Whole-Exome Analysis of Late-Onset Alzheimer’s Disease Reveals Novel Candidate Genes Involved in Cognitive Function

MedicalResearch.com Interview with:

Dr. Carter

Gregory Carter, PhD
Associate Professor at The Jackson Laboratory

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

Response: Late-onset Alzheimer’s disease (LOAD) is the most common form of the disease and the major cause of dementia in the aging population. To date, the complex genetic architecture of LOAD has hampered both our ability to predict disease outcome and to establish research models that effectively replicate human disease pathology.

Therefore, most basic research into Alzheimer’s disease has focused on early-onset forms caused by mutations in specific genes, which has provided key biological insights but to date has not translated to effective disease preventatives or cures.

Our study analyzes both common and rare human genetic variants to identify those significantly associated with .late-onset Alzheimer’s disease, beginning with a large data set from the Alzheimer’s Disease Sequencing Project. We also analyzed RNA sequencing data from post-mortem human and mouse model samples to prioritize candidate genes.

We found a new common coding variant significantly associated with disease, in addition to those in genes previously associated with late-onset Alzheimer’s disease. We also found five candidate genes conferring a significant rare variant burden.  Continue reading

Changing One Gene in One Gut Bacteria Altered Metabolism and Weight Gain (in mice)

MedicalResearch.com Interview with:

A. Sloan Devlin, PhD Assistant Professor Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School

Dr. Devlin

A. Sloan Devlin, PhD
Assistant Professor
Department of Biological Chemistry and Molecular Pharmacology
Harvard Medical School

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

Response: It is known that the microbiome, the collection of bacteria that live in and on our bodies, influences the development of metabolic diseases including diabetes and obesity. The ways in which the microbiome affects host metabolism, however, are poorly understood. One reason for this lack of understanding is because the gastrointestinal tract contains hundreds of species of bacteria producing many different kinds of metabolites. Untangling the effects of these bacteria and the molecules they make is a significant challenge.

In this study, we decided to concentrate on a group of metabolites found in the human gut called bile acids. When we eat a meal, these compounds are released into the gastrointestinal tract where they act as detergents that aid in digestion. Once these molecules reach the lower gastrointestinal tract, the gut bacteria residing there chemically modify these compounds, producing a pool of over 50 different bile acids total.

Imbalances in this bile acid pool are thought to influence the progression of diet-induced obesity. However, it is unclear which specific bile acids are responsible for either beneficial or detrimental effects on host metabolism. We set out to address this question by first identifying a selective type of bacterial enzyme called a bile salt hydrolase, then by genetically deleting this enzyme from a common gut bacterium and investigating how this change affected host metabolism.

Continue reading

Novel Mechanisms and Clinical Aspects for an Aggressive Prostate Cancer Risk Locus Uncovered

MedicalResearch.com Interview with:

Gong-Hong Wei, PhD Professor, Academy Research Fellow Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu University of Oulu, Finland

Dr. Gong-Hong Wei,

Gong-Hong Wei, PhD
Professor, Academy Research Fellow
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu
University of Oulu, Finland

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

Response: Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related death in men, with more than 1,100,000 new cases diagnosed and 300,000 deaths yearly around the globe. Among the risk factors for prostate cancer development, the genetic heritability of prostate cancer has been reported near 60%. Over the past decade, genome-wide association studies have identified more than 150 independent single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, we know very little mechanisms accounting for these associations.

SNP rs11672691 at the chromosome 19q13 locus has been found not only associated with prostate cancer risk but also aggressiveness, a form of prostate cancer often with worse prognosis and eventually progression to incurable stage. However, how this genomic variant accounts for prostate cancer severity remains totally unknown. Here we found the association of rs11672691 with additional clinical features of aggressive prostate cancer in an independent cohort of patients with prostate cancer, and discovered a rs11672691-mediated gene regulatory network including several novel genes, HOXA2, CEACAM21 and PCAT19, likely causing prostate cancer progression to incurable stage. In particular, the risk G (guanine) allele of rs11672691 was associated with higher RNA levels of PCAT19 and CEACAM21, and poor prognosis in prostate cancer patients. Rs11672691 G allele enhances chromatin binding of HOXA2 to regulate the expression of CEACAM21 and PCAT19. Using the CRISPR-Cas9 genome editing method, we revealed that rs11672691 genotype directly influence HOXA2 in regulating PCAT19 and CEACAM21 expression, and prostate cancer cellular phenotype.

Continue reading

Yin Yang 1 Regulatory Protein May Help Breast Cancer Evade Treatment

MedicalResearch.com Interview with:

Luca Magnani, Ph.D CRUK Fellow/Senior Research Fellow Department of Surgery and Cancer Imperial Centre for Translational and Experimental Medicine Room 140 1st floor ICTEM building Imperial College Hammersmith London, UK

Dr. Magnani

Luca Magnani, Ph.D
CRUK Fellow/Senior Research Fellow
Department of Surgery and Cancer
Imperial Centre for Translational and Experimental Medicine
Room 140 1st floor ICTEM building
Imperial College Hammersmith
London, UK

MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by the Yin Yang1 molecule?

Response: This study was designed to investigate the evidence of non-genetic mechanisms that could contribute to breast cancer biology. Specifically, we developed a map of regulatory regions from luminal breast cancer patients. Regulatory regions are pieces of DNA that are not transcribed into protein-coding genes but they provide information about where and how much each gene should be activated.

It is worth highlighting that cancer is not only the consequence of gene mutations but also the result of the wrong genes expressed at the wrong time.  To catalogue regulatory regions we looked for specific modifications that are strongly associated with their activity (epigenetic modifications). Doing so we developed the first extensive catalogue  of non-coding DNA regions that might play an essential role in regulating how breast cancer cell behaves. Regulatory regions do their job by interacting with specific molecules called transcription factors. These molecules can read the information stored in these regulatory regions and contribute to regulate gene expression. Yin Yang 1 is one of such molecules and was previously thought as a ambiguous player capable of activating or repressing gene activity.   Continue reading

So Far, Genes Don’t Explain How Many Calories We Consume

MedicalResearch.com Interview with:
“In-N-Out meal #1” by Chris Makarsky is licensed under CC BY 2.0Dr. Christina Holzapfel PhD
Junior Research Group Leader at
Institute for Nutritional Medicine
Technical University of Munich

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

Response: A lot of articles about genetic factors and nutritional intake have been published in the last years. Findings are inconsistent and it is not clear, whether genetic variants, especially associated with body mass index, are associated with nutritional intake.

Therefore we performed a systematic literature search in order to get an overview about the association between single nucleotide polymorphisms and total energy, carbohydrate and fat intakes. We identified about specific search terms and their combinations more than 10,000 articles. Of these, 39 articles were identified for a relationship between genetic factors and total energy, carbohydrate, or fat consumption.

In all studies, we most frequently encountered the fat mass and obesity (FTO) associated gene as well as the melanocortin 4 receptor gene (MC4R). There are indications of a relationship between these two genes and total energy intake. However, the evaluation of the studies did not provide a uniform picture. There is only limited evidence for the relationship between the FTO gene and low energy intake as well as between the MC4R gene and increased energy intake.

Continue reading

Gene Biomarker Can Predict Brain Tumor Patients Who Have Better Outcomes

MedicalResearch.com Interview with:

Arnab Chakravarti MD Professor and Chair of Radiation Oncology Arthur G. James Cancer Hospital and Richard J. Solove Research Institute The Ohio State University Comprehensive Cancer Center

Dr. Chakravarti

Arnab Chakravarti MD
Professor and Chair of Radiation Oncology
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
The Ohio State University Comprehensive Cancer Center

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

Response: Historically, the treatment for grade two gliomas has been a black box without really a standard-of-care therapy. In the past, it was really dealer’s choice, where it was based upon physician and patient preference. Either radiation alone, radiation plus chemotherapy, or chemotherapy alone, there wasn’t really any data to guide therapeutic decision-making. Then about three years ago the landmark study RTOG 9802 was published, which demonstrated a survival benefit with the addition of chemotherapy to radiation versus radiation alone. That became the standard of care for the treatment of grade two gliomas.

One of the tricky issues with regards to these tumors is that there’s a wide range of outcomes.

There are patients that succumb to disease within months, others that live decades. It’s very
important to personalize care for the individual patient and that’s why biomarkers, prognostic and predictive biomarkers are so important. The 9802 study showed us for the general population of patients that the addition of chemotherapy to radiation improved outcomes versus radiation alone.

The patient population that was selected for our study were the high-risk low-grade glioma
patients. Patients who are generally over the age of 40, tumor sizes that exceeded 6 cm in terms of maximum dimension, tumors that invaded the corpus callosum, astrocytic histology of patients with neurological symptoms. These are typically the patients that were included in the study. Really the main objective of this study was to determine the efficacy of treatment compared to historical controls. Continue reading

Gene Deficit May Give Immunity to Effects of Cocaine

MedicalResearch.com Interview with:
“Cocaine concealed in washing powder” by The National Crime Agency is licensed under CC BY 2.0

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

Response: Drug addiction is a chronically relapsing neuropsychiatric disease that affects 15.5 million people in Europe at a cost of 65.7 billion euros per year. All addictive drugs have in common to cause an artificial increase in the release of a neurotransmitter called dopamine, a very basic effect that can be found in all studied animal species from the fly to the man. The release of dopamine takes place in a region of the brain called the ventral striatum, or Nucleus Accumbens (NAc), which is directly involved in reward and reinforcement processes. An excess of dopamine release by the dopaminergic neurons projecting to the NAc from the Ventral Tegmental Area (VTA) triggers long-term changes in the brain, which can lead to addiction.

Cocaine is a prototypical addictive drug, since it is heavely abused in Western societies and extensively studied in animal models as well as humans.

We discovered that mice lacking the Maged1 gene showed a marked decrease in cocaine-elicited release of dopamine in the NAc and were entirely unresponsive to cocaine at behavioral level. In fact, they did not show any behavioral reaction normally observed after cocaine treatment, such as cocaine-elicited hyperlocomotion, sensitization (an increased effect of the drug following repeated administrations) or addictive behaviors, such as increased preference for places where the animal expects to obtain a cocaine reward or cocaine self-administration.

In a subsequent set of experiments, the researchers tried to identify what brain regions are responsible for Maged1 influence on cocaine effects and found that Maged1 expression is specifically required in the prefrontal cortex, and not in the neurons producing dopamine in the VTA, for the development of cocaine sensitization and dopamine release.  Continue reading

Parents and Siblings of Supercentenarians Also Live Extended Lives

MedicalResearch.com Interview with:
“siblings” by Katina Rogers is licensed under CC BY 2.0Stacy L. Andersen, PhD

Assistant Professor of Medicine
Project Manager
New England Centenarian Study
Long Life Family Study
Boston University School of Medicine
Boston Medical Center
Boston, MA 02118

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

Response: Exceptional longevity appears to run in families. Previous studies have found that people who have siblings who live into their 90s or who reach 100 years of age have a greater chance themselves of living longer than the general population. Yet it is supercentenarians, those who reach the age of 110 years, who represent the true extreme of the human lifespan.  We wanted to determine whether the parents and siblings of supercentenarians were more likely to reach very old ages than family members of younger centenarians.

We collected family tree information for 29 participants of the New England Centenarian Study aged 110-119 years. Proof of age documents and familial reconstruction methods were used to validate ages and dates of birth and death of the supercentenarian as well as his or her parents and siblings. Mean age at death was compared to birth year and sex-specific US and Swedish cohort life table estimates conditional on survival to age 20 for siblings to omit deaths due to nonheritable factors such as infectious disease or accidents and survival to age 50 (the approximate age at which women are no longer able to reproduce) for parents.  Continue reading

Bad Genes and Unhealthy Lifestyle Contribute to Cardiovascular Risk

MedicalResearch.com Interview with:

Pim van der Harst MD, MSc Professor and Scientific Director Cardiac Catheterization Laboratory University Medical Center Groninger

Dr. van der Harst

Pim van der Harst MD, MSc
Professor and Scientific Director Cardiac Catheterization Laboratory
University Medical Center Groninger

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

Response: Cardiovascular disease is the leading cause of morbidity and mortality worldwide. The disease is driven by both genetic (inherited) and lifestyle factors such as smoking, physical activity and body mass index (BMI).

However, little is known about the interplay between genetic and lifestyle factors. So we looked into how lifestyle influences risk in individuals with a low genetic risk compared to those with a high genetic risk.

 

MedicalResearch.com: What are the main findings?

Response: We studied 339,003 unrelated individuals participating in UK Biobank project and looked into 5 very important cardiovascular conditions: coronary artery disease, atrial fibrillation, stroke, hypertension and type 2 diabetes.

We then calculated the genetic risk of these individuals bases on the DNA information and assessed their lifestyle. We found that both genetics and an unhealthy lifestyle increased the risk of developing these conditions in an additive way.

Risk appears simply as a summation of bad genes and an unhealthy lifestyle, there is no multiplier effect. A healthy lifestyle is always beneficial, independent of the luck you had with your genes. However, we do see patterns suggesting that for some conditions the risk is approximately the same for those with good genes and poor lifestyle compared to those with poor genes and a poor lifestyle. Best is to have both, good genes and a healthy lifestyle. 

MedicalResearch.com: What should readers take away from your report?

Response: No matter how good your genes are, a good lifestyle is always beneficial. However, if you have a high genetic risk you really should pay even more attention an adhering to a healthy lifestyle, otherwise they are in double trouble. Also our study is important as it lays a foundation for personalized risk assessment. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Now we can combine the personal genetics with a person’s lifestyle we should work towards personalized risk assessment and estimate the effect of lifestyle changes for an individual.

No disclosures

Citation: 

Associations of Combined Genetic and Lifestyle Risks With Incident Cardiovascular Disease and Diabetes in the UK Biobank Study – M. Abdullah Said, Niek Verweij, Pim van der Harst. JAMA Cardiology 2018 

The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.

 

Risky Drinking By Either Sex Can Affect Future Offspring

MedicalResearch.com Interview with:

Toni Pak, Ph.D. Professor and Department Chair Department of Cell and Molecular Physiology Loyola University Chicago Maywood, Ill 

Dr. Pak

Toni Pak, Ph.D.
Professor and Department Chair
Department of Cell and Molecular Physiology
Loyola University Chicago
Maywood, Ill 

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

Response: We have known for many years that drinking alcohol during pregnancy can lead to developmental delays and birth defects in offspring. However, our data demonstrate that drinking large quantities of alcohol in a “binge” fashion before pregnancy can also impact future offspring and importantly, this is true for drinking behaviors of both parents, not just the mother.

Our previous data support the idea that alcohol is affecting the parental sperm and eggs to induce these modifications in the offspring, but this most recent work shows the extent of those effects on social behavior, pubertal maturation, and stress hormones as the offspring grow to adulthood.

This means that the risky behaviors of young people, such as the extremely popular practice of binge drinking, have potentially far-reaching consequences for generations to come.

Continue reading

CRISPR-Gold Has Potential To Edit Brain Genes

MedicalResearch.com Interview with:

Niren Murthy PhD Professor of Bioengineering University of California at Berkeley

Prof. Murthy

Niren Murthy PhD
Professor of Bioengineering
University of California at Berkeley

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

Response: In this paper we delivered Cas9 RNP in the brain using a delivery vehicle termed CRISPR-Gold.  We were able to knock out the mGluR5 gene and rescue mice from autism using CRISPR-Gold.  The background here is that there is a great need for safe and effective CRISPR delivery vehicles, and that brain gene editing has great therapeutic potential.  This paper demonstrates for the first time that non-viral delivery of Cas9 RNP into the brain can have therapeutic effects.

MedicalResearch.com: What should clinicians and patients take away from your report?

Response: Brain gene editing has tremendous therapeutic potential, and can be achieved with non-viral Cas9 RNP delivery

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response:   We need to be able to edit the brains of large animals.  The particles will need to be modified for this, we are currently working on this.  GenEdit, a start-up company spun out from our lab, is also working on this.

Disclosures: I was a co-founder of GenEdit, but now have no equity in GenEdit, there should be no conflict of interest

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Bumwhee Lee, Kunwoo Lee, Shree Panda, Rodrigo Gonzales-Rojas, Anthony Chong, Vladislav Bugay, Hyo Min Park, Robert Brenner, Niren Murthy, Hye Young Lee. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nature Biomedical Engineering, 2018; DOI: 10.1038/s41551-018-0252-8

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

 

 

 

 

 

 

Genetic Variants Help Identify Men At Highest Risk of Prostate Cancer

MedicalResearch.com Interview with:

Fredrick R. Schumacher, PhD, MPH. Associate Professor, Department of Population & Quantitative Health Sciences Case Western Reserve University Cleveland

Dr. Schumacher

Fredrick R. Schumacher, PhD, MPH.
Associate Professor, Department of Population & Quantitative Health Sciences
Case Western Reserve University
Cleveland

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

Response: Our study examines the genetic underpinnings of prostate cancer initiation using technology to test variants across the genome. Our study focused on men of European ancestry and included over 80,000 men with prostate cancer and 60,000 men without disease. We discovered 63 novel genetic variants associated with prostate cancer risk, which increases our knowledge of prostate cancer genetic risk factors by more than 60%.

A genetic risk score created from the combination of 163 new and known prostate cancer risk variants revealed men with the highest genetic risk score are nearly seven times more likely to develop disease compared to the average man. Additionally, men with the lowest genetic risk score have a 85% risk reduction of developing prostate cancer compared to the average. Lastly, these new discoveries uncover several biological mechanisms involved in the initiation of prostate cancer.

Continue reading

Protein Functions of DISC1 Gene Linked to Schizophrenia Identified

MedicalResearch.com Interview with:
Marcelo Pablo Coba PhD
Assistant Professor of Psychiatry
Zilkha Neurogenetic Institute
Keck School of Medicine of USC

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

Response: Psychiatric diseases such as schizophrenia (SCZ) are complex brain disorders where a multitude or risk factors have been implicated in contributing to the disease, with a low number of genes that have been strongly implicated in a very low number of cases.

One of these genes is Disrupted in schizophrenia 1 (DISC1), which was first described in 2000 as a balanced translocation that segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Because DISC1 does not have an identified protein function such as enzymatic, channel, transporter, etc… the field moved to try to understand what proteins are associated (physically connected) to DISC1 and to try to explain DISC1 function through the function of its protein interactors. This means that if DISC1 binds proteins X, Y and Z, then mutations in the DISC1 gene should affect the functions of   these proteins. Therefore, there has been much effort in trying to identify DISC1 protein interactors. However this task has not been straightforward.

Continue reading

Genes Linked To Large Brains in Humans Identified

MedicalResearch.com Interview with:
“The human Brain” by Kristian Mollenborg is licensed under CC BY 2.0David Haussler PhD

Investigator, Howard Hughes Medical Institute
Distinguished Professor, Biomolecular Engineering
Scientific Director, UC Santa Cruz Genomics Institute
Scientific Co-Director, California Institute for Quantitative Biosciences  and

Sofie Salama, PhD
Research Scientist in BIomolecular Engineering
Howard Hughes Medical Institute Senior Scientist

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

Dr. Haussler:  Researchers specializing in this area are interested understanding which evolutionary changes in our genome underlie human-specific brain features including our large (3X greater than chimpanzee) brain.

It has been my personal dream to peer into human evolution at the level of individual genes and gene functions.  Continue reading

RNA-Editing Tool Corrects Collagen Deficit in Severe Blistering Disorder

MedicalResearch.com Interview with:
http://www.proqr.com/team-and-boards/Daniel de Boer
Founding Chief Executive Officer
ProQR

MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by dystrophic epidermolysis bullosa?

Response: Dystrophic epidermolysis bullosa (DEB) is caused by a mutation in the COL7A1 gene which is responsible for the formation of a protein called type VII collagen (C7). This protein helps bind the inner and outer layers of the skin together. Mutations in one part of COL7A1 gene, exon 73, are the most common cause of DEB resulting in a non-functional C7 protein. ProQR’s QR-313 is designed to skip exon 73 of the COL7A1 gene, leading to a shortened C7 protein called C7Δ73. The current studies are intended to determine whether C7Δ73 functions the same as normal C7 protein. This mechanism can hopefully restore normal skin function for DEB patients.

DEB is a rare genetic skin disease characterized by easy blistering of the skin, poorly healing wounds and skin infections. DEB is present at birth and in severe cases leads to skin cancer, which can significantly reduce a patient’s lifespan. There are currently no treatments for DEB that target the underlying cause of the disease. The current standard of care consists of expensive time-consuming wound care, antibiotics to prevent infection and pain medications. As a result, this disease presents a huge burden to the patients themselves, as well as people who help with daily care.

Continue reading

If Maternal Grandmother is Obese, So is Grandchild?

MedicalResearch.com Interview with:
“Great Grandmother” by David Amsler is licensed under CC BY 2.0Rebecca Somerville MB BCh BAO, BMedSci, MRCPI, MPH, PhD
School of Public Health, Physiotherapy and Sports Science
University College Dublin
Dublin, Ireland 

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

Response: Rates of obesity in the Western world have increased dramatically over recent decades. The negative health consequences of obesity are well known and significant amounts of research have been conducted into the causes and possible solutions. While it is clear that there have been massive changes in diet and physical activity at a societal level that are primarily responsible for this ‘obesity epidemic’, it is less clear the extent to which obesity, once established, or risk factors for same, can be perpetuated down generations. Family studies lend opportunity to explore these questions, however there are few world wide which incorporate 3 generations.

We therefore sought to examine patterns of central adiposity, as measured by waist circumference, between grandparents and their grandchildren, separately in maternal and paternal lines. We were able to utilize prospectively collected data from the Lifeways Cross-Generation Cohort Study. This is a longitudinal birth cohort, established in Ireland in 2001, involving up to 7 members of the same family (mother, father, child and 4 grandparents). In the 589 families where a child had a waist circumference measurement we found that, at the age of both 5 and 9, there was a direct relationship between the waist circumference of the maternal grandmother and her grandchild (both male and female). This remained after adjustment for a wide range of confounding variables including mother’s waist circumference. There was no relationship seen with any of the other grandparents.

Continue reading

Genetic Factors Control Heart Rate in Response to Exercise

MedicalResearch.com Interview with:

Professor Patricia Munroe PhD Professor of Molecular Medicine William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London

Prof. Munroe

Prof. Patricia Munroe PhD
Professor of Molecular Medicine
William Harvey Research Institute
Barts and The London School of Medicine and Dentistry
Queen Mary University of London

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

Response: Over the years, it has become increasingly evident that impaired capacity to increase heart rate during exercise and reduce heart rate following exercise are important predictors of all-cause and cardiovascular mortality. A person’s capability to regulate their heart rate is the result of complex interactions of biological systems, including the autonomic nervous and hormonal systems. Prior work has demonstrated that genetic factors significantly contribute to variations in resting heart rate among different individuals, but less was known about the genetic factors modulating the response of heart rate to exercise and recovery.

Continue reading

LPA Gene Variants Linked To Cardiac Events Despite Statins

MedicalResearch.com Interview with:

Wei-Qi Wei, MD, PhD Assistant Professor Department of Biomedical Informatics Vanderbilt University Nashville, TN 37203

Dr. Wei-Qi Wei

Wei-Qi Wei, MD, PhD
Assistant Professor
Department of Biomedical Informatics
Vanderbilt University
Nashville, TN 37203

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

Response: The study was motived by the clinical observation that some patients develop coronary heart disease events despite taking statins, one of our most effective drugs to reduce cardiovascular risk. We collected data within the eMERGE network of people taking statins and monitored them for development of coronary heart disease events over time.  We  conducted a genome-wide association study of those with events compared to those without events.

Our results showed that single nucleotide polymorphisms (SNPs) on the LPA gene were associated with a significantly increased risk of coronary heart disease events. Individuals with the variant were 50% more likely to have an event. More importantly, even among patients who achieved ideal on-treatment LDL cholesterol levels (<70 mg/dL), the association remained statistically significant.

We then did a phenome-wide association study to see if other diseases or conditions were associated with these LPAvariants. The major associated conditions were all cardiovascular. This sort of study can highlight potential other indications for a drug targeting this pathway and suggest potential adverse events that might be experienced from targeting this pathway. Clearly, more and larger studies will be needed to truly understand the potential risks and benefits of a future drug targeting this pathway.  Continue reading

Functional Brain ‘Fingerprint’ Identified in Schizophrenia

MedicalResearch.com Interview with:

Tobias Kaufmann UiO Institute of Clinical Medicine

Dr. Kaufmann

Tobias Kaufmann PhD
Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine
University of Oslo, Oslo, Norway

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

Response: Over the past years, a lot of work has pointed toward impaired brain networks in schizophrenia. With this work we assessed brain network stability across different loads of a cognitive task using functional magnetic resonance imaging of the brain.

Based on our earlier work on adolescents with pre-clinical signs of mental illness who showed decreased stability of networks across different tasks and conditions, we hypothesized that brain networks in adults with schizophrenia show similar properties of decreased stability. Our results confirmed this hypothesis. Stability was reduced in several large-scale brain networks across the sampled age range from early adulthood to the sixties. Further, network stability was associated with polygenic risk for schizophrenia as well as cognitive task performance.

Continue reading

Benefits and Complexities of More Breast Cancer Genes to Screen For

Dr-Allison W. Kurian

Dr. Kurian

MedicalResearch.com Interview with:
Allison W. Kurian, M.D., M.Sc.

Associate Professor of Medicine (Oncology) and of Health Research and Policy
Director, Women’s Clinical Cancer Genetics Program
Stanford University School of Medicine
Stanford, CA 94305-5405 

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

Response: Changes in genetic sequencing technology and regulation have allowed much cheaper testing of many more genes in recent years. We investigated how these changes have affected hereditary cancer risk evaluation in women newly diagnosed with breast cancer.

The main findings are that more comprehensive multiple-gene sequencing tests have rapidly replaced more limited tests of two genes (BRCA1 and BRCA2) only. This has helped patients by doubling the chance of finding an important gene mutation that can change their treatment options.

However, there are important gaps in how this new, more comprehensive sequencing is used: more testing delays and more uncertain results, particularly among racial/ethnic minority women.  Continue reading

How Many Diseases Should Newborns Be Screened For?

MedicalResearch.com Interview with:
“Newborn” by Brad Carroll is licensed under CC BY 2.0Dr Sian Taylor-Phillips MPhys, PhD
Associate Professor Screening and Test Evaluation /
NIHR Career Development Fellow
Division of Health Sciences
Warwick Medical School
University of Warwick Coventry

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

Response: In newborn blood spot screening a small amount of blood is taken from newborn babies heels, and this is tested for a range of rare diseases. The idea is to detect each disease earlier when it is more treatable. However, it would be better not to test for some diseases, for example if the test is inaccurate so worries parents that their baby may have a serious illness when they do not. Some countries test for as few as 5 diseases and others as many as 50. In this study we investigated how different countries choose which diseases to test for.

We found that many national recommendations on whether to screen newborn babies for rare diseases do not assess the evidence on the key benefits and harms of screening. Evidence about the accuracy of the test was not considered in 42% of recommendations, evidence about whether early detection at screening has health benefits was not consulted in 30% of recommendations, and evidence around the potential harm of overdiagnosis where babies have variants of the disease that would never have caused any symptoms or ill effects was not considered in 76% of recommendations.

We also found through meta-analysis that when a systematic review was used to bring together the evidence then countries were less likely to recommend screening for the disease.

Continue reading

New Hope For Patients With Rare Form of Overeating Disorder

MedicalResearch.com Interview with:
“Mmm...hamburgers” by jeffreyw is licensed under CC BY 2.0
Dr. Peter Kühnen
Institute for Experimental Pediatric Endocrinology
Charité Universitätsmedizin Berlin
Berlin Germany 

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

Response: We are focusing our interest on rare monogenic forms of obesity.

The hormones leptin and MSH are playing a pivotal role for the regulation of satiety and body weight. Mutations within this pathway, e.g. in the leptin receptor gene, are leading to severe hyperphagia and early onset obesity.  Although tremendous effort it is extremely difficult for the affected patients to stabilize their body weight for a longer period of time. For this reason it has been analyzed within this investigated initiated trial whether patients with a leptin receptor mutation benefit from a treatment with the MC4R agonist setmelanotide. The treatment led to a reduction of the initially increased hunger feeling and to a reduction of body weight. Additionally, we identified molecular evidences that a specific signaling cascade of the MSH receptor (MC4R) is of importance for the regulation of body weight. Continue reading

Chemotherapy Choice Can Be Aided By Assessing TDP Profile

MedicalResearch.com Interview with:

Ed Liu, M.D President and CEO The Jackson Laboratory (JAX)

Dr. Ed Liu

Ed Liu, M.D
President and CEO
The Jackson Laboratory (JAX)

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

Response: A few years ago we and others identified a complex genomic instability profile commonly found in the genomes of breast, ovarian and endometrial carcinomas, which is characterized by hundreds of isolated head-to-tail duplications of DNA segments, called tandem duplications. We refer to this configuration as the tandem duplicator phenotype, or TDP.

In this study, we perform a meta-analysis of over 2,700 cancer genomes from over 30 different tumor types and provide a detailed description of six different types of TDP, distinguished by the presence of tandem duplications of different sizes. Collectively, these profiles are found in ~50% of breast, ovarian and endometrial carcinomas as well as 10-30% of adrenocortical, esophageal, stomach and lung adeno-carcinomas. We show that distinct genetic abnormalities associate with the distinct TDPs, clearly suggesting that distinct molecular mechanisms are driving TDP formation. In particular, we provide strong evidence of a casual relationship between joint abrogation of the BRCA1 and TP53 tumor suppressor genes and the emergence of a short-span (~11 Kb) TDP profile. We also observe a significant association between hyper-activation of the CCNE1 pathway and TDP with medium-span (~230 Kb) tandem duplications, and between mutation of the CDK12 gene and medium- and large-span TDP (coexisting 230 Kb and 1.7 Kb tandem duplications).

Importantly, we find that different forms of TDP result in the perturbation of alternative sets of cancer genes, with short-span TDP profiles leading to the loss of tumor suppressor genes via double transections, and larger-span TDP profiles resulting in the duplication (i.e. copy number gain) of oncogenes and gene regulatory elements, such as super-enhancers and disease-associated SNPs.  Continue reading

Epigenetic DNA Variants Predictive of Coronary Artery Disease

MedicalResearch.com Interview with:

Stella Aslibekyan, PhD Associate Professor PhD Program Director Department of Epidemiology University of Alabama at Birmingham

Dr. Aslibekyan

Stella Aslibekyan, PhD
Associate Professor
PhD Program Director
Department of Epidemiology
University of Alabama at Birmingham

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

Response: When the human genome was sequenced in 2003, there were somewhat unrestrained expectations of unraveling all etiologic mysteries and discovering breakthrough treatments. Needless to say, that did not happen, in part because individual genetic variants can only account for a small fraction of trait variability. Since then, epigenetics– the study of mitotically heritable changes in gene expression– has emerged as another promising avenue for understanding disease risk. The best studied epigenetic process in humans is DNA methylation, and earlier studies (including some from our group) have shown interesting associations between changes in methylation in specific genomic regions and cardiovascular disease traits, e.g. plasma cholesterol levels.

In this project, we have combined DNA methylation data on thousands of individuals from multiple international cohorts and interrogated epigenetic contributions to circulating tumor necrosis factor alpha (TNFa), a marker of systemic inflammation. We identified and replicated several epigenomic markers of TNFa, linked them to variation in gene expression, and showed that these methylation changes (which were located in interferon pathway genes) were predictive of coronary heart disease later in life. Interestingly, the variants we discovered were not sequence-dependent (in other words, they were not associated with any genetic mutations), highlighting the role of the environment.

Continue reading

Mouse Model Shows Gene Therapy Can Reverse Blue Cone Vision Disorder

MedicalResearch.com Interview with:

Wen-Tao Deng,

Dr. Wen-Tao Deng

Wen-Tao Deng, Ph.D.
Department of Ophthalmology, College of Medicine|
University of Florida, Gainesville, FL

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

Response: Blue cone monochromay (BCM) is a devastating vision disorder characterized by loss function of both L- and M-cones due to mutations in the L- and M-opin gene cluster on the X chromosome. BCM patients display severely reduced visual acuity, loss of color-vision, myopia, nystagmus, and minimally detectable cone-mediated electroretinogram. In our studies, we showed that an M-opsin knockout mouse model resembles human BCM, and expression of either human M- or L-opsin individually or combined through adeno-associated viral vector promotes regrowth of cone outer segments and rescues M-cone function in the treated M-opsin dorsal retin

Continue reading