Most Patients Who Carry BRCA1/2 Pathogenic Variants Are Unaware

MedicalResearch.com Interview with:

Michael F. Murray, MD, FACMG, FACP Director for Clinical Operations in the Center for Genomic Health Yale School of Medicine

Dr. Murray

Michael F. Murray, MD, FACMG, FACP
Director for Clinical Operations in the Center for Genomic Health
Yale School of Medicine

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

Response: Population screening for the cancer risk associated with the BRCA1 and BRCA2 genes has been suggested by some.  We screened a cohort of about 50,000 adult patient volunteers at Geisinger Health System in Pennsylvania for this risk.  Continue reading

Age, Sex and Genetics Can Identify Groups at Higher Risk of Alzheimer’s Disease

MedicalResearch.com Interview with:

Ruth Frikke-Schmidt, Professor, Chief Physician, MD, DMSc, PhD Department of Clinical Biochemistry Rigshospitalet, Blegdamsvej & Deputy Head Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen

Dr. Frikke-Schmidt

Ruth Frikke-Schmidt, Professor, Chief Physician, MD, DMSc, PhD
Department of Clinical Biochemistry
Rigshospitalet, Blegdamsvej &
Deputy Head
Department of Clinical Medicine
Faculty of Health and Medical Sciences
University of Copenhagen

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

 

Response: Alzheimer’s disease and other forms of dementia are devastating, neurodegenerative disorders affecting more than 47 million people in 2015, a number projected to triple by 2050 (1,2). Available curative treatments are lacking, and no useful risk prediction tools exist. The potential for prevention is however substantial, emphasized by the recently observed incidence decline in Western societies, likely caused by improved treatment and prevention of vascular risk factors (1,3,4). Population growth and aging, will however triple dementia prevalence by 2050, if no action is taken. Acting now with ambitious preventive interventions, delaying onset of disease by five years, is estimated to halve the prevalence globally (1,5).

Despite important preventive efforts over the last decades – resulting in decreased smoking, lower blood pressure and lower cholesterol levels in the general population – physical inactivity, overweight, and diabetes remain threats for our health care system, and in particular for cardiovascular disease and dementia. Intensifying preventive efforts in general is thus of crucial importance, and especially for those patients at highest risk who most likely will benefit the most from early and targeted prevention. Risk stratification and specific treatment goals according to the estimated absolute 10-year risk, has been implemented in cardiovascular disease for years (6,7). There is an un-met need for similar strategies in dementia, underscored by the publication of several randomized multicomponent trials that seem to improve or maintain brain function in at-risk elderly people from the general population (8-10) Continue reading

Significant Sex Differences in Genetic Associations with Longevity

MedicalResearch.com Interview with:

Yi Zeng, Ph.D.| Professor, Center for Study of Aging and Human Development and Geriatrics Division, School of Medicine, Duke University Professor, National School of Development, Chief Scientist of Raissun Institute for Advanced Studies, Peking University Distinguished Research Scholar, Max Planck Institute for Demographic Research Foreign member of the Royal Netherlands Academy of Arts and Sciences

Dr. Yi Zeng

Yi Zeng, Ph.D.|
Professor, Center for Study of Aging and Human Development and Geriatrics Division, School of Medicine, Duke University
Professor, National School of Development, Chief Scientist of Raissun Institute for Advanced Studies, Peking University
Distinguished Research Scholar, Max Planck Institute for Demographic Research
Foreign member of the Royal Netherlands Academy of Arts and Science

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

Response: Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized healthcare.

Continue reading

Breast and Ovarian Cancers: More Genes Than BRCA1 and BRCA2

MedicalResearch.com Interview with:
Ambry GeneticsShuwei Li, PhD
Principal Statistical Geneticist
Ambry Genetics

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

Response: Breast cancer is the most commonly diagnosed cancer, while ovarian cancer is the fifth leading cause of death due to cancer, in US women. Since the discovery of BRCA1 and BRCA2, multiple genes have been reported as risk factors; however, it is still unclear whether the known findings represent the complete genetic landscape of breast and ovarian cancers.

Our team performed exome sequencing on more than 10,000 breast and/or ovarian cancer patients and nearly 4,000 controls. We observed increased risk of breast cancer associated with PALB2, ATM, CHEK2 and MSH6 genes, and increased risk of ovarian cancer associated with MSH6, RAD51C, TP53 and ATM genes.   Continue reading

Women Whose Mothers Lived to 90, Likely To Have Health Old Age

MedicalResearch.com Interview with:

Aladdin H. Shadyab, PhD  MS, MPH, CPH Department of Family and Preventive Medicine UCSD twitter.com/TheDrAladdin

Dr. Aladdin Shadyab

Aladdin H. Shadyab, PhD  MS, MPH, CPH
Department of Family Medicine and Public Health
University of California, San Diego
twitter.com/TheDrAladdin

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

Response: Previous studies have shown that offspring of long-lived parents are not only likely to live longer but to also avoid major chronic diseases (e.g., coronary heart disease), have fewer chronic disease risk factors, and to have better cognitive and physical function in late life. However, few studies have examined parental longevity in relation to an overall measure of successful aging that included reaching old age free of both major diseases and disabilities.

The objective of our study was to determine if parental longevity predicted healthy aging, defined as survival to age 90 without any major age-related diseases (coronary heart disease, stroke, diabetes, cancer, or hip fracture) or physical limitations. The participants of our study were from the Women’s Health Initiative, a large, longitudinal study among postmenopausal women from the United States.

We observed that women whose mothers survived to at least age 90 years were 25% more likely to achieve healthy aging. We also observed that women whose fathers only lived to age 90 did not have increased likelihood of healthy aging. However, women whose mother and father both lived to age 90 were the most likely to achieve healthy aging.

Continue reading

Study Identifies Gene Mechanism Linked to Fear and Aggression

MedicalResearch.com Interview with:

Prof. Carmen Sandi Director, Brain Mind Institute Laboratory of Behavioral Genetics Brain Mind Institute Ecole Polytechnique Federale de Lausanne Lausanne, Switzerland 

Prof. Sandi

Prof. Carmen Sandi
Director, Brain Mind Institute
Laboratory of Behavioral Genetics
Brain Mind Institute
Ecole Polytechnique Federale de Lausanne
Lausanne, Switzerland 

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

Response: We are interested in understanding how the brain regulates social behaviors and aggression, both in healthy individuals and individuals with psychiatric disorders. In our recent publication in Molecular Psychiatry, we investigated the impact of an alteration in a gene, St8sia2, that plays important roles during early brain development. Alterations in this gene have been linked with schizophrenia, autism and bipolar disorder, and individuals with these disorders frequently present high aggressiveness. In addition, expression of this gene in the brain can be altered by stressful insults during very early life and development.

Our study shows that genetic and environmental conditions linked to a reduction in the expression of this neuroplasticity gene during early life can lead to impaired fear learning and associated pathological aggression. We could further reveal that deficits in St8sia2 expression lead to a dysfunction in a receptor in the amygdala (a brain region critically involved in emotionality and fear learning), the GluN2B subunit of NMDA Receptors.

This allowed us to target this receptor with D-cycloserine, a drug that facilitates NMDA receptor function. This treatment, when given acutely, ameliorated the capacity to learn from adversity and reduced individuals’ aggressiveness.  Continue reading

Genes From Dad Influence How Mom Cares for Babies

MedicalResearch.com Interview with:
“Family” by IsaacVakeroKonor is licensed under CC BY 3.0Professor Rosalind John
Head of Biomedicine Division, Professor
School of Biosciences
Cardiff University
Cardiff UK

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

Response: I have been studying a really remarkable family of genes called “imprinted genes” for the last 20 years. For most genes, we inherit two working copies — one from our mother and one from our father. But with imprinted genes, we inherit only one working copy – the other copy is switched off by epigenetic marks in one parent’s germline. This is really odd because we are all taught at school that two copies of a gene are important to protect us against mutations, and much safer than only one copy. So why turn off one copy?

Maternal care boosted by paternal imprinting in mammals

Maternal care boosted by paternal imprinting in mammals

When my research group were studying these genes in mice, we found out that one of them, called Phlda2, plays an important role in the placenta regulating the production of placental hormones. Placental hormones are critically important in pregnancy as they induce adaptations in the mother required for healthy fetal growth. There was also some indirect evidence that placental hormones play a role in inducing maternal instinct. Women are not born with a maternal instinct –  this behaviour develops during pregnancy to prepare the mother-to-be for the new and demanding role of caring for her baby. This led to my idea that this gene expressed in the offspring’s placenta could influence maternal behaviour, which was entirely novel. 

Until now direct experimental evidence to support the theory that placental hormones trigger this “motherly love” by acting directly on the brain of the mother has been lacking. To test the theory that our imprinted gene could influence the mother’s behaviour by regulating placental hormones, we generated pregnant mice by IVF carrying embryos with different copies of Phlda2. We used IVF to keep all the mothers genetically identical. This resulted in genetically identical pregnant female mice exposed to different amounts of placental hormones – either low, normal or high.

We found that female mice exposed in pregnancy to low amounts of placental hormones were much more focused on nest building (housekeeping) and spent less time looking after their pups or themselves than normal mice. In contrast, female mice exposed to high placental hormones neglected their nests and spent more time looking after their pups and more time self-grooming. We also found changes in the mother’s brain before the pups were born so we know that the change in priorities started before birth. 

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

Response: This study is important because it shows, for the first time, that genes from the dad expressed in the placenta influence the quality of care mothers gives to their offspring. Perhaps more significantly, this study highlights the importance of a fully functional placenta for high quality maternal care.

We have shown in a mouse model that genes in the placenta and placental hormones are important for priming maternal nurturing in an animal model. Human placenta have the same imprinted genes and also manufactures placental hormones. It is possible that problems with the placenta could misprogram maternal nurturing in a human pregnancy and these mothers may not bond well with their newborn. It is also possible that problems with the placenta could contribute to depression in mothers. We are all familiar with postnatal depression but many more mothers experience depression in pregnancy with 1 in 7 mothers reporting clinically significant symptoms. 

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

Response: After we found out that Phlda2 could influence maternal behaviour in mice, we asked whether there were changes in this gene in human placenta from pregnancies where women were either diagnosed with clinical depression or self reported depression in pregnancy. Phlda2 seems to be OK but we found another gene that belongs to the same imprinted gene family called PEG3 that is expressed at lower than normal levels in women with depression. Strangely, this seems to only be in placenta from boys. 

MedicalResearch.com: Is there anything else you would like to add?

Response: To explore this further, we have just started our own human cohort study called “Grown in Wales” at Cardiff University focused on prenatal depression. We are now looking at placental hormones in the mother’s blood and gene expression in the placenta to test the idea that the genes we are studying in mice are misregulated in the placenta of pregnancies where the mothers suffer with depression. This work is now funded by the Medical Research Council.

Citation: 

Maternal care boosted by paternal imprinting in mammals

D. J. Creeth, G. I. McNamara,, S. J. Tunster, R. Boque-Sastre,, B. Allen,, L. Sumption, J. B. Eddy,A. R. Isles, R. M. John PLOS
Published: July 31, 2018

Aug 2, 2018 @ 11:48 pm 

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Alzheimer’s Disease: Genes Modify Effect of High Fat Diet

MedicalResearch.com Interview with:
The Jackson LaboratoryCatherine Kaczorowski, Ph.D.

Associate Professor and Evnin Family Chair in Alzheimer’s Research
Kristen O’Connell, Ph.D., Assistant Professor
Amy Dunn, Ph.D., Postdoctoral Associate
The Jackson Laboratory


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

Dr. Amy Dunn: “Alzheimer’s disease is complex, with both genetic and environmental factors determining symptom onset and disease progression, though our current understanding of how genetic and environmental factors interact to influence disease risk is incomplete. We recently developed a panel of genetically diverse mice carrying human familial AD mutations (AD-BXDs) that better model human AD in order to determine how genetics and diet interact to modify disease onset and severity.

We fed a high fat diet to AD-BXDs and monitored metabolic and cognitive function over the duration of the HFD feeding.  We observed accelerated working memory decline in most of the AD-BXD mouse strains, however, the impact of high fat diet on memory was dependent on individual genetic differences across the panel, with some AD-BXD strains maintaining cognitive function on high fat diet (resilient strains).

Our data suggest that diet and genetic background interact to mediate vulnerability to AD pathogenesis, and that metabolic factors (e.g. obesity, body composition) that may contribute to cognitive decline differentially in normal aging versus AD. “

Continue reading

PITS Gene Linked To Rare Neurologic Disorders

MedicalResearch.com Interview with: 

Paul C Marcogliese, Ph.D. Postdoctoral Associate, Laboratory of Dr. Hugo Bellen Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas 77030

Dr. Marcogliese

Paul C Marcogliese, Ph.D.
Postdoctoral Associate,
Laboratory of Dr. Hugo Bellen
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas 77030

Loren D. Pena, MD PhD Pediatric Medical Genetics Specialist Division of Medical Genetics, Department of Pediatrics Duke University School of Medicine, Durham, NC

Dr. Peña


Loren D. Pena, MD PhD
Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Department of Pediatrics
University of Cincinnati
Cincinnati, OH 45229


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

Response: The Undiagnosed Diseases Network (UDN) is a multi-site collaboration across the US that seeks to help diagnose patients with rare disorders that are ill-defined.

Dr. Loren D.M. Pena and Dr. Vandana Shashi at the Duke-Columbia clinical site of the UDN had seen a patient with a severe neurological disorder. While the patient had no symptoms at birth, the patient began falling at about 3 years of age, eventually losing motor coordination and developing seizures. In the interim, the regression has progressed to a severely debilitating state. Re-analysis of the participant’s exome data by our site bioinformatician at Columbia (Nicholas Stong) in Dr. David Goldstein’s laboratory revealed a truncating variant in the single exon gene IRF2BPL that could be the candidate disease-causing gene. The UDN clinicians at Duke then contacted the UDN Model Organism Screening Center (MOSC) led by Dr. Hugo Bellen at Baylor College of Medicine and the Howard Hughes Medical Institute for functional analysis. In parallel, four more patients were found with truncating mutations causing a similar disorder though the UDN and GeneMatcher.org. Additionally, two patients with missense variants in IRF2BPL were identified that displayed seizures and some developmental delay or autism spectrum disorder but no motor regression.

Work in MOSC by Dr. Paul Marcogliese using fruit flies revealed that the IRF2BPL truncating variants are severe loss of function mutations and one of the missense variants was a partial loss of function. Additionally, it was found that the fruit fly IRF2BPL gene, called pits, is expressed in the neurons of the adult fly brain. Lowering the levels of pits by about 50% in fly neurons leads to progressive behavioural abnormalities and neurodegeneration. By combining the human genetics, bioinformatics and model organism data, IRF2BPL was found to be a novel disease-causing gene in humans.

Continue reading

Genetic Testing Could Identify Individuals At Risk of Osteoporosis

MedicalResearch.com Interview with:

Stuart Kim - PhD Professor of Developmental Biology, Emeritus Bio-X Affiliated Faculty James H. Clark Center Stanford University

Dr. Kim

Stuart Kim PhD
Professor of Developmental Biology, Emeritus
Bio-X Affiliated Faculty
James H. Clark Center
Stanford University 

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

Response: Osteoporosis is caused by a reduction in bone mass, and leads to a high incidence of bone fracture because the weakened bone is less able to withstand the stress of slips and falls. Osteoporosis affects millions of elderly, is responsible for as many as 50% of fractures in women and 25% of fractures in men over the age of 50, and accounts for $19 billion in annual health care costs in the US. Identification of people with an increased genetic risk for osteoporosis could reduce the incidence of bone fracture. Low BMD is also a risk factor for stress fractures. For athletes and military personnel undergoing harsh rigors of training, stress fractures are common injuries that limit playing time, military effectiveness and competitive success.

Using data from UK Biobank, a genome-wide association study identified 1,362 independent SNPs that clustered into 899 loci of which 613 are new. These data were used to train a genetic algorithm using 22,886 SNPs as well as height, age, weight and sex as predictors. Individuals with low genetic scores (about 2% of those tested) showed a 17-fold increase in risk for osteoporosis and about a 2-fold increase in risk of fractures. Continue reading

Novel Models of Late-Onset Alzheimer’s Disease Based on GWAS

MedicalResearch.com Interview with:

Gregory Carter

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: Animal models for late-onset Alzheimer’s disease (LOAD) will be of significant benefit for the discovery and characterization of links between specific genetic factors and the molecular pathways associated with the disease. To date, most animal models have been based on rare, early-onset Alzheimer’s disease genes that incompletely capture the complexity of LOAD and have not translated well to therapies. Therefore, developing and utilizing animal models based on genes hypothesized to play a role in LOAD will provide new insights into its basic biological mechanisms.  Continue reading

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.

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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.

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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.

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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.

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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