Author Interviews, Genetic Research, Personalized Medicine / 13.02.2015

Prof. Jozef GECZMedicalResearch.com Interview with: Prof. Jozef Gecz NH&MRC Senior Principal Research Fellow Professor of Human Genetics School of Paediatrics and Reproductive Health Faculty of Health Sciences The University of Adelaide at the Women's and Children's Hospital North Adelaide, SA Medical Research: What is the background for this study? What are the main findings? Prof. Gecz: Cerebral palsy is the most frequent movement disorder of children for many years considered to be due to brain injury. Given that cerebral palsy incidence has not changed dramatically over many years while medical care is constantly improving, we look for other causes and specifically genetic mutation. By investigating 183 children with cerebral palsy and for many also one or both of their parents we find that for at least 14% of these we can find plausible explanation in genetic mutation being involved in the causation of their cerebral palsy. Importantly, we find that 10% of these mutations are de novo, which means that these mutations are not present in the parents (specifically in their blood as that is the tissue source we tested). 4% of mutations were inherited from unaffected mothers to affected sons. Previous estimates suggested 2% genetic contribution to Cerebral palsy. We now know that it is at least 14% and likely more. If you are looking for compensation for this condition, contact an Indiana cerebral palsy lawyer.
Author Interviews, Genetic Research, Leukemia, NEJM, Personalized Medicine / 11.02.2015

David G. Kent, Ph.D From the Cambridge Institute for Medical Research and Wellcome Trust–Medical Research Council Stem Cell Institute University of CambridgeMedicalResearch.com Interview with: David G. Kent, Ph.D From the Cambridge Institute for Medical Research and Wellcome Trust–Medical Research Council Stem Cell Institute University of Cambridge Medical Research: What is the background for this study? What are the main findings? Dr. Kent: Cancers are the result of the sequential acquisition of errors in the genetic code.  Most studies have focused on the sum of these mutations (e.g., A+B+C = cancer) but no study in patients has asked the question of whether or not the order of genetic mutations impacts the disease (e.g., does A to AB equal B to BA).  We studied patients with chronic blood disorders (known as myeloproliferative neoplasms, or MPNs) that are precursors to cancer to access the earliest stages of tumour development and studied whether or not the order of mutation acquisition impacted disease.  We studied patients with mutations in two genes (JAK2 and TET2) and showed that the order of acquisition of these mutations impacted timing of clinical presentation, disease subtype, frequency of thrombotic events, and differed in their response to targeted therapy in the lab.
AHA Journals, Author Interviews, Genetic Research, Heart Disease / 10.02.2015

MedicalResearch.com Interview with: Wolfgang Sadee, Dr.rer.nat. Felts Mercer Professor of Medicine and Chair, Pharmacology Director and Elizabeth S Barrie, PhD Center for Pharmacogenomics The Ohio State University Columbus OH MedicalResearch: What is the background for this study? What are the main findings? Dr. Sadee and Dr. Barrie: We have determined that two frequent genetic variants can interact in a way that lowers the carrier’s risk for a heart attack. These genetic variants are single nucleotide polymorphisms (SNPs) - single base changes in the DNA sequence - of the dopamine-beta hydroxylase gene (DBH), which converts dopamine to norepinephrine. Both act as hormones in the periphery and as neurotransmitters vital to the brain's activity central nervous system. Numerous studies had tested genetic variants in DBH for effects on brain functions. In contrast to expectations, however, our work demonstrates that our two genetic variants lower DBH activity primarily in the periphery, in tissues with sympathetic innervation mediated by norepinephrine, such as the heart, lung, and liver.  As a result, we searched for genetic influence on risk of various diseases of the cardiovascular system and the lung, metabolic disorders, and more.   Each of the two DBH variants alone was associated with a number of disease states; however, when considering both variants in combination, a strong protective effect on the risk for heart attacks was discovered in several clinical trials. Such combined effects arising from interactions between two genetic variants may be more common than currently realized, possibly providing a path towards effective biomarker panels for personalized medicine.
Author Interviews, Genetic Research, JAMA, Personalized Medicine / 09.02.2015

Andres Moreno De Luca, MD Investigator and Resident Physician Autism & Developmental Medicine Institute Department of Radiology Geisinger Health System Danville, PA 17822MedicalResearch.com Interview with: Andres Moreno De Luca, MD Investigator and Resident Physician 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: The main finding of our study is that family background contributes to the variability in cognitive, behavioral, and motor performance seen in children with 16p11.2 deletions, and perhaps other genetic syndromes, and this may be attributed in part to genetic background effects. In the general population the best predictor of a child’s outcomes in traits such as cognitive ability, height, BMI, etc. is the biparental mean performance in such domains and this is due in part to genetic background. For example, if a child’s parents have IQ scores of 130 and 110, it is expected that the child will have an IQ within 2 standard deviations of 120 (bi-parental mean). However, when studying individuals with genetic conditions, most researchers tend to overlook the influence of familial/genetic background on the affected child’s outcomes and commonly attribute the manifestations (or lack thereof) to the genetic mutation alone. This creates confusion when studying children with neurodevelopmental disorders, such as autism, which show significant clinical variability, as some children with a specific genetic mutation (e.g. deletion 16p11.2) may have intellectual disability without autism, while other children with the same mutation may have autism without intellectual disability. Based on these observations, some researchers have argued that deletion 16p11.2 is incompletely penetrant. However, our study showed that the 16p11.2 deletion has a detrimental effect on cognitive and behavioral performance for all children, but the clinical status (affected vs. unaffected) and ultimate performance level is influenced by the parental performance.
Author Interviews, Genetic Research, Nature, Rheumatology / 06.02.2015

psoriasis_kneesMedicalResearch.com Interview with: Professor Anne Barton FRCP PhD and Dr John Bowes PhD Centre for Musculoskeletal Research and Centre for Genetics and Genomics, The University of Manchester, Manchester UK Medical Research: What is the background for this study? Response: Psoriatic arthritis (PsA) is an inflammatory condition causing pain and stiffness in joints and tendons. Approximately one third of patients with psoriasis will go on to develop PsA resulting in a reduction in their quality of life caused by increasing disability and additional health complications. A key area of research within the Arthritis Research UK Centre for Genetics and Genomics in the Centre for Musculoskeletal Research is the identification of risk factors for the development of Psoriatic arthritis; this will allow us to understand the underlying cause of disease and ultimately help identify psoriasis patients at high risk of PsA, allowing early treatment to be introduced to reduce the impact of PsA. Our study focuses on the identification of genetic risk factors for Psoriatic arthritis; we compared the frequency of genetic variants, referred to as single nucleotide polymorphisms (SNPs), between large numbers of DNA samples from patients with PsA and healthy control samples. When the frequency of the SNP is significantly different between cases and controls, the SNP is said to be associated with risk of developing Psoriatic arthritis and this association is interpreted as being important in the disease process. Medical Research: What are the main findings? Response: When we analysed the data from the study we found a new association to SNPs on chromosome 5, and when we investigated these SNPs for association with skin-only psoriasis, we did not find any evidence for association. In addition, we also found SNPs that were specifically associated with Psoriatic arthritis at a gene on chromosome 1. This gene is known to be associated with psoriasis, but our results show that there are different SNPs associated with PsA and psoriasis at this gene. Hence, our results identify new SNPs that are specifically associated with PsA. In addition, identifying which cells are the key drivers of inflammation in Psoriatic arthritis will help us to focus on how the genetic changes act in those cells to cause disease. Our results show that many of the PsA associated SNPs occur in regions of the genome that are important in the function of CD8+ cells,  an important cell type in the immune system.
Author Interviews, Genetic Research / 30.01.2015

Peter White, Ph.D. Principal Investigator, Center for Microbial Pathogenesis Director, Biomedical Genomics Core Director of Molecular Bioinformatics, The Research Institute at Nationwide Children's Hospital Assistant Professor of Pediatrics, The Ohio State UniversityMedicalResearch.com Interview with: Peter White, Ph.D. Principal Investigator, Center for Microbial Pathogenesis Director, Biomedical Genomics Core Director of Molecular Bioinformatics, The Research Institute at Nationwide Children's Hospital Assistant Professor of Pediatrics, The Ohio State University Medical Research: What is the background for this study? What are the main findings? Dr. White: Next generation sequencing has revolutionized genomics research and has opened the door to a new era of genomic medicine. It’s now possible to sequence a patients entire genome in about two days, but the output from the sequencer must go through multiple computationally challenging steps before it can be processed for clinically relevant information. The challenge we found is that this data analysis process was requiring days to perform, by highly qualified bioinformaticians and required enormous computational resources. To overcome the challenges of analyzing that large amount of genomic sequence data, we developed a computational pipeline called “Churchill”, which we published in the latest issue of Genome Biology (http://genomebiology.com/2015/16/1/6/abstract). Churchill fully automates the analytical process required to take raw sequence data through a series of complex and computationally intensive processes, ultimately producing a list of genetic variants ready for clinical interpretation and tertiary analysis. The major impact of our work was the development of a novel balanced parallelization strategy that allows efficient analysis of a whole genome sequencing sample in as little as 90 minutes.
Author Interviews, General Medicine, Journal Clinical Oncology, Leukemia, Pediatrics / 29.01.2015

MedicalResearch.com Interview with: Jun J. Yang  Ph.D. Assistant Member Dept. of Pharm. Sci. St. Jude Children's Research Hospital Memphis, TN 38105 Medical Research: What is the background for this study? What are the main findings? Dr. Yang: Mercaptopurine is highly effective in acute lymphoblastic leukemia (ALL) and essential for the cure of this aggressive cancer. However, it also has a narrow therapeutic index with common toxicities. Identifying genetic risk factors for mercaptopurine toxicity will help us better understand how this drug works and also potentially enable clinicians to individualize therapy based on patients’ genetic make-up (precision medicine). In addition to confirming the role of TPMT, we have identified another important genetic risk factor (a genetic variation in a gene called NUDT15) for mercaptopurine intolerance. Patients carrying the variant version of NUDT15 are exquisitely sensitive and required up to 90% reduction of the normal dose of this drug. TPMT variants are more common in individuals of African and European ancestry, whereas NUDT15 variants are important in East Asians and Hispanics.
Author Interviews, Genetic Research, Melanoma, Nature / 25.01.2015

MedicalResearch.com Interview with: Prof Lukas Sommer. Ph.D. Cell and Developmental Biology University of Zurich Institute of Anatomy Zurich Switzerland MedicalResearch: What is the background for this study? What are the main findings? Prof. Lukas Sommer:   Melanoma, the most aggressive of all skin cancers, is often fatal for patients due to the pronounced formation of metastases. Up to date, a melanoma’s rampant growth was mainly attributed to genetic causes, such as mutations in certain genes. However, we now reveal that so-called epigenetic factors also play a crucial role in the formation of metastases in malignant skin cancer. Epigenetic factors do not influence the gene sequence directly, but rather cause certain genes and chromosomal segments to be packed in different densities – and thus make them accessible for reading. In our study we identified “EZH2” as an epigenetic control protein found very frequently in malignant melanoma cells compared to normal cells. In these cells, “EZH2” controls genes that govern both tumor growth and genes that are important for the formation of metastases. We exploited this central position of EZH2 to combat the cancer by using a pharmacological inhibitor to suppress the activity of EZH2. As a result, we were able to prevent the growth and malignant spread of the cancer in an animal model and in human melanoma cells.
Author Interviews, Genetic Research, Mental Health Research, Scripps / 25.01.2015

Dr. Gavin Rumbaug Professor (Associate) The Scripps Research InstituteMedicalResearch.com Interview with: Gavin Rumbaug Professor (Associate) The Scripps Research Institute Medical Research: What is the background for this study? What are the main findings? Response: We have developed a genetic approach that protects animal models against a type of genetic disruption that causes intellectual disability, including serious memory impairments and altered anxiety levels. The findings focus on treating the effects of mutations to a gene known as Syngap1. In our new study, we examined the effect of damaging Syngap1 mutations during development and found that the mutations disrupt a critical period of neuronal growth—a period between the first and third postnatal weeks in mouse models. We found that a certain type of cortical neuron grows too quickly in early development, which then leads to the premature formation of certain types of neural circuits. These findings help explain why genetic treatments in adult mice are not very effective.
Author Interviews, CDC, OBGYNE, Opiods / 25.01.2015

Dr. Jennifer Lind PharmD, MPH Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, CDCMedicalResearch.com Interview with: Dr. Jennifer Lind PharmD, MPH Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, CDC Medical Research: What is the background for this study? Dr. Lind:  CDC researchers published a new study estimating the proportion of women aged 15-44 years who filled a prescription for opioid pain medications.  Opioids are prescribed by healthcare providers to treat moderate to severe pain. They are also found in some prescription cough medications. Opioids include medications like codeine, oxycodone, hydrocodone, or morphine. For this study, researchers used data from two large insurance claims datasets—one on Medicaid and one on private insurance—and looked at data from 2008-2012. Medical Research: What are the main findings? Dr. Lind: Opioid medications are widely used among women of reproductive age in the United States, regardless of insurance type. On average, more than a third (39 percent) of women aged 15-44 years enrolled in Medicaid, and more than one fourth (28 percent) of those with private insurance filled a prescription for an opioid pain medication each year during 2008-2012. Taking these medications early in pregnancy, often before women know they are pregnant, can increase the risk for some birth defects (such as spina bifida) and other poor pregnancy outcomes (such as preterm birth or low birth weight).
Author Interviews, Genetic Research, JAMA, Ophthalmology / 21.01.2015

Prof. David Mackey Centre for Ophthalmology and Vision Science/Lions Eye Institute Perth Managing Director/Chair of University of Western Australia, Perth, Australia Centre for Eye Research Australia, Melbourne UniversityMedicalResearch.com Interview with: Prof. David Mackey Centre for Ophthalmology and Vision Science/Lions Eye Institute Perth Managing Director/Chair of University of Western Australia, Perth, Australia Centre for Eye Research Australia, Melbourne University MedicalResearch: What is the background for this study? What are the main findings? Prof. Mackey: Too much or too little sun? Excessive sun exposure is associated with the eye disease pterygium, while lack of outdoor activity in childhood increases the risk of myopia (short sightedness). Measuring the amount of early sun damage to a person’s eyes would be of great use to researchers and potential use in clinical practice. Over the last few years we have developed a biomarker for sun exposure to the eye by photographing Conjunctival UV Auto-Fluorescence (CUVAF). The study published in JAMA Ophthalmology looked at the genetic and environmental factors that contribute to CUVAF levels in three Australian studies from Tasmania, Perth and Brisbane. People who live in sunnier environments closer to the equator have more evidence of sun damage using CUVAF.  However, genetic factors also play a role.
AHA Journals, Author Interviews, Genetic Research, Heart Disease, Lipids / 15.01.2015

Jean-Claude Tardif MD Professor of Medicine Director of the Research Centre Montreal Heart Institute Montreal, Quebec CanadaMedicalResearch.com Interview with: Jean-Claude Tardif MD Professor of Medicine Director of the Research Centre Montreal Heart Institute Montreal, Quebec Canada MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Tardif: Epidemiological and mechanistic studies have suggested that high-density lipoproteins (HDL) could have beneficial cardiovascular properties. However, several medications targeting HDL have failed in recent clinical trials, including the CETP inhibitor dalcetrapib in the dal-Outcomes trial. We hypothesized that dalcetrapib would be beneficial in the subset of patients with the appropriate genetic profile. We conducted the pharmacogenomic analysis of approximately 6000 patients from the dal-Outcomes study which showed that patients with the AA genotype at a specific genetic location (rs1967309) of the adenylate cyclase (ADCY9) gene benefited from a 39% reduction in cardiovascular events including cardiovascular death, myocardial infarction, stroke, unstable angina and the need for coronary revascularization when treated with dalcetrapib compared to placebo. In contrast, patients with the GG genotype had a 27% increase in cardiovascular events. We then obtained confirmatory evidence from the dal-Plaque-2 imaging study which revealed that patients with the protective genotype (AA) had a reduction in their carotid artery wall thickness and that those with the genotype associated with clinical harm (GG) had an increase in their wall thickness.
Author Interviews, Genetic Research, PTSD, UCLA / 15.01.2015

Armen K. Goenjian, M.D., L.D.F.A.P.A., F.A.C.G.S. Research Professor of Psychiatry Department of Psychiatry and Biobehavioral Sciences David Geffen School of Medicine at UCLAMedicalResearch.com Interview with: Armen K. Goenjian, M.D., L.D.F.A.P.A., F.A.C.G.S. Research Professor of Psychiatry Department of Psychiatry and Biobehavioral Sciences David Geffen School of Medicine at UCLA Medical Research: What is the background for this study? Response: Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops after exposure to a traumatic event such as rape, war, natural disaster, and accident. Symptoms include recurrent intrusive traumatic memories, flashbacks, nightmares, hyper-vigilance, jumpiness, and anxiety. Dopaminergic and serotonergic systems have been implicated in PTSD. Catechol-O-methyltransferase (COMT) is an enzyme that degrades dopamine, an important brain neuro-hormone that regulates human behavior, thoughts and emotions.  Tryptophan hydroxylase is the rate limiting step in the synthesis of serotonin, another important neuro-hormone that regulates arousal, sleep, anxiety, and mood. This study evaluated the association of four COMT gene loci, and the joint effect of COMT and tryptophan hydroxylase 2 (TPH-2) genes on PTSD symptoms.
Author Interviews, BMC, Genetic Research, Heart Disease, Pharmacology / 12.01.2015

Caroline Attardo Genco, PhD Professor Department of Medicine, Section of Infectious Diseases Department of Microbiology Boston University School of Medicine Boston MA 02118MedicalResearch.com Interview with: Caroline Attardo Genco, PhD Professor Department of Medicine, Section of Infectious Diseases Department of Microbiology Boston University School of Medicine Boston MA MedicalResearch: What is the background for this study? What are the main findings? Dr. Genco: Atherosclerosis is a common cardiovascular disease associated with heart attack and stroke. Although it has been shown that a diet high in fat as well as exposure to certain bacteria can cause atherosclerosis (the buildup of fats, cholesterol, and other substances on artery walls which can restrict blood flow), we have for the first time identified distinct gene pathways that are altered by these different stimuli. One of these bacteria, Porphyromonas gingivalis, is found in the mouth of humans with periodontal disease. Another is the bacteria Chlamydia pneumoniae, which causes pneumonia. We found that even though these three different stimuli all cause atherosclerosis, the gene pathways are distinct depending upon stimulus. This is the first study that has performed side-by-side comparison of genome-wide gene expression changes to address this issue. In this study, we used four experimental groups to compare genome-wide expression changes in vascular tissue. The first group was subjected to Porphyromonas gingivalis, while the second group received Chlamydia pneumoniae. The third group was placed on a high-fat Western style diet, while the fourth group was the control group. In collaboration with the Clinical and Translational Science Institute (CTSI) at Boston University, we performed genome-wide microarray profiling and analysis of vascular tissue from all groups to reveal gene pathways altered in vascular tissue by each treatment group. These findings may explain how specific infections or high-fat diet may cause atherosclerotic plaques to undergo changes that affect their size and stability and may ultimately lead to a heart attack.
Author Interviews, Breast Cancer, Genetic Research, Nature / 11.01.2015

MedicalResearch.com Interview with: Dr. Pentao Liu PhD and Dr. Walid Khaled PhD Wellcome Trust Sanger Institute Cambridgeshire United Kingdom Medical Research: What is the background for this study? What are the main findings? Dr. Pentao Liu: The significance of this research is that it aims to tackle the worst type of breast cancer. Triple Negative Breast Cancer (TNBC) has the poorest patient survival rate compared to other forms of breast cancer.  At present there are no targeted therapies available for TNBC, leaving the non-specific chemotherapy as the only treatment option. In this study we identify a new key gene in  Triple Negative Breast Cancer which could potentially be inhibited for the targeted treatment of TNBC. In this study we report the identification of a novel gene for Triple Negative Breast Cancer. By analyzing genomics data from 3,000 patients we find BCL11A to be highly expressed in TNBC. We then demonstrate experimentally that upregulation of BCL11A drives tumour development while its downregulation leads to reduction in tumour size. In the experimental mouse model, inactivation of this gene completely abolishes breast tumour development.
Author Interviews, Breast Cancer, Genetic Research / 10.01.2015

Dr. Chao Cheng PhD Department of Genetics Geisel School of Medicine at Dartmouth Hanover 03755, NHMedicalResearch.com Interview with: Dr. Chao Cheng PhD Department of Genetics Geisel School of Medicine at Dartmouth Hanover 03755, NH   MedicalResearch: What is the background for this study? What are the main findings? Dr. Chao Cheng: Cancer survival prognosis—“How long do I have, Dr.?” is a topic of great importance to cancer patients and their families. While clinical and pathological variables, such as cancer type, stage, grade, and patient demographics, have long been used to predict survival outcomes, only recently have molecular signatures become incorporated into survival prediction. A molecular approach holds great promise for improving prediction accuracy and additionally elucidating mechanisms of disease, however it is fraught with difficulty due to assay “noise” and “big data” statistical issues, such as the multiple comparisons problem In this study, we began by analyzing transcription factor binding profiles across available cell lines. By restricting our analysis to transcription factors, DNA expression regulators known to be involved in tumor genesis, we reasoned that we could avoid many of the “big data” issues and achieve results that would make mechanistic and biological sense. We first employed a statistical method we described previously to calculate which genes were the major downstream targets of our transcription factors. With these targets identified, we then analyzed gene expression data using a bioinformatics method to infer the relative activity of each transcription factor based upon the overall expression levels of their gene targets. From here, we incorporated cancer survival data and examined how each transcription factor’s regulatory activity did, or did not, correlate with survival. The most prognostic transcription factor was E2F4, a member of the E2F family and a known regulator of the cell cycle. We therefore restricted our analysis to E2F4 and examined how its activity level impacted survival in breast cancer patients. We found that tumors with high E2F4 regulatory activity as compared to low E2F4 regulatory activity had much worse survival outcomes. These results were stable even after controlling for tumor stage, grade, patient age, and treatment, and were based on data from over 1900 patients across eight independent datasets. These results demonstrate that E2F4 is an independent and enhancing predictor of survival above the currently examined variables.
Author Interviews, Case Western, Genetic Research / 05.01.2015

Michael A. Weiss, MD, PhD The Cowan-Blum Professor and Chairman of the Department of Biochemistry Distinguished Research Professor andMedicalResearch.com Interview with: Michael A. Weiss, MD, PhD The Cowan-Blum Professor and Chairman of the Department of Biochemistry Distinguished Research Professor and Professor of Medicine in the Endocrine Division at the Case Western Reserve School of Medicine in Cleveland, Ohio. Joseph Racca Researcher and graduate student Department of BiochemistryJoseph Racca Researcher and graduate student Department of Biochemistry Case Western Reserve School of Medicine in Cleveland, Ohio. Medical Research: What is the background for this study? What are the main findings? Response: The function of the gene responsible for male differentiation, sex-determining region of the Y chromosome (SRY), was first demonstrated in transgenic mouse models by P. Koopman, R. Lovell-Badge and colleagues in the early 1990s. These findings were corroborated by identification of mutations in human SRY that are associated with human sex reversal: XY, 46 gonadal dysgenesis leading to somatic sex reversal (Swyer’s Syndrome). Such mutations may occur spontaneously in spermatogenesis or be inherited. The characterization of the molecular defects associated with these mutations has unmasked novel biological and biochemical activities of SRY. More broadly, such studies have also increased our understanding of an entire family of related transcription factors (Sry-box related; SOX), which broadly function in metazoan development (from worms, fish and flies to mammals). Within human SRY, the majority of clinical mutations occur in the region of the protein responsible for specific DNA binding and DNA bending, the primary molecular actions of SRY at target genes. Our study bridges structure (i.e., protein folding and stability) and function (i.e., transcriptional activation of target genes and related cell-biological processes such as trafficking and proteosomal degradation). In our current study, we highlighted the importance of a structural scaffold in human SRY, specifically a key single amino acid that buttresses the unique L-shape structure of this domain. The mutation of interest represents a “perfect storm” leading to deleterious effects on multiple activities, including specific DNA binding, cellular localization, and both protein and cellular stability (lifetime), among other properties, together leading to sex reversal and cancer (gonadoblastoma) in the proband patient. Our integrated multi-disciplinary approach allowed us to characterize these various facets of SRY in the context of its biological site of action: the pre-Sertoli cell in an embryonic gonadal ridge just prior to its morphological differentiation into a testis. We are grateful to Prof. Patricia K. Donahoe (Harvard Medical School and the Massachusetts General Hospital), who generously provided this micro-dissected pre-Sertoli cell line.
Author Interviews, Genetic Research, Neurological Disorders, PNAS, Scripps / 26.12.2014

Elizabeth A. Thomas, Ph.D. Associate Professor Department of Molecular and Cellular Neuroscience The Scripps Research InstituteMedicalResearch.com Interview with: Elizabeth A. Thomas, Ph.D. Associate Professor Department of Molecular and Cellular Neuroscience The Scripps Research Institute   Medical Research: What is the background for this study? What are the main findings? Response: Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression, and in turn, influence resistance or susceptibility to disease.  Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, and are being proposed for therapeutic use in several neurological disorders.  Our previous studies have shown that selective HDAC inhibitors can cause beneficial effects in mouse models of Huntington’s disease, improving symptoms, and reducing severity of the disease.  Our current studies show that one such compound can alter DNA methylation, an epigenetic mark that can be inherited, leading to changes in gene expression that are seen in the parent mouse exposed directly to the drug, as well as in offspring from the drug-treated male mice.  Concurrent with these changes, we observed that offspring from drug-treated males shown improved disease symptoms, showing a delay in disease onset and a reduction of motor and cognitive symptoms that included improved performance in tests of balance, speed and memory. These finding have significant implications for human health as they enforce the concept that ancestral drug exposure may be a major molecular factor that can affect disease outcome in a subsequent generation.  One exciting aspect of our study is that the parental drug treatment made the offspring better, not worse, like other compounds known to cause transgenerational effects.
Author Interviews, Breast Cancer, JNCI / 21.12.2014

MedicalResearch.com Interview with: Dr Ranjit Manchanda Consultant Gynaecological Oncologist, St Bartholomew’s Hospital, London, UK Honorary Sr Lecturer, Women’s Cancer, EGA Institute for Women's Health, University College London, UK  and Professor Ian Jacobs Vice President, The University of Manchester Dean & Head School of Medicine Faculty of Medical & Human Sciences, Director MAHSC (Manchester Academic Health Science Centre) Medical Research: What is the background for this study? What are the main findings? Dr. Jacobs:  Background- Women carrying a BRCA1/2 gene alteration have a very high risk of developing breast and ovarian cancer and men carrying this alteration have an increased risk of prostate and breast cancer. Approximately 45-65% women who have this inherited genetic change will develop breast cancer and 15-35% ovarian cancer. They also have a 50% chance of passing these genes on to their children. At risk individuals can access available options of screening and prevention through the National Health Service (NHS). Some population groups across the world are known to have a higher frequency of BRCA 1/2 gene alterations than others. One example is Ashkenazi Jews who have a 1 in 40 likelihood of having a BRCA1/2 gene alteration. This is 10-20 times higher than in the general non-Jewish population. At present in the UK, genetic testing is available within the NHS to individuals who have a strong family history of cancer. However, many people are not aware of their family history or its significance and do not seek advice. Many other individuals with BRCA1/2 gene alterations do not have a family history at all. The current approach misses a large number of people at risk who could benefit from knowing about their BRCA 1/2 mutation status and the ability to access opportunities for prevention or screening. In order to address this the GCaPPS study has investigated the best method of screening for risk of inherited (familial) cancer by exploring the alternative approach of offering the genetic test to all men and women >18 years in the Ashkenazi Jewish population. It does so by comparing the benefits and disadvantages of: (i) The current system of testing only those with a family history and (ii) The new option of testing everyone in the population. Main Findings: Over half of the BRCA1/BRCA2 carriers detected did not give a strong family history of cancer and would not have been identified by current family history based testing criteria used in the NHS (National Health Service) in the UK and most health systems internationally. Reassuringly population-based genetic testing in Ashkenazi Jews did not adversely affect short term psychological health or quality-of-life. A health economic analysis indicated that population-based screening for BRCA-mutations in Ashkenazi Jewish women ≥30years would be highly cost-effective compared to the traditional family history based approach. Such an approach if implemented could reduce the incidence of and deaths from breast and ovarian cancer as well as reducing cost and save the NHS funds.
Author Interviews, Cognitive Issues, Genetic Research, JAMA / 13.12.2014

David H. Ledbetter, Ph.D., FACMG Executive Vice President & Chief Scientific Officer, Geisinger Health System Danville, PA 17822MedicalResearch.com Interview with: David H. Ledbetter, Ph.D., FACMG Executive Vice President & Chief Scientific Officer, Geisinger Health System Danville, PA 17822 Medical Research: What is the background for this study? What are the main findings? Dr. Ledbetter: One of the biggest challenges in clinical care and research of children with autism and related neurodevelopment disorders is the remarkable clinical variability between individuals. This heterogeneity is reduced, but still significant, when considering individuals who have neurodevelopment disorders due to the identical genetic mutation such as deletion 16p11.2. We proposed that family background, genetic or environmental, may contribute to the variability in cognitive, behavioral and motor performance profiles of children with a sporadic (new) mutation in 16p11.2. Our study confirmed that a significant portion of the clinical variability seen in these children is due to the performance level of their parents and unaffected siblings and suggested that this may be due in part to genetic background effects as these traits are all known to have very high heritability.
Author Interviews, Genetic Research, NEJM, NIH / 13.12.2014

Dr. Constantine A. Stratakis, M.D., D.Sc National Institutes of Health, Clinical Research Center Bethesda, MD 20892-1862MedicalResearch.com Interview with: Dr. Constantine A. Stratakis, M.D., D.Sc National Institutes of Health, Clinical Research Center Bethesda, MD 20892-1862 Medical Research: What is the background for this study? What are the main findings? Dr. Stratakis: We have been working for years on the genetics of pituitary tumors in association with other conditions. A few years ago (attached), we studied for the first time a series of pediatric giants that we sequenced for then known genes. We found a few MEN1 and AIP mutations but all mutations were present in older kids with gigantism. This left out the youngest among the giants without any genetic defect. This was the first time I realized that I was dealing with a different disease. We started looking for additional genetic defects and when we found the Xq26 microduplications in 3 kindreds. We contacted the custodians of the largest series in the world - Dr. Beckers in Liege. He screened his cases, once we gave him the coordinates, and boom - it was there... The most significant thing here is that this is a new disease really: the early pediatric gigantism is almost exclusively due to Xq26 microduplications unless it is part of a family with another syndrome (AIP, MEN1, Carney complex). If there is no family history and you are dealing with a toddler with gigantism, based in these data, there is a more than 80% chance of having an Xq26 defect. This is pretty amazing! In addition, assuming that GPR101 is the responsible gene (which needs to be confirmed with additional studies) this identifies a new molecular pathway of increasing growth hormone secretion, most likely due to upregulation of GHRH - all of this needs to be confirmed in further human and animal studies. The Xq26 genomic micro-arrangements (which contain the GPR101, but also 3 other genes) is the big news here...
Author Interviews, Genetic Research, Memory / 09.12.2014

Sandra Barral Rodriguez, Ph.D Assistant Professor G. H. Sergievsky Center & Taub Institute Columbia University Medical Center New York, NY 10032MedicalResearch.com Interview with: Sandra Barral Rodriguez, Ph.D Assistant Professor G. H. Sergievsky Center & Taub Institute Columbia University Medical Center New York, NY 10032 Medical Research: What is the background for this study? What are the main findings? Dr. Barral: We already know that there is a substantial genetic contribution to the variability observed in different cognitive tasks including memory performance. Previous work reported heritability estimates for episodic memory ranging between 30% and 60%. However, we can’t fully explain why some individuals demonstrate a better memory performance in late life, while others do not. We have previously defined a cognitive endophenotype based on exceptional episodic memory performance (EEM) and demonstrated that there is a familial aggregation of EEM in families selected on their basis of their exceptional survival, the Long Life Family Study. We performed genome-wide linkage analysis of long-lived families selected on the basis of their exceptional episodic memory and the follow-up SNP association analysis with episodic memory in four independent cohorts of more than 4,000 non-demented elderly cohorts. Our results provide strong evidence for potential candidate genes related to exceptional episodic memory on 6q24.
Author Interviews, Diabetes, Heart Disease / 07.12.2014

Simin Liu, MD, ScD, Professor of Epidemiology School of Public Health, Professor of Medicine The Warren Alpert School of Medicine Director, Molecular Epidemiology and Nutrition Brown UniversityMedicalResearch.com Interview with: Simin Liu, MD, ScD, Professor of Epidemiology School of Public Health, Professor of Medicine The Warren Alpert School of Medicine Director, Molecular Epidemiology and Nutrition Brown University MedicalResearch: What is the background for this study? What are the main findings? Dr. Liu: Cardiovascular Disease (CVD) and type 2 diabetes (T2D) are highly heritable and share many risk factors and show ethnic-specific prevalence. Nevertheless, a comprehensive molecular-level understanding of these observations is lacking. We conducted a comprehensive assessment of whole genome assessment using network-based analysis in >15,000 women and identified eight molecular pathways share in both diseases as well as several “key driver” genes that appear to form the gene networks in which these pathways connect and interact.
Alcohol, Author Interviews, Nature, University Texas / 05.12.2014

MedicalResearch.com Interview with: R. Dayne Mayfield PhD and Sean Farris Post Doc Fellow Harris Lab Waggoner Center for Alcohol and Addiction Research University of Texas at Austin MedicalResearch: What is the background for this study? Response: Alcoholism is psychiatric disorder adversely affecting the health of millions of individuals worldwide. Despite considerable research efforts, alcoholism cannot be attributed to any individual gene. We sought out to identify coordinately regulated gene networks, rather than a single candidate gene, that may be collectively driving the consumption of alcohol.
Author Interviews, General Medicine, Genetic Research, Nature / 03.12.2014

MedicalResearch Interview with: Prof Dr Isabelle Mansuy Lab of Neuroepigenetics University/ETH Zürich Brain Research Institute Zürich, Switzerland   MedicalResearch: What is the background for this study? What are the main findings? Prof. Mansuy: It is recognised that being exposed to traumatic stress in early life increases the susceptibility to psychiatric and metabolic diseases later in life. This is true for people directly exposed but also for their progeny across generations. It is also known that sometimes, stress exposure in early life can help an individual develop response strategies and be better prepared for later stressful experiences. The mechanisms of such beneficial effects and the question of whether they can be transmitted or not are not known. This study in mice was designed to answer these questions. The main findings are that exposure to traumatic stress of mouse newborns makes the animals and their progeny more efficient in challenging tasks when adult. For instance, they are more able to adapt to rules that change in a complex task to get a water ration when they are thirsty. This suggests more adaptive behaviours in challenging situations that are transmitted across generation. The study identifies the mineralocorticoid receptor, a stress hormone receptor in the brain, as an important molecular mediator of this effect and demonstrates that its expression is altered in the brain by epigenetic mechanisms.
Allergies, Author Interviews, Genetic Research / 28.11.2014

Dr. Hakon Hakonarson MD PhD The Center for Applied Genomics, The Children’s Hospital of Philadelphia Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PennsylvaniaMedicalResearch.com Interview with: Dr. Hakon Hakonarson MD PhD The Center for Applied Genomics, The Children’s Hospital of Philadelphia Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania Medical Research: What is the background for this study? What are the main findings? Dr. Hakonarson: We have built the world’s largest pediatric biobank at the Center for Applied Genomics at CHOP. Eosinophilic esophagitis (EoE) is among the projects we have sampled in collaboration with the EoE Center in collaboration with Dr. Spergel. We have nearly 1,000 samples now of this relatively rare disorder, which is now well powered for GWAS.  We previously  reported association of the TSLP locus with Eosinophilic esophagitis. Here we report genome-wide significant associations at four additional loci; c11orf30 and STAT6, which have been previously associated with both atopic and autoimmune diseases, and two EoE-specific loci, ANKRD27 that regulates the trafficking of melanogenic enzymes to epidermal melanocytes and CAPN14, that encodes a calpain whose expression is highly enriched in the esophagus in EoE.  This discovery not only improves our understanding of the pathobiology of  EoE, but also represents novel targets for the development of new therapies to treat the disease.
Author Interviews, BMJ, Genetic Research, Vitamin D / 19.11.2014

MedicalResearch.com Interview with: Børge G Nordestgaard, MD, DMSc Professor, University of Copenhagen Chief Physician, Herlev Hospital, Copenhagen University Hospital Dept. Clinical Biochemistry Herlev Ringvej Herlev, Denmark Medical Research: What is the background for this study? What are the main findings? Prof. Nordestgaard: Many people take vitamin D supplements with the hope of reducing morbidity and mortality. However, it is unclear whether low vitamin D per se is a direct cause of increased mortality or whether it is simply a marker of poor lifestyle in general and/or underlying hidden disease. Our study involved 95,766 white participants of Danish descent from three cohorts in Copenhagen, who had genetic variants known to affect vitamin D levels. We found that genetically low vitamin D levels were associated with increased all-cause mortality, cancer mortality, and other mortality, but not with cardiovascular mortality. This is important as such genetics studies cannot be explained by poor lifestyle or hidden disease, as neither can change your genes.
Author Interviews, Genetic Research, Nature, NYU/NYMC / 06.11.2014

Leslie Mitchell, PhD New York University Langone Medical Center Boeke Lab, Institute for Systems Genetics NY NY, 10016MedicalResearch.com Interview with: Leslie Mitchell, PhD New York University Langone Medical Center Boeke Lab, Institute for Systems Genetics NY NY, 10016 Medical Research: What is the background for this study? What are the main findings? Dr. Mitchell: One of our major interests is building synthetic chromosomes. Typically we construct synthetic chromosomes using a bottom-up approach, first designing the sequence in silico and then synthesizing and piecing together the DNA to build the designer molecule. While eukaryotic chromosomes are usually linear in structure, oftentimes we build our designer synthetic chromosomes as circular molecules to take advantage of cloning technologies available in E. coli, an organism that tolerates only circular chromosomes. We developed the telomerator as a means by which to convert circular synthetic chromosomes into linear molecules, which more closely resemble the native chromosomes found in eukaryotic cells. We discovered that the telomerator is an extremely effective tool for generating linear derivatives of circular synthetic chromosomes. There are two main reasons for this.
  • First, the action of the telomerator can be assessed using a simple phenotypic assay so it is easy to differentiate cells that encode linear synthetic chromosomes from those with the circular format.
  • Second, the telomerator encodes ‘telomere seed sequences’ that are exposed and recognized by the cell upon linearization, thus the ends of a newly linearized chromosome are protected, which ensures its stability over generations. We put the telomerator to the test by integrating it in 54 different positions on a circular synthetic yeast chromosome called synIXR (Dymond et al. 2011). In 51 of the 54 positions we could successfully linearize the synIXR chromosome and recover viable cells, however many of the different linear derivatives conferred growth defects. We determined the mechanism underlying both the growth defects and lethality associated with linearization to be telomere position effect. In other words, when essential genes were re-positioned near telomeres their reduction in expression due to subtelomeric silencing was detrimental to the cell.
Alcohol, Author Interviews, Genetic Research / 05.11.2014

Victor M. Karpyak, M.D., Ph.D. Medical Director, Intensive Addiction Treatment Program Director, Mayo Clinic Addiction Services Consultant, Department of Psychiatry and Psychology Assistant Professor of Psychiatry Mayo Clinic College of Medicine MedicalResearch.com Interview with: Victor M. Karpyak, M.D., Ph.D.  Medical Director, Intensive Addiction Treatment Program Director, Mayo Clinic Addiction Services Consultant, Department of Psychiatry and Psychology Assistant Professor of Psychiatry  Mayo Clinic College of Medicine Medical Research: What is the background for this study? Dr. Karpyak: The staggering costs of alcohol use disorders call for the development and implementation of evidence-based treatment strategies. Several medications (acamprosate, naltrexone, and disulfiram) were approved for treatment of alcohol use disorders; yet, only a fraction of patients respond to each medication. Clearly, response predictors are needed to improve treatment efficacy and personalize recommendations for treatment selection. It is expected that pharmacogenomic research will aid the discovery of such predictors.
Author Interviews, Genetic Research / 24.10.2014

Dr. Toomas Kivsild PhD Department of Archaeology and Anthropology University of Cambridge, CambridgeMedicalResearch.com Interview with: Dr. Toomas Kivsild PhD Department of Archaeology and Anthropology University of Cambridge, Cambridge Medical Research: What is the background for this study? What are the main findings? Dr. Kivsild: Native populations of Siberia are known to have certain physiological characteristics such as high basal metabolic rate, and high blood pressure and low levels of serum lipids, that have been explained as traits that have evolved as a consequence of the adaptation of Siberians to their cold environment. Genetic basis of cold adaptation is still poorly understood. In our previous study using genome-wide genotyping scans we detected a 3 Mbp region of high haplotype homozygosity in chromosome 11 as a candidate of strong positive selection in Northeast Siberians. There were 79 protein coding genes mapping to this homozygosity region but we could not determine which of the genes was driving the signal we observed. In this forthcoming paper we have used high coverage whole genome sequences from 25 individuals from Northeast Siberia and we were able to determine the most likely SNP that is responsible for the high haplotype homozygosity in the chromosome 11 in Northeast Siberians maps to CPT1A gene which is a key regulator of long-chain fatty-acid oxidation in mitochondria. What makes this finding most interesting is that the same SNP had previously been found in Greenland and Canadian Inuits in association with high infant mortality and hypoketotic hypoglycemia. There are only a few other similar cases, like the sickle cell and APOL1 alleles, where disease associated genetic variants may have risen to high frequency in modern day populations due to the adaptive advantage they have presented in the past populations.