Author Interviews, Genetic Research, Neurological Disorders, Novartis / 29.03.2023 Interview with: Sitra Tauscher-Wisniewski, MD Vice President Clinical Development & Analytics Novartis Gene Therapies What is the background for this study? Would you briefly describe the condition of Spinal muscular atrophy (SMA)? Response: At the 2023 Muscular Dystrophy Association Conference, we presented new data from two of our  Long-Term Follow-Up (LTFU) studies, LT001 and LT002, which show the continued efficacy and durability of Zolgensma across a range of patient populations, with an overall benefit-risk profile that remains favorable. LT001 is a 15-year ongoing observational LTFU study following the Phase 1 START patients, who were the very first patients to receive our gene replacement therapy. LT-002 is a voluntary Phase 4 15-year ongoing follow-up safety and efficacy study of Zolgensma IV and investigational intrathecal (IT) OAV101 in patients previously treated in the Phase 3 IV studies (STR1VE-US, STR1VE-EU, STR1VE-AP, SPR1NT) and the Phase 1 IT study (STRONG). Spinal muscular atrophy (SMA) is a rare, devastating genetic disease that leads to progressive muscle weakness, paralysis, and when left untreated in one of its most severe forms (SMA Type 1), permanent ventilation or death in 90% of cases by age 2. It is caused by a lack of a functional survival motor neuron 1 (SMN1) gene, and in the most severe forms results in the rapid and irreversible loss of motor neurons, affecting muscle functions, including breathing, swallowing and basic movement. (more…)
Addiction, Author Interviews, Genetic Research, Nature / 29.03.2023 Interview with: Alexander S. Hatoum, PhD Research Assistant Professor Institute for Behavioral Genetics Washington University in St. Louis What is the background for this study? Response: It is well known that someone with one substance use disorder will have another sometime in their lifetime or concurrently.  Further, individuals that do manifest two or more substance use disorders in their lifetime have the most morbid conditions. However, research often ignores the comorbidity and focuses on diagnosis of one substance use disorder at a time (i.e. opioid use disorder or alcohol use disorder). We set out to identify the biology behind the cross-substance liability. (more…)
Author Interviews, Biomarkers, Cancer Research, Genetic Research / 27.03.2023 Interview with: Florence Le Calvez-Kelm, Ph.D. Genomic Epidemiology Branch International Agency for Research on Cancer Lyon, France and Trevor Levin Ph.D. Founder and CEO of Convergent Genomics that produces the Uroamp assay San Francisco, CA What is the background for this study? Response: Bladder cancer is one of the most expensive and challenging to diagnose and treat. Therefore, identifying cost-effective urine bladder cancer biomarkers to complement or replace the gold-standard invasive and costly cystoscopy for the early detection and monitoring of this highly recurrent disease is crucial. At the international Agency for research on Cancer (IARC-WHO), we have developed a simple urine-based assay TERT promoter mutations, the most common mutations in bladder cancer, and showed that the urine biomarker could detect bladder cancer patients at diagnosis but many years prior to clinical diagnosis. However, in this study, we wanted to see whether a more comprehensive genomic profiling of urine samples collected years prior to clinical diagnosis of bladder cancer could identify even more patients before they develop any symptoms. The study was based on the UroAmp test, a general urine test that identifies mutations in 60 genes, developed by the Oregon Health Science University spin out company, Convergent Genomics. Drawing on previous research to identify genetic mutations linked to bladder cancer, the research team narrowed the new test down to focus on mutations within just ten genes. Working with colleagues from the Tehran University of Medical Sciences in Iran, they trialled the potential new test using samples from the Golestan Cohort Study, which has tracked the health of more than 50,000 participants over ten years, all of whom provided urine samples at recruitment. Forty people within the study developed bladder cancer during that decade, and the team were able to test urine samples from twenty-nine of them, along with samples from 98 other similar participants as controls. (more…)
Author Interviews, Genetic Research / 21.03.2023 Interview with: Ernest Turro, PhD Associate Professor Genetics and Genomics Sciences The Turro group runs a research program on statistical genomics, with a dual focus on rare diseases and blood-related traits at the Icahn School of Medicine Mount Sinai Health System What is the background for this study? Would you describe the Rareservoir database? Response:   The main motivation for our work is that only half of the approximately 10,000 catalogued rare diseases have a resolved genetic cause (or aetiology). Patients with these diseases are unable to obtain a genetic diagnosis which could otherwise inform prognosis, treatment for themselves and affected relatives. One route towards resolving the remaining aetiologies is to enroll large numbers of rare disease patients into research studies so that statistical analyses can be performed comparing the genetic with the clinical characteristics of the study participants. One major endeavour, the 100,000 Genomes Project (100KGP), sequenced the genomes and collected clinical phenotype data for 34,523 UK patients and 43,016 unaffected relatives across 29,741 families. The scale of this study is unprecedented, partly thanks to the ever-decreasing cost of DNA sequencing (25 years ago, it cost $1bn to sequence a whole genome, while now it costs only a few hundred dollars). Working with such large datasets is notoriously cumbersome. To overcome this, we developed a computational approach (the Rareservoir) that distills the most important information into a relatively small database, allowing us to apply our statistical methods nimbly. We noted that the "genetic variants" that cause rare diseases are typically kept rare in the human population by natural selection because affected individuals tend to have few children, if any. This meant that we could discard the genetic information corresponding to variants that are common in the human population without throwing away the key disease-causing variants. By focussing on these "rare variants", we were able to perform our analyses using a small database (a `Rareservoir’), only 5.5GB in size, hastening our progress significantly. (more…)
Author Interviews, Cancer Research, Genetic Research, JAMA, Personalized Medicine, Vanderbilt / 18.03.2023 Interview with: Jonathan Mosley, MD, PhD Associate Professor Division of Clinical Pharmacology Departments of Internal Medicine and Biomedical Informatics Vanderbilt University Medical Center What is the background for this study? Response: Prostate cancer is an important source of morbidity and mortality among men. Earlier detection of disease is essential to reduce these adverse outcomes. Prostate cancer is heritable, and many single nucleotide polymorphisms (SNPs) associated with disease risk have been identified. Thus, there is considerable interest in using tools such as polygenic risk scores, which measure the burden of genetic risk variants an individual carries, to identify men at elevated risk of disease. (more…)
Alzheimer's - Dementia, Author Interviews, Genetic Research, Race/Ethnic Diversity, Stanford / 21.02.2023 Interview with: Yann Le Guen, Ph.D. Assistant Director, Computational Biology Quantitative Sciences Unit Stanford Medicine What is the background for this study? Response: Apart from aging, the strongest contributing factor for late-onset Alzheimer’s disease is a specific allele of the APOE gene, which has three common alleles E2, E3, and E4. While E3 is the most common and considered as the reference, E2 is associated with decreased Alzheimer’s disease risk and E4 is associated with increased Alzheimer’s disease risk. Notably the prevalence of E4 among Alzheimer’s patient is high with about 60% of these carrying at least one E4 allele, while solely about 30% Americans carry one E4 allele. It’s worth emphasizing that individuals with an E4/E4 genotype have an exponential increased in their risk to develop AD (10 times as likely than the reference E3/E3 genotype), and individuals with an E3/E4 genotype have an intermediate risk. Though, most studies of Alzheimer’s disease genetic have been focused on European ancestry, this is beginning to change thanks to NIH’s efforts to fund more studies in non-European ancestry individuals. Our study built on these recent efforts to assess the Alzheimer disease risk associated with an APOE variant (R145C) present in about ~4% African Americans, but extremely rare in Europeans. (more…)
Author Interviews, Genetic Research, NIH, Pediatrics / 20.02.2023 Interview with: Natalie Shaw, M.D., MMSc. Principal Investigator Head of the Pediatric Neuroendocrinology Group Dr. Shaw holds a secondary appointment in NIEHS Reproductive and Developmental Biology Laboratory. What is the background for this study? Would you briefly describe the two affected conditions? Dr. Shaw: Congenital arhinia is a rare congenital malformation characterized by the complete absence of an external nose and internal olfactory (smell) structures.  It is frequently associated with eye and reproductive defects.  Facioscapulohumeral muscular dystrophy (FSHD) type 2 is a form of muscular dystrophy that presents in young adulthood.  Both conditions are caused by mutations in the gene SMCHD1.  In FSHD type 2, we know that loss of SMCHD1 activity leads to expression of a toxic protein called DUX4 in muscle.  The cause of arhinia was unknown. (more…)
Author Interviews, Coffee, Genetic Research, JAMA, Kidney Disease / 15.02.2023 Interview with: Dr. Sara Mahdavi, PhD Clinical Scientist and Clinical Instructor Research Appointment in the Faculty of Medicine University of Toronto Toronto, ON What is the background for this study? Response: This was a long-term study spanning 16 years and began with a population of young adults who were medically assessed on a regular basis. It was remarkable to see just how striking the effects of coffee were in the group that had the susceptible genetic variant, what we termed “slow caffeine metabolizers” yet no effect whatsoever in those who did not were termed “fast metabolizers”. (more…)
Author Interviews, Genetic Research, JAMA, Karolinski Institute, Weight Research / 31.01.2023 Interview with: Lisa Dinkler, Ph.D. | Postdoctoral researcher Center for Eating Disorders Innovation (CEDI) Department of Medical Epidemiology and Biostatistics Karolinska Institutet, Stockholm What is the background for this study? Response: Avoidant restrictive food intake disorder (ARFID) is a relatively recently defined eating disorder. Affected people severely restrict their food intake in terms of total amount or variety. This leads to serious physical, psychological, and social consequences such as weight loss, nutritional deficiencies, and social isolation. Compared to people with other eating disorders – such as anorexia nervosa, bulimia nervosa, and binge-eating disorder – food restriction in people with ARFID is not driven by body dissatisfaction or the desire to lose weight. Despite how serious ARFID is, we still know very little about what causes it – making it difficult to develop effective treatments. We do know that genetic factors contribute significantly to the development of other eating disorders (so-called heritability), but we did not yet know to which degree genetic factors play a role in the development of ARFID. We therefore conducted the first twin study of ARFID, using a sample of ~34,000 Swedish twins including ~700 children with ARFID. (more…)
Author Interviews, Genetic Research, Infections, Neurological Disorders / 14.12.2022 Interview with: Dr. Eli Hatchwell, MA MB BChir (Cantab) DPhil (Oxon) BA (OU) Chief Scientific Officer Population Bio UK, Inc. Begbroke Science Park Begbroke Hill Begbroke, Oxfordshire United Kingdom What is the background for this study? Response: Progressive Multifocal Leukoencephalopathy (PML) is a devastating condition that is associated with a number of clinical situations, including treatment with a variety of drugs. Of these, the best known is natalizumab (Tysabri), which is a very successful drug in the treatment of MS (multiple sclerosis). Only a small proportion of patients treated with natalizumab develop PML and this has always been a mystery. The study was based on a hypothesis that some individuals have an underlying susceptibility to developing PML, based on the presence of variants in genes that are important in the immune system. The study identified several of these variants. (more…)
Author Interviews, Cancer Research, Colon Cancer, Genetic Research, Nature / 18.10.2022 Interview with: Royce Zhou, MD/PhD Candidate Icahn School of Medicine at Mount Sinai What is the background for this study? Response: The background of this story is to see whether things outside of the cancer cell, such as the tumor microenvironment, can lead to epigenetic changes within the cancer cell. These changes are largely believed to be due to factors inside the cell, not outside. Super-enhancers are the top 1-2% of enhancers in the genome. They control cell identity genes and oncogenes in cancer. (more…)
Author Interviews, Exercise - Fitness, Genetic Research, Lifestyle & Health, Nature / 08.09.2022 Interview with: Marcel den Hoed, PhD Researcher,Department of Immunology, Genetics and Pathology Uppsala University What is the background for this study? What are the main findings? Response: In this paper we performed a multi-ancestry meta-analysis of 51 genome-wide association studies, in data from over 700,000 individuals. This yielded 11 DNA regions that are robustly associated with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), and 88 DNA regions for self-reported leisure screen time (LST). Around half of the identified DNA regions are also associated with objectively assessed physical activity traits in data from the UK Biobank. Causal inference using a Mendelian randomization approach subsequently showed bidirectional causal effects between LST and body mass index (BMI), with the effect of LST on BMI being 2-3-fold larger than vice versa. Less LST and more MVPA protect from diabetes, attention deficit hyperactivity disorder, depression, and earlier age at death, with all causal effects of MVPA and leisure screen time being mediated or confounded by BMI. Further analyses showed that DNA regions associated with LST are more often located close to genes whose expression in skeletal muscle is altered by strength training than expected by chance, suggesting that these genes may influence the likelihood of adopting an active lifestyle by influencing the response to training. (more…)
Author Interviews, Genetic Research, Heart Disease / 04.08.2022 Interview with: Christine Seidman, MD Thomas W. Smith Professor of Medicine and Genetics Director, CV Genetics Center Brigham and Women’s Hospital Harvard Medical School Dept of Genetics Boston, MA 02115  What is the background for this study?    Response: Heart failure is a common and incurable disorder that is known to arise from many different underlying causes.  By exploiting a new technology, single nuclear transcriptional analyses, we aimed to define molecular profiles in human hearts tissues that were obtained from patients with different genetic and non-genetic causes of heart failure. Our goal was to determine if there were distinctive signatures that could provide new opportunities to develop precise treatments, based on the specific cause of heart failure. (more…)
Author Interviews, Diabetes, Genetic Research, Herpes Viruses / 12.05.2022 Interview with: Prof. Annette Peters PhD Chair of Epidemiology Institute of Medical Information Sciences, Biometry and Epidemiology, Ludwig-Maximilians University Munich, Germany Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany German Center for Diabetes Research (DZD), München-Neuherberg, Germany  What is the background for this study?  What are the main findings? Response: A large number of genetic, behavioural and environmental risk factors have been identified as contributing to the risk of type 2 diabetes. However, little is known about a potential link between virus infections and type 2 diabetes developments. We had the unique opportunity to use a multiplex assay to measure antibodies for herpes viruses by the Waterboer laboratory at the German Cancer Center in Heidelberg and set out to investigate the potential associations in the prospective KORA cohort. First of all, we detected that herpes virus antibodies were highly prevalent in the study population at baseline and increased with age. We found an association between Herpes simplex virus 2 and cytomegalovirus and type 2 diabetes during a seven year follow-up. These associations were robust against controlling for other known risk factors. (more…)
Aging, Alzheimer's - Dementia, Author Interviews, Brigham & Women's - Harvard, Genetic Research, Nature / 20.04.2022 Interview with: Michael B. Miller, MD, PhD Instructor, Harvard Medical School Department of Pathology Brigham and Women's Hospital  What is the background for this study? Would you explain what is meant by somatic genetic changes and how they might occur?  Response: Changes, also called mutations, in the DNA sequence of genes can be passed from parents to their children, and explain why many diseases run in families. This kind of DNA change is called a germline mutation and is present in every cell in a person’s body. Gene mutations can also occur in a subset of cells of a person, in which case they are called somatic mutations. Somatic mutations are well known as a cause of cancer, and recent research has found that somatic mutations can also happen in non-cancerous cells that appear otherwise normal. Recent studies have even found that somatic mutations are present in neurons, cells in the brain that transmit electrical signals and play an important role in how the brain functions. Furthermore, in neurons, somatic mutations increase with age, so we set out to understand if somatic mutations might be playing a role in age-related brain diseases like Alzheimer’s. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, Genetic Research, Nature / 18.04.2022 Interview with: Jason Vassy, MD, MPH Brigham and Women's Hospital Division of General Internal Medicine & Primary Care Brigham’s Precision Population Health at Ariadne Labs and VA Boston  What is the background for this study?    Response: A person’s risk of developing diseases such as type 2 diabetes or breast cancer may be influenced by thousands of genetic differences, the effects of which can be combined to derive a single score, often called a polygenic risk score (PRS). PRS might be useful to help patients and their physicians make tailored decisions about their health care, but several challenges to the clinical implementation of PRS remain. Most importantly, most PRS are less accurate in individuals of non-European descent, since most genomic research to date has been conducted in European populations. Another key challenge is that physicians and patients will need support to understand polygenic risk score and use them to make medical decisions. Clinical guidelines do not yet exist to help a physician know whether and how they should treat a patient with a high-risk score differently than an average-risk patient. We designed the Genomic Medicine at VA (GenoVA) Study to address some of these challenges. (more…)
Author Interviews, Genetic Research, Sleep Disorders, UCSF / 20.03.2022 Interview with: Ying-Hui Fu, PhD Professor, Neurology Weill Institute for Neurosciences UCSF  What is the background for this study?  Response: Most people are aware that a lack of sleep is associated with all sorts of health issues. However, familial natural short sleeper (FNSS) individuals sleep 4-6.5 hours a night most of their live and stay healthy. We set out to determine whether natural short sleep mutations can offer protection from various diseases. We chose Alzheimer as an example to start. (more…)
Author Interviews, Genetic Research, Heart Disease, Technology / 17.03.2022 Interview with: Ali Torkamani, Ph.D. Director of Genomics and Genome Informatics Scripps Research Translational Institute Professor, Integrative Structural and Computational Biology Scripps Research La Jolla, CA 92037  What is the background for this study?  Response: Prior research has shown that people with higher polygenic risk for coronary artery disease achieve greater risk reduction with statin or other lipid lowering therapy. In general, adherence to standard guidelines for lipid lowering therapy is low - about 30% of people who should be on lipid lowering therapy are, with no correlation to their genetic risk. We set out to see whether communicating personalized risk, including polygenic risk, for coronary artery disease would drive the adoption of lipid lowering therapy. (more…)
Author Interviews, Columbia, Genetic Research, Hematology, NEJM / 16.12.2021 Interview with: Markus Y Mapara, MD Professor of Medicine Director of the Blood and Marrow Transplantation Columbia University Medical Center What is the background for this study? What are the main findings?  Response: Sickle cell disease is caused by a point mutation in the beta-globin gene of hemoglobin  resulting in the production of abnormal hemoglobin which leads to formation of sickle-shaped RBC under conditions of low oxygen. Sickle cell disease affects about 100,000 patients in the US which are predominantly African  American. The only curative approach is to perform an allogeneic bone marrow transplant which is however fraught with significant treatment-related risks if a matched sibling donor is not available. The current study describes the successful application of a novel gene therapy  to treat patients with sickle cell disease. The strategy is based on a gene-addition approach to introduce the genetic information for a Hemoglobin F-like molecule termed HgAT87Q into hematopoietic stem cells. The expression of this novel  hemoglobin prevents polymerization of HgbS  and has now been demonstrated to prevent the occurrence of vaso-occlusive pain crises in sickle cell disease patients. (more…)
Author Interviews, Genetic Research, NEJM / 10.11.2021 Interview with: Professor Sir Mark Caulfield Professor of Clinical Pharmacology William Harvey Research Institute Queen Mary University of London What is the background for this study? Response: Rare diseases affect 6% of the population in western nations and there are approximately 10,000 different disorders and many remain without a genomic diagnosis after usual testing during their life time. In 2013 the UK Government launched the 100,000 Genomes Project and created Genomics England to investigate the role of whole genome sequencing in rare disease, cancer and infection. Whole genome sequencing gives the most comprehensive read out of the entire genome. To do this we partnered with the National Institute for Health Research (NIHR) BioResource and 9 hospitals across England1. Our New England Journal of Medicine paper published on the 11th November 2021 reports findings on the early rare disease participants who helped us pilot procedures and processes that would be used to enrol at scale across the NHS and revealed the potential benefits for rare disease1. (more…)
Author Interviews, Genetic Research, Ophthalmology / 08.06.2021 Interview with: Louis Pasquale, MD, FARVO Professor of Ophthalmology Icahn School of Medicine at Mount Sinai. Site Chair of the Department of Ophthalmology Mt. Sinai Hospital and Vice Chair of Translational Ophthalmology Research Mount Sinai Healthcare System What is the background for this study? Response: Studies on the relation between caffeine intake and glaucoma have been contradictory, although our work suggested an adverse association amongst people with a self-reported family history of glaucoma. (more…)
Author Interviews, Genetic Research, Parkinson's / 06.05.2021 Interview with: Clemens R. ScherzerClemens R. Scherzer, M.D. Center for Advanced Parkinson Research Harvard Medical School Brigham and Women’s Hospital Boston, MA What is the background for this study? Response: Parkinson's disease is the fastest growing brain disorder. The number of patients is projected to double to 14 million by 2040. The total cost of Parkinson's is $52 billion every year in the U.S. Yet, there are no medicines available to slow the disease. Current treatments temporarily alleviate symptoms, but do not address the underlying disease process, which continues to relentlessly progress. To begin to solve this puzzle, we searched the genome of 3,821 Parkinson's disease patients for genetic variants linked to rapid progression over time to dementia, which is a major determinant for a Parkinson's disease patient’s quality of life. These patients were deeply characterized in the International Genetics of Parkinson Disease Progression (IGPP) Consortium, a grass-roots, collaborative network of Parkinson’s investigators, with 31,578 longitudinal study visits over up to 12 years from disease onset.  (more…)
Author Interviews, Cancer Research, Gastrointestinal Disease, Genetic Research / 03.05.2021 Interview with: Judy H. Cho, MD, Dean of Translational Genetics Director of The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai What is the background for this study? Would you briefly describe Crohn's disease? Whom does it primarily affect? Response: Crohn’s disease is a chronic inflammatory intestinal disease, which affects ~3 million Americans a year. Its most typical age of onset ranges from 15-30 years, and many of those diagnosed also exhibit frequent abnormal healing and complications that constrict the digestive tract. The highest risk genetic mutations that increase risk for Crohn’s disease are found in the gene NOD2; these were first reported 20 years ago. Biological mechanisms by which NOD2 mutations drive Crohn’s disease, and especially fibrotic complications, have been incompletely described up until this point. Further, the reasons why many patients fail to respond to the commonly administered anti-TNF treatments also remain incompletely understood. (more…)
AACR, Author Interviews, Cancer Research, Genetic Research, NIH / 23.04.2021 Interview with: Nishanth Ulhas Nair, Ph.D. Affiliation: Staff Scientist at Cancer Data Science Laboratory, Center for Cancer Research National Cancer Institute (NCI), National Institutes of Health (NIH) Bethesda, Maryland, USA. Date: April 22, 2021 Dr. Raffit Hassan and Dr. Eytan Ruppin at the National Cancer Institute (NCI) are the senior authors of this study. What is the background for this study? Response: Malignant mesothelioma is an aggressive cancer with limited treatment options and poor prognosis. An in-depth knowledge of genetic, transcriptomic and immunogenic events involved in mesothelioma is critical for successful development of prognostics and therapeutic modalities. In this study we aim to address this by exploring a new large scale patient tumor dataset of 122 mesothelioma patients, called NCI mesothelioma patient data, along with their genomic, transcriptomic, and phenotypic information. Unlike previous large-scale studies which have been focused on malignant pleural mesothelioma patients, our dataset contains an approximately equal representation of malignant pleural and peritoneal mesothelioma patients which allows to identify any differences between them. (more…)
AACR, Baylor College of Medicine Houston, Cancer Research, Genetic Research, Prostate Cancer, Race/Ethnic Diversity, Social Issues / 10.04.2021 Interview with: Nicholas Mitsiades MD Associate Professor of Medicine - Hematology and Oncology Baylor College of Medicine Oncologist at the Dan L Duncan Comprehensive Cancer Center What is the background for this study? Response: African American men have higher risk of developing prostate cancer and up to 2.2-times higher mortality rate from prostate cancer relative to men of other ancestries. This is the largest health disparity across all cancers in the US. Socioeconomic factors, especially access to healthcare, definitely contribute to this disparity. African American men are diagnosed with prostate cancer at a more advanced stage than other races, and this is unfortunately very common at Ben Taub Hospital, our safety-net hospital in the Houston area, where we serve large racial and ethnic minority populations and patients who lack commercial insurance. (more…)
Author Interviews, Cost of Health Care, Genetic Research, Hematology, JAMA / 22.03.2021 Interview with: Patrick DeMartino MD Pediatric Hematology and Oncology Fellow Doernbecher Children's Hospital Oregon Health & Science University What is the background for this study? Response: Dozens of gene therapies are expected to be on the market within a decade or so. Much has been written about the high prices of the therapies currently on the market (exceeding $1 million). However, only a small number of patients are eligible for these existing therapies each year. Gene therapy for sickle cell disease (SCD) appears promising and would potentially apply to a relatively large number of individuals in the U.S. We sought to explore potential affordability challenges associated with a gene therapy for SCD. (more…)
Author Interviews, Genetic Research, Ophthalmology, Science / 12.03.2021 Interview with: eye-eyecolor-geneticsDr Pirro Hysi Senior Lecturer in Ophthalmology Kings College London What is the background for this study? Response: - Iris (eye) color is an important human trait. It is one of the main features that makes our faces unique and recognizable. Iris color is similar to other pigmentatio traits, like hair and skin color, in that it is determined by the concentration and relative ratios of the melanin pigment. Pigmentation traits are roughly determined by several of the same genes regulating pigmentation, but many other genes seem to selectively determine pigmentation in any of these tissues. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease / 08.03.2021 Interview with: Giordano Bottà, PhD CEO and Co-founder Allelica The Polygenic Risk Score Company What is the background for this study? Response: Previous research identified that polygenic risk score (PRS) has the highest predictive power compared to other risk factors and identifies individuals with the same risk of those with familial hypercholesterolemia, but are invisible to traditional risk assessment. We explored for the first time the interplay between the main causes of atherosclerosis, LDL cholesterol and PRS.  We were interested in helping cardiologists understand why some individuals have bad arteries full of plaques while others don't in presence of the same LDL levels and no additional risk factors. Our findings explain why this is the case: LDL does not affect everyone the same. We believe that we are at the forefront of a change of paradigm in cardiovascular risk assessment: LDL levels cannot be accessed without considering the genetics of an individual. (more…)
Author Interviews, Genetic Research / 03.02.2021 Interview with: Igor Chesnokov, Ph.D Department of Biochemistry and Molecular Genetics School of Medicine University of Alabama at Birmingham, Alabama What is the background for this study? Response: DNA replication is fundamentally important for tissue development, growth and homeostasis. Impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Meier-Gorlin Syndrome (MGS) is an autosomal recessive disorder that is also known as ear, patella, short stature syndrome and/or microtia, absent patella, micrognathia syndrome, traits highlighting the core clinical phenotypes. The genes affected by MGS mutations include many members of pre-replicative complex (pre-RC), such as Origin Recognition Complex (ORC) subunits (Orc1, Orc4, Orc6), Cdc6, Cdt1, CDC45, MCM5 as well as Geminin, suggesting that the clinical phenotype is caused by defects in DNA replication initiation. As the pre-RC complex is essential for DNA replication, the mutations in its components are expected to impair cell proliferation and reduce growth. The smallest subunit of ORC, Orc6, is the most divergent and enigmatic among ORC subunits. Orc6 is important for DNA replication in all species. Metazoan Orc6 proteins consist of two functional domains: a larger N-terminal domain important for binding of DNA and a smaller C-terminal domain important for protein-protein interactions. A mutation coding for a tyrosine 232 to serine alteration (Y232S) in the C-terminal domain of Orc6 is linked to MGS in humans. Recently, a new Orc6 mutation was described that also resulted in MGS. Unlike the previously described MGS mutation, this amino acid substitution, Lysine 23 to Glutamic acid (K23E), localizes in the N-terminal domain of Orc6.  (more…)
Author Interviews, Breast Cancer, Genetic Research, JAMA, Race/Ethnic Diversity / 22.01.2021 Interview with: Kent Hoskins, MD Eileen Lindsay Heidrick Professor in Oncology Division of Hematology/Oncology University of Illinois at Chicago Director of Cancer Genetics Co-Leader, Breast Cancer Research Group University of Illinois Cancer Center What is the background for this study? Response: The racial disparity in breast cancer mortality emerged in the US in the late 1980s in the wake of widespread implementation of mammography screening and the development of successful systemic adjuvant therapies for early breast cancer. Unfortunately, more than three decades later, Black women in the US still have a 40% higher mortality rate from breast cancer compared with non-Hispanic White women despite similar disease incidence. Health disparities research has primarily focused on the fact that Black women have a higher incidence of the aggressive triple-negative subtype, and that they are more likely to present with more advanced stages of disease. As important as those factors are, in recent years our group and others reported that Black women with hormone receptor-positive breast cancer have worse survival than non-Hispanic white women even after adjustment for stage at diagnosis and treatment. Since nearly 2/3 of breast cancers in Black women are hormone receptor-positive, this is a significant contributor to the overall mortality disparity. Importantly, these studies also suggested that Black women disproportionately develop biologically aggressive forms of hormone-dependent breast cancer, which is typically considered a more favorable disease subtype. Using data on more than 70,000 patients from the SEER registry that is linked to data from Genomic Health Laboratory, which provides the Oncotype DX recurrence score (the most commonly ordered prognostic/predictive multi-gene expression assay for early breast cancer), we set out to address three questions: 1) is there evidence of disproportionately aggressive tumor biology among Black women with hormone receptor (HR)-positive breast cancer, as reflected in the Oncotype DX recurrence score? 2) Is there a racial survival disparity even among patients with early stage, axillary node-negative tumors with comparable recurrence scores on the Oncotype assay? and 3) Is there is a difference in the prognostic accuracy of the Oncotype assay between Black and non-Hispanic white patients, since there was limited representation of Black women in the development and validation of the Oncotype assay and other prognostic/predictive assays?  (more…)