Chin K.,Kyoto University |
Takegami M.,Kyoto University |
Takegami M.,Japan National Cardiovascular Center Research Institute |
Takahashi K.-I.,Red Cross |
And 9 more authors.
Chest | Year: 2013
Background: Dyslipidemia is often comorbid with obstructive sleep apnea (OSA), but few populationbased studies have investigated their relationship. Short sleep duration is associated with hypertension and diabetes; however, its association with dyslipidemia is not well known. We investigated relationships among OSA, sleep duration, and the lipid profile in a community-based study. Methods: We measured the respiratory disturbance index (RDI) and sleep duration by a type 3 portable device and actigraph in 275 men in a Japanese company. Fasting blood parameters were obtained from periodic inspection data. Results: According to Japanese criteria, 143 subjects had dyslipidemia. Percent sleep time of oxygen saturation as measured by pulse oximetry (SpO2) <90% and prevalence of severe OSA were greater and sleep duration and mean SpO2 during sleep were lower in subjects with dyslipidemia than in those without. Univariate analysis showed that the RDI was positively correlated with serum triglyceride (TG) levels (ρ = 0.20, P < .01), and sleep duration was negatively correlated with serum total cholesterol (TC) levels (γ = -0.13, P = .03) and serum low-density lipoprotein cholesterol levels (γ = -0.12, P = .04). Stepwise multiple regression analysis revealed that TG was correlated with RDI (β = 0.14, P = .02), BMI (β = 0.20, P < .01), and alcohol intake (β = 0.20, P < .01), and that TC was correlated with sleep duration (β = -0.13, P = .03), age (β = 0.15, P = .02), and waist/hip ratio (β = 0.15, P = .02). Conclusions: Short sleep duration was associated with TC levels and RDI was positively associated with TG levels among working-aged men in an urban Japanese company. Correcting the status of OSA and/or short sleep duration might improve the lipid profile and cardiovascular consequences. © 2013 American College of Chest Physicians.
Chung S.,University of Chicago |
Chung S.,Tokyo Medical University |
Low S.-K.,Center for Genomic Medicine |
Low S.-K.,Tokyo Medical University |
And 5 more authors.
Breast Cancer Research | Year: 2013
Introduction: Chemotherapy-induced alopecia is one of the most common adverse events caused by conventional cytotoxic chemotherapy, yet there has been very little progress in the prevention or treatment of this side effect. Although this is not a life-threatening event, alopecia is very psychologically difficult for many women to manage. In order to improve the quality of life for these women, it is important to elucidate the molecular mechanisms of chemotherapy-induced alopecia and develop ways to effectively prevent and/or treat it. To identify the genetic risk factors associated with chemotherapy-induced alopecia, we conducted a genome-wide association study (GWAS) using DNA samples from breast cancer patients who were treated with chemotherapy.Methods: We performed a case-control association study of 303 individuals who developed grade 2 alopecia, and compared them with 880 breast cancer patients who did not show hair loss after being treated with conventional chemotherapy. In addition, we separately analyzed a subset of patients who received specific combination therapies by GWASs and applied the weighted genetic risk scoring (wGRS) system to investigate the cumulative effects of the associated SNPs.Results: We identified an SNP significantly associated with drug-induced grade 2 alopecia (rs3820706 in CACNB4 (calcium channel voltage-dependent subunit beta 4) on 2q23, P = 8.13 × 10-9, OR = 3.71) and detected several SNPs that showed some suggestive associations by subgroup analyses. We also classified patients into four groups on the basis of wGRS analysis and found that patients who classified in the highest risk group showed 443 times higher risk of antimicrotubule agents-induced alopecia than the lowest risk group.Conclusions: Our study suggests several associated genes and should shed some light on the molecular mechanism of alopecia in chemotherapy-treated breast cancer patients and hopefully will contribute to development of interventions that will improve the quality of life (QOL) of cancer patients. © 2012 Chung et al.; licensee BioMed Central Ltd.
News Article | February 15, 2017
A study from Massachusetts General Hospital (MGH) researchers has found that a pattern of gene variants associated with an "apple-shaped" body type, in which weight is deposited around the abdomen, rather than in the hips and thighs, increases the risk for type 2 diabetes and coronary heart disease, as well as the incidence of several cardiovascular risk factors. The report appears in the February 14 issue of JAMA. "People vary in their distribution of body fat - some put fat in their belly, which we call abdominal adiposity, and some in their hips and thighs," says Sekar Kathiresan, MD, director of the MGH Center for Genomic Medicine, associate professor of Medicine at Harvard Medical School, and senior author of the JAMA report. "Abdominal adiposity has been correlated with cardiometabolic disease, but whether it actually has a role in causing those conditions was unknown. We tested whether genetic predisposition to abdominal adiposity was associated with the risk for type 2 diabetes and coronary heart disease and found that the answer was a firm 'yes'." While several observational studies have reported greater incidence of type 2 diabetes and heart disease among individuals with abdominal adiposity, they could not rule out the possibility that lifestyle factors - such as diet, smoking and a lack of exercise - were the actual causes of increased disease risk. It also could have been possible that individuals in the early stages of heart disease might develop abdominal adiposity because of a limited ability to exercise. The current study was designed to determine whether body type really could increase cardiometabolic risk. To answer that question, the research team applied a genetic approach called mendelian randomization, which measures whether inherited gene variants actually cause outcomes such as the development of a disease. Using data from a previous study that identified 48 gene variants associated with waist-to-hip ratio adjusted for body mass index - an established measure for abdominal adiposity - they developed a genetic risk score. They then applied that score to data from six major genome-wide association studies and to individual data from the U.K. Biobank - a total research group of more than 400,000 individuals - to determine any association between a genetic predisposition to abdominal adiposity and cardiometabolic disease and its risk factors. The results clearly indicated that genetic predisposition to abdominal adiposity is associated with significant increases in the incidence of type 2 diabetes and coronary heart disease, along with increases in blood lipids, blood glucose and systolic blood pressure. No association was found between the genetic risk score and lifestyle factors, and testing confirmed that only the abdominal adiposity effects of the identified gene variants were associated with cardiometabolic risk. "These results illustrate the power of using genetics as a method of determining the effects of a characteristic like abdominal adiposity on cardiometabolic outcomes," says lead author Connor Emdin, DPhil, of the MGH Center for Genomic Medicine and the Cardiology Division. "The lack of association between the body type genetic risk score and confounding factors such as diet and smoking provides strong evidence that abdominal adiposity itself contributes to causing type 2 diabetes and heart disease." Emdin continues, "Not only do these results allow us to use body shape as a marker for increased cardiometabolic risk, they also suggest that developing drugs that modify fat distribution may help prevent these diseases. Future research also could identify individual genes that could be targeted to improve body fat distribution to reduce these risks." Additional co-authors of the JAMA paper are Amit Khera, MD, Pradeep Natarajan, MD, Derek Klarin, MD, and Seyedeh Zekavat, all of the MGH Center for Genomic Medicine; and Allan Hsiao, MPhil, Massachusetts Institute of Technology. Support for the study includes National Institutes of Health grants R01 HL127564, and T32 HL0007734; the Ofer and Shelly Nemirovsky MGH Research Scholar Award; and grants from the Rhodes Trust, and the Donovan Family Foundation. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
News Article | November 21, 2016
LA JOLLA -- (Nov. 21, 2016) When a receptor on the surface of a T cell -- a sentry of the human immune system -- senses a single particle from a harmful intruder, it immediately kicks the cell into action, launching a larger immune response. But exactly how the signal from a single receptor, among thousands on each T cell, can be amplified to affect a whole cell has puzzled immunologists for decades. Now, Salk scientists have discovered the key to the amplification of an "invader" signal. The T cell receptor that detects the intruder turns into a mini-machine, activating and releasing copy after copy of a protein called ZAP70. The finding, published in Nature Immunology on November 21, 2016, could help scientists design better immune-mediated treatments for cancer or autoimmune diseases. "This is really the first amplification method that's been found at this level of the immune response," says senior author Björn Lillemeier, an associate professor in Salk's Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis and the Waitt Advanced Biophotonics Center. "It answers a longstanding question that has bugged immunologists for more than three decades." T cells are central in the adaptive immune response, which is the body's ability to recognize pathogens and respond to them. A single T cell's receptors screen thousands of molecules at any given second, but most of them originate from the body's own proteins and have to be ignored as "self." Researchers have struggled to explain how, in the wake of overwhelming "self" signals, a T cell can detect and respond to one or two "invader" signals. Lillemeier's lab studied ZAP70, a protein that associates with T cell receptors and becomes activated when the receptors recognize a foreign molecule. To track the activity and location of ZAP70 molecules, the team tagged them with a fluorescent marker while anchoring each T cell receptor in place. To the group's surprise, ZAP70 molecules were being activated by the T cell receptors and then moving away, spreading throughout the cell. "This is a completely different method of amplification than we expected," says Zachary Katz, a research associate in the Lillemeier lab and first author of the new work. "Everyone always thought the amplification would be determined by the interaction between the foreign molecule and the T cell receptor, but this is happening downstream of the receptor." By churning out ZAP70 and sending it throughout the cell--as opposed to just activating a handful of ZAP70s and keeping them tethered to the T cell receptor--the immune cells can rapidly spread a signal throughout the cell. "What we saw is that at the beginning of signaling, you have lots of ZAP70 being released from the T cell receptor to amplify and distribute the signal," says Lillemeier. "But once the signaling is established, the T cell receptor actually adapts and stops releasing so much of ZAP70." Questions remain on how the process works, including what the ultimate destinations of the ZAP70 molecules are and how they go on to transmit signals. But the observation, Lillemeier says, is progress toward understanding how T cells identify and react to pathogens. "It's really important to understand this process since T cells are at the center of the adaptive immune response," he says. "If the receptors are not controlled well, you're sick; you might either have an autoimmune disease or you can't respond to infections." Being able to make the receptors have a stronger or weaker signal -- perhaps by changing how much ZAP70 they activate and release -- could help treat these kinds of diseases, he adds. Other researchers on the study were Lucie Novotná and Amy Blount of the Salk Institute. The work and the researchers involved were supported by grants from the Nomis Foundation, the Waitt Foundation and the James B. Pendleton Charitable Trust, the National Institutes of Health, a Pioneer Fund Postdoctoral Scholar Award, the Salk Institute Cancer Center core facilities funded by the National Cancer Institute and the Mass Spectrometry Core of the Salk Institute supported by the Helmsley Center for Genomic Medicine. About the Salk Institute for Biological Studies: Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
News Article | November 21, 2016
LA JOLLA -- (Nov. 21, 2016) The Salk Institute for Biological Studies has received a $25 million grant -- a renewal of the largest research gift in the Institute's 56-year history -- that will be used to continue exploring an ambitious range of projects aimed at understanding the role chronic inflammation plays in driving human disease. The grant from The Leona M. and Harry B. Helmsley Charitable Trust extends the historic $42 million Helmsley gift made to the Salk Institute in 2013. That gift established the Helmsley Center for Genomic Medicine, which enables Salk's leading scientists to delve into the genetic underpinnings of some of humankind's most devastating afflictions, and paves the way to new therapies for chronic illnesses, including cancer, diabetes, inflammatory bowel disease and Alzheimer's disease. "Helmsley is delighted to be able to provide the Salk Institute this critical renewal grant so that its scientists are able to continue the amazing research that stems from our initial grant in 2013," says Stephanie Cuskley, chief executive officer of the Helmsley Charitable Trust. "We are honored to partner with the Salk Institute and help support its world-class researchers." The new grant will start January 1, 2017 and provide three years of funding support for Salk research teams drawing from several areas of expertise including cancer, stem cells and metabolism. Led by senior investigators Inder Verma, Ronald Evans and Rusty Gage, scientists who will continue to be funded by Helmsley include Reuben Shaw, Juan Carlos Izpisua Belmonte, Marc Montminy, Clodagh O'Shea, Alan Saghatelian, Tony Hunter, Greg Lemke, Paul Sawchenko, Satchidananda Panda and Geoffrey Wahl. Additional support will also be provided to Jan Karlseder, Martin Hetzer, Ye Zheng, Diana Hargreaves, Janelle Ayres, Dmitry Lyumkis, Patrick Hsu and Jesse Dixon. The funding provided by the grant will continue as well to support many core facilities at the Salk Institute. A central theme of this program is that chronic inflammation lies at the root of most of the health problems in the world today. This Helmsley grant is designed to promote collaborative interdisciplinary research that will yield new diagnostic tools, therapeutics and preventive measures for a broad range of disorders. Amazing discoveries in diabetes, neuroscience and cancer have already been made since the original grant three years ago, resulting in two clinical trials. The impact of this support is remarkable and the Salk Institute is very grateful to the Helmsley Charitable Trust for sponsoring this highly productive partnership. With support from the existing Helmsley grant, the Salk Institute launched its successful Salk Fellows program in 2014. To date, the program has brought three scientists from broad disciplines to the Institute to trigger innovation and collaboration in single-particle cryo-electron microscopy, three-dimensional genomic organization and the gene editing technology known as CRISPR. The current Helmsley-Salk Fellows have each garnered a prestigious Director's Early Independence Award from the National Institutes of Health. In 2009, Helmsley awarded a $5.5 million grant to establish the Salk Center for Nutritional Genomics to study nutrition at the molecular level and its impact on the role of metabolism in diabetes, obesity, cancer, exercise physiology and lifespan. Helmsley expanded support with an additional $15 million grant in 2010 to create a collaborative stem cell project involving Salk and Columbia University to fast-track the use of induced pluripotent stem cells to gain new insight into disease mechanisms and screen for novel therapeutic drugs. Salk President Elizabeth Blackburn says the funding is vital for the pursuit of transformative research that will have worldwide impact on people's health for generations to come. "The Helmsley Charitable Trust has made extraordinary gifts to support Salk science over the past decade," says Blackburn. "We are tremendously grateful to Helmsley for their commitment to improve health and for supporting pioneering research here at the Institute." About the Salk Institute for Biological Studies: Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at salk.edu. The Leona M. and Harry B. Helmsley Charitable Trust aspires to improve lives by supporting exceptional efforts in the U.S. and around the world in health, place-based initiatives, and education and human services. Since beginning its grantmaking in 2008, Helmsley has committed more than $1.5 billion for a wide range of charitable purposes. For more information, visit http://www. .
PubMed | World Health Organization, Harvard University, U.S. National Cancer Institute, Cancer Research UK Research Institute and 3 more.
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2015
Recent genome-wide association studies have identified common variants at multiple loci influencing lung cancer risk. To decipher the genetic basis of the association signals at 3q28, 5p15.33, 6p21.33, 9p21 and 12p13.33, we performed a meta-analysis of data from five genome-wide association studies in populations of European ancestry totalling 12316 lung cancer cases and 16831 controls using imputation to recover untyped genotypes. For four of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant at these risk loci.
Gorlova O.,Dartmouth College |
Fedorov A.,University of Toledo |
Logothetis C.,University of Houston |
Amos C.,Dartmouth College |
And 2 more authors.
BMC Evolutionary Biology | Year: 2014
Background: The existence of introns in eukaryotic genes is believed to provide an evolutionary advantage by increasing protein diversity through exon shuffling and alternative splicing. However, this eukaryotic feature is associated with the necessity of exclusion of intronic sequences, which requires considerable energy expenditure and can lead to splicing errors. The relationship between intronic burden and evolution is poorly understood. The goal of this study was to analyze the relationship between the intronic burden and the level of evolutionary conservation of the gene. Results: We found a positive correlation between the level of evolutionary conservation of a gene and its intronic burden. The level of evolutionary conservation was estimated using the conservation index (CI). The CI value was determined on the basis of the most distant ortholog of the human protein sequence and ranged from 0 (the gene was unique to the human genome) to 9 (an ortholog of the human gene was detected in plants). In multivariable model, both the number of introns and total intron size remained significant predictors of CI. We also found that the number of alternative splice variants was positively correlated with CI.The expression level of a gene was negatively correlated with the number of introns and total size of intronic region. Genes with a greater intronic burden had lower density of missense and nonsense mutations in the coding regions of the gene, which suggests that they are under a stronger pressure from purifying selection. Conclusions: We identified a positive association between intronic burden and CI. One of the possible explanations of this is the idea of a cost-benefits balance. Evolutionarily conserved (functionally important) genes can "afford" the negative consequences of maintaining multiple introns because these consequences are outweighed by the benefit of maintaining the gene. Evolutionarily conserved and functionally important genes may use introns to create novel splice variants to tune the gene function to developmental stage and tissue type. © 2014 Gorlova et al.; licensee BioMed Central Ltd.
PubMed | Nanjing Medical University, Center for Genomic Medicine, University of Western Australia and Nanjing University
Type: | Journal: BioMed research international | Year: 2015
Autologous osteochondral transplantation (AOT) is a method for articular cartilage repair. However, several disadvantages of this method have been reported, such as transplanted cartilage degeneration and the lack of a connection between the grafted and adjacent cartilage tissues. To evaluate the effect of intra-articular administration of trichostatin A (TSA) on AOT, we conducted a case control study in a rabbit model. International Cartilage Repair Society (ICRS) macroscopic scores, the modified ODriscoll histology scores, and real-time PCR were utilized to evaluate the results. At 4 weeks, both macroscopic and histological assessments showed that there was no significant difference between the TSA and control groups. However, the mean macroscopic and histological scores for the TSA-treated group were significantly higher than the scores for the control group at 12 weeks. TSA was shown to directly reduce collagen type II (COL2), aggrecan, matrix metalloproteinase (MMP), and a disintegrin and metalloproteinase domain with thrombospondin motifs 5 (ADAMTS-5) expression and to simultaneously repress the upregulation of MMP-3, MMP-9, and MMP-13 levels induced by interleukin 1 (IL-1) in chondrocytes. In conclusion, TSA protects AOT grafts from degeneration, which may provide a benefit in the repair of articular cartilage injury.
Perell K.,Blegdamsvej |
Perell K.,Center for Genomic Medicine |
Vincent M.,Copenhagen University |
Vainer B.,Copenhagen University |
And 8 more authors.
Molecular Oncology | Year: 2015
Identification of the primary tumor site in patients with metastatic cancer is clinically important, but remains a challenge. Hence, efforts have been made towards establishing new diagnostic tools. Molecular profiling is a promising diagnostic approach, but tissue heterogeneity and inadequacy may negatively affect the accuracy and usability of molecular classifiers. We have developed and validated a microRNA-based classifier, which predicts the primary tumor site of liver biopsies, containing a limited number of tumor cells. Concurrently we explored the influence of surrounding normal tissue on classification. MicroRNA profiling was performed using quantitative Real-Time PCR on formalin-fixed paraffin-embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust for normal liver tissue contamination. Performance was estimated by cross-validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74.5% upon independent validation. Two-thirds of the samples were classified with high-confidence, with an accuracy of 92% on high-confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding normal tissue from the biopsy site may critically influence molecular classification. A significant improvement in classification accuracy was obtained when the influence of normal tissue was limited by application of a statistical contamination model. © 2014 Federation of European Biochemical Societies.
Jochumsen N.,Technical University of Denmark |
Marvig R.L.,Technical University of Denmark |
Marvig R.L.,Center for Genomic Medicine |
Damkiaer So.,Technical University of Denmark |
And 5 more authors.
Nature Communications | Year: 2016
Colistin is an antimicrobial peptide that has become the only remaining alternative for the treatment of multidrug-resistant Gram-negative bacterial infections, but little is known of how clinical levels of colistin resistance evolve. We use in vitro experimental evolution and whole-genome sequencing of colistin-resistant Pseudomonas aeruginosa isolates from cystic fibrosis patients to reconstruct the molecular evolutionary pathways open for high-level colistin resistance. We show that the evolution of resistance is a complex, multistep process that requires mutation in at least five independent loci that synergistically create the phenotype. Strong intergenic epistasis limits the number of possible evolutionary pathways to resistance. Mutations in transcriptional regulators are essential for resistance evolution and function as nodes that potentiate further evolution towards higher resistance by functionalizing and increasing the effect of the other mutations. These results add to our understanding of clinical antimicrobial peptide resistance and the prediction of resistance evolution. © 2016 The Author(s).