients with autosomal dominant RP, we found this mutation in nearly 4% of families.  Even more surprisingly, when we looked closely at the affected families, and worked with our collaborators to test other patients, we discovered that all of the families with the dominant-acting SAG mutation -- 12 total -- were of Hispanic origin.  By interviewing informative family members we learned that these families have their roots in the Southwestern United States.  Historically, the mutation may have arisen hundreds of years ago, consistent with genetic variation tracking with the mutation. (more…)
Author Interviews, Eating Disorders, Genetic Research / 24.06.2017

MedicalResearch.com Interview with: Camron D. Bryant Ph.D Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry Boston University, Boston, MA MedicalResearch.com: What is the background for this study? What are the main findings? Response: We previously used genome-wide linkage analysis, fine mapping, gene validation, and pharmacological targeting to identify a negative regulatory role for the gene casein kinase 1-epsilon (Csnk1e) in behavioral sensitivity to drugs of abuse, including psychostimulants and opioids. Parallel human candidate genetic association studies identified an association between multiple genetic variants in CSNK1E with heroin addiction in multiple populations. Drug addiction is a multi-stage process that begins with the initial acute subjective and physiological responses that can progress to chronic administration, tolerance, and withdrawal. The recovery process begins with abstinence from drug taking but can quickly be derailed by relapse to drug taking behavior. Preclinical pharmacological studies also support a role for CSNK1E in reinstatement of opioid self-administration and relapse to alcohol drinking. Despite the evidence that disruption of Csnk1e gene and protein function can affect various behaviors associated with drug and alcohol addiction, it is unclear what stage of the addiction process these genetic and pharmacological manipulations modulate. In this study, we show that disruption of the Csnk1e gene resulted in an enhancement of the rewarding properties of the highly potent and addictive opioid, fentanyl.  Unexpectedly, we also discovered that disruption of Csnk1e also enhanced binge eating – but only in female mice. (more…)
Alzheimer's - Dementia, Author Interviews, Genetic Research / 22.06.2017

MedicalResearch.com Interview with: Mikko Hiltunen, PhD Professor of Tissue and Cell Biology University of Eastern Finland School of Medicine, Institute of Biomedicine Kuopio,  Finland  MedicalResearch.com: What is the background for this study? What are the main findings? Response:  We wanted to assess among the population-based METSIM (METabolic Syndrome In Men) cohort whether protective variant in APP gene (APP A673T) affects the beta-amyloid levels in plasma. The rationale behind this was that previous genetic studies have discovered that the APP A673T variant decreases the risk of having Alzheimer’s disease (AD). However, the protective functional outcome measures related to this variant were lacking and thus we anticipated that the elucidation of plasma samples in terms of beta-amyloid levels would provide the much needed link between APP A673T variant and potential protective functions. (more…)
Author Interviews, Cancer Research, Genetic Research / 22.06.2017

MedicalResearch.com Interview with: Antonis Antoniou PhD Reader in Cancer Risk Prediction Academic Course Director MPhil in Epidemiology Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care Strangeways Research Laboratory Cambridge University of Cambridge MedicalResearch.com: What is the background for this study? What are the main findings? Response: Several studies demonstrated that women with genetic faults in the BRCA1 and BRCA2 genes are at increased risk of developing breast and ovarian cancer. Having accurate age-specific cancer risk estimates for women with mutations is essential for their optimal clinical management. Most studies to date that estimated cancer risks for BRCA1 and BRCA2 mutation carriers have been "retrospective", in other words they look at what happened in the past. Estimates from such studies are prone to biases because they rely on the experience of women who have already developed cancer and on self-reported cancer family history information on relatives - which may have inaccuracies. The ideal epidemiological study design for estimating cancer risks are prospective studies.  In prospective studies, healthy women with genetic faults are followed over time and overcome these potential biases. However, to date, published  prospective studies have been very small. In the present study we used data from a prospective cohort of women with BRCA1 and BRCA2 mutations who were recruited from 1997 to 2011 and were followed over time. The study included almost 10,000 women who were included in the analyses, and was made possible through collaborations between scientists from Europe, North America and Australia.  The prospective study design explains why it has taken 20 years of hard work to get these results. Most importantly, it took an enormous long-term contribution and commitment from the women themselves to allow the scientists to be able to assemble this dataset. Here, we were able to estimate more precisely the breast and ovarian cancer risks for women with faults in BRCA1 and BRCA2.  These risk estimates will provide more confidence in the counseling and clinical management of women with faults in the BRCA1 and BRCA2  genes. A novel finding in this study is that breast cancer risk for women with faults in BRCA1 and BRCA2  increases rapidly at a young age then remains at a constant high level for the rest of their lives. It peaks in the 40’s for BRCA1 mutation carriers and in the 50’s for BRCA2 carriers, but  carriers of mutations in both genes  are at about the same high risk in later life. This is important information to inform the clinical management of older mutation carriers. This study also shows clearly that for women with a mutation, there are other factors that are important in modifying the breast cancer risk. The study has demonstrated that the extent of the woman’ family history of cancer and the exact place on the gene where her mutation is located are very important in determining the actual risk. (more…)
Author Interviews, Genetic Research, Nature, Scripps / 21.06.2017

MedicalResearch.com Interview with: Michael Farzan PhD Co-chair and Professor Department of Immunology and Microbiology Florida Campus The Scripps Research Institute Jupiter, Florida MedicalResearch.com: What is the background for this study? What are the main findings? Response: CRISPR is system for immune protection of bacteria.  It has now been widely adopted for use in editing mammalian cells.  The most commonly used CRISPR effector protein is Cas9.  Cas9 binds a guide RNA to recognize a DNA target, for example an incoming virus infecting a bacterium, or a gene in a human chromosome.  In bacteria, Cas9 requires a second protein to clear the guide RNA from a longer "CRISPR array", basically a string of guide RNAs. We have been studying a CRISPR effector protein related to Cas9 called Cpf1.  In bacteria it was know that, unlike Cas9, Cpf1 could cleave a CRISPR array by itself, without assistance from a second protein.  We knew that if it could do the same thing in human cells, it would help to simplify a number of gene-editing applications.  We were able to show that Cas9 could indeed excise multiple guide RNAs from a single message RNA in human cells.  We further showed that this approach was more efficient than the previous ways that guide RNAs were generated for gene editing, even more so when multiple guide RNAs were needed. (more…)
Author Interviews, Endocrinology, Genetic Research / 21.06.2017

MedicalResearch.com Interview with: Constantine A. Stratakis, MD, DMSci Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Bethesda MedicalResearch.com: What is the background for this study? Response: The pituitary and adrenal glands operate on a kind of feedback loop. In response to stress, the pituitary release ACTH (Adrenocorticotropic hormone), which signals the adrenal glands to release cortisol. Rising cortisol levels then act on the pituitary, to shut down ACTH production. In a previous study, Jacque Drouin of the Institute for Clinical Research in Montreal and colleagues had determined that the CABLES1 protein was a key player in this feedback mechanism, switching off pituitary cell division in cultures exposed to cortisol. Since this feedback mechanism appears to be impaired in many corticotropinomas, we investigated the presence of Cables1 gene mutations and copy number variations in a large group of patients with Cushing’s disease. (more…)