'Lo último en obesidad'. Este es el título del Simposio Internacional que organizamos en la Fundación Ramón Areces los días 1 y 2 de diciembre de 2015. En colaboración con la Fundación General CSIC, reunió a algunos de los mayores expertos en la materia para analizar cómo reducir este grave problema de salud pública.
'Lo último en obesidad'. Este es el título del Simposio Internacional que organizamos en la Fundación Ramón Areces los días 1 y 2 de diciembre de 2015. En colaboración con la Fundación General CSIC, reunió a algunos de los mayores expertos en la materia para analizar cómo reducir este grave problema de salud pública.
Richard Frye, MD, PhD, FAAP, FAAN, CPI, will discuss:
*The enteric (gut) microbiome has an important influence on health and disease states in humans.
* The enteric microbiome influences the human host using chemical mediators, some of which can directly affect mitochondrial function
* Short chain fatty acids produced by gut bacteria not only modulate mitochondrial function and cellular regulatory pathways, but can also be used as mitochondrial fuels.
What you should know about genetic testing for mitochondrial disordersmitoaction
Amanda Balog, CGC, Senior Genetic Counselor, Mitochondrial and Metabolic Genetics, of GeneDx discusses: "What You Should Know About Genetic Testing for Mitochondrial Disorders."
Exercise and nutrition in Mitochondrial Diseasemitoaction
Mark Tarnopolsky, MD, PhD, FRCP,
Depts. of Pediatrics (Neuromuscular + Neurometabolic Disease) and Medicine (Cell Biology/Metabolism, Neurology and Rehabilitation), McMaster University, Hamilton, CANADA
Compare the use of Lonza KGM Gold Bullet kit and Rheinwald and Green complete FAD medium in primary human epidermal keratinocytes culture and its applicability cells cultured by these medium in the construction of reconstituted skin equivalent model
'Lo último en obesidad'. Este es el título del Simposio Internacional que organizamos en la Fundación Ramón Areces los días 1 y 2 de diciembre de 2015. En colaboración con la Fundación General CSIC, reunió a algunos de los mayores expertos en la materia para analizar cómo reducir este grave problema de salud pública.
Richard Frye, MD, PhD, FAAP, FAAN, CPI, will discuss:
*The enteric (gut) microbiome has an important influence on health and disease states in humans.
* The enteric microbiome influences the human host using chemical mediators, some of which can directly affect mitochondrial function
* Short chain fatty acids produced by gut bacteria not only modulate mitochondrial function and cellular regulatory pathways, but can also be used as mitochondrial fuels.
What you should know about genetic testing for mitochondrial disordersmitoaction
Amanda Balog, CGC, Senior Genetic Counselor, Mitochondrial and Metabolic Genetics, of GeneDx discusses: "What You Should Know About Genetic Testing for Mitochondrial Disorders."
Exercise and nutrition in Mitochondrial Diseasemitoaction
Mark Tarnopolsky, MD, PhD, FRCP,
Depts. of Pediatrics (Neuromuscular + Neurometabolic Disease) and Medicine (Cell Biology/Metabolism, Neurology and Rehabilitation), McMaster University, Hamilton, CANADA
Compare the use of Lonza KGM Gold Bullet kit and Rheinwald and Green complete FAD medium in primary human epidermal keratinocytes culture and its applicability cells cultured by these medium in the construction of reconstituted skin equivalent model
A normal cell can be transformed into a cancerous cell. Discuss the therapeutic strategies that are employed to target the cellular transformation process for cancer prevention and treatment.
Newlife India has done research on Genetics of ovarian failure. Maire Peter has done the research on the same. By virtue of the extenssive reasearch we are able to give best results on IVF treatments.
Tamoxifen And CYP2D6: Using Pharmacogenetics to discover a new drugRyan Squire
Dr. Matthew Goetz, assistant professor of oncology and pharmacology at the Mayo Clinic, shared his pharmacogenomic research findings related to risks and occurrence of breast cancer. He explained that in order to truly personalize medicine, you must account for all possible theories and variables. Goetz continued to say that although many believe pharmacology to be boring, it is a key component of the future model of care. Some may say, so this drug doesn’t work–why not just try another drug? It’s much more complicated than that.
Dr. Goetz touched on the variety of cases in his study in breast cancer patients, some with strange and perplexing results. When giving the same drug to multiple patients, each yielded a variety of different results. Some patients had successful reduction in tumor size, while others resulted in no change and some even experienced tumor growth as a result of the drug. Personalized health care is the answer to this, for lack of a better term, ’shot-in-the-dark’ type of therapy. If physicians can understand each patient’s biology and genetic makeup individually, they can better apply treatments and medications. This would therefore reduce health care costs and enable patients to receive much more efficient treatments.
“Inheritance” in images, from Darwin’s “tree of life” to DNA’s iconic crystallography to the epigenetic dynamicsHowever, the script needs to be interpreted and receives meaning only from the interplay with the environment
A normal cell can be transformed into a cancerous cell. Discuss the therapeutic strategies that are employed to target the cellular transformation process for cancer prevention and treatment.
Newlife India has done research on Genetics of ovarian failure. Maire Peter has done the research on the same. By virtue of the extenssive reasearch we are able to give best results on IVF treatments.
Tamoxifen And CYP2D6: Using Pharmacogenetics to discover a new drugRyan Squire
Dr. Matthew Goetz, assistant professor of oncology and pharmacology at the Mayo Clinic, shared his pharmacogenomic research findings related to risks and occurrence of breast cancer. He explained that in order to truly personalize medicine, you must account for all possible theories and variables. Goetz continued to say that although many believe pharmacology to be boring, it is a key component of the future model of care. Some may say, so this drug doesn’t work–why not just try another drug? It’s much more complicated than that.
Dr. Goetz touched on the variety of cases in his study in breast cancer patients, some with strange and perplexing results. When giving the same drug to multiple patients, each yielded a variety of different results. Some patients had successful reduction in tumor size, while others resulted in no change and some even experienced tumor growth as a result of the drug. Personalized health care is the answer to this, for lack of a better term, ’shot-in-the-dark’ type of therapy. If physicians can understand each patient’s biology and genetic makeup individually, they can better apply treatments and medications. This would therefore reduce health care costs and enable patients to receive much more efficient treatments.
“Inheritance” in images, from Darwin’s “tree of life” to DNA’s iconic crystallography to the epigenetic dynamicsHowever, the script needs to be interpreted and receives meaning only from the interplay with the environment
Presentación realizada por la Dra. Pilar Escudero del HCU Lozano Blesa, en el marco de la I Jornada de actualización e innovación en Oncología que tuvo lugar en el CIBA en enero de 2015.
Rodent Models of Pharmacotherapy and Chronotherapy for Obesity and Cardiometa...InsideScientific
Join Christopher Axelrod and Sander Kooijman, PhD for a discussion on their research into combatting obesity using various new therapies.
Key Topics Include:
Obesity is a chronic disease with limited treatment options that achieve long term weight control
Systemic mitochondrial uncoupling prevents weight gain without altering food intake and improves glucose metabolism independent of body weight
Mitochondrial-targeted drugs such as BAM15 may have clinical utility in the treatment of obesity and related diseases
Mimicked shift work resulted in obesity in male mice and poor blood glucose clearance in female mice
Understanding the circadian regulation of energy metabolism provides an opportunity to maximize the effectiveness of chronotherapy
Dr. Manuel Hidalgo - Simposio Internacional ' Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
Clinical Impact of New NAFLD/NASH Data From San Francisco 2018hivlifeinfo
Expert faculty summarize key NAFLD/NASH studies from this important annual conference. Use these slides to review data on noninvasive screening, clinical outcomes, emerging treatments.
Ira M. Jacobson, MD
Philip N. Newsome, PhD, FRCPE
Format: Microsoft PowerPoint (.ppt)
File Size: 421 KB
Released: December 3, 2018
Dr. José Baselga - Simposio Internacional 'Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
Jordi Torren - Coordinador del proyecto ESVAC. Agencia Europea de Medicamento...Fundación Ramón Areces
El martes 5 de junio del 2018 organizamos una Jornada en la Fundación Ramón Areces, en la cual se habló sobre el consumo de antibióticos y transmisión de resistencia entre humanos y animales.
Dominique L. Monnet Director del programa ARHAI (Antimicrobial Resistance an...Fundación Ramón Areces
El martes 5 de junio del 2018 organizamos una Jornada en la Fundación Ramón Areces, en la cual se habló sobre el consumo de antibióticos y transmisión de resistencia entre humanos y animales.
El jueves 24 de mayo del 2018 organizamos una Conferencia con Antonio Cabrales en la Fundación Ramón Areces. Una conferencia en la cual el tema fue: Estilo negociador y confianza, ¿hay diferencias entre hombres y mujeres?
Teresa Puig - Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Espa...Fundación Ramón Areces
El lunes y martes 21 y 22 de mayo del 2018 realizamos un Simposio Internacional en la Fundación Ramón Areces, tratando el tema de la superconductividad y presión: una relación fructífera en el camino hacia la superconductividad a temperatura ambiente.
Elena Bascones - Instituto de Ciencia de Materiales de Madrid (ICMM-CSIC), Es...Fundación Ramón Areces
El lunes y martes 21 y 22 de mayo del 2018 realizamos un Simposio Internacional en la Fundación Ramón Areces, tratando el tema de la superconductividad y presión: una relación fructífera en el camino hacia la superconductividad a temperatura ambiente.
El jueves 17 de mayo del 2018 se organizó una Mesa Redonda en la Fundación Ramón Areces, en la cual se habló sobre las subidas de tipos en la era Trump y la nueva globalización.
El jueves 17 de mayo del 2018 se organizó una Mesa Redonda en la Fundación Ramón Areces, en la cual se habló sobre las subidas de tipos en la era Trump y la nueva globalización.
El miércoles 16 de mayo del 2018 celebramos una Jornada en la Fundación Ramón Areces, en la cual se habló sobre las nuevas fronteras de investigación sobre la distribución comercial y el comportamiento del consumidor.
El miércoles 16 de mayo del 2018 celebramos una Jornada en la Fundación Ramón Areces, en la cual se habló sobre las nuevas fronteras de investigación sobre la distribución comercial y el comportamiento del consumidor.
Juan Carlos López-Gutiérrez - Unidad de Anomalías Vasculares, Hospital Unive...Fundación Ramón Areces
El jueves y viernes 10 y 11 de mayo del 2018 realizamos en la Fundación Ramón Areces un Simposio Internacional, en el cual se trató el tema del mosaicismo somático en malformaciones vasculares.
Víctor Martínez-Glez. - Instituto de Genética Médica y Molecular (INGEMM). I...Fundación Ramón Areces
El jueves y viernes 10 y 11 de mayo del 2018 realizamos en la Fundación Ramón Areces un Simposio Internacional, en el cual se trató el tema del mosaicismo somático en malformaciones vasculares.
Rudolf Happle - Dermatología, University of Freiburg Medical Center, Freiburg...Fundación Ramón Areces
El jueves y viernes 10 y 11 de mayo del 2018 realizamos en la Fundación Ramón Areces un Simposio Internacional, en el cual se trató el tema del mosaicismo somático en malformaciones vasculares.
Rafael Doménech - Responsable de Análisis Macroeconómico, BBVA Research. Fundación Ramón Areces
El martes 8 de mayo de 2018 realizamos una conferencia en la Fundación Ramón Areces, en la cual se habló sobre el futuro de las pensiones: una visión global.
El martes 8 de mayo de 2018 realizamos una conferencia en la Fundación Ramón Areces, en la cual se habló sobre el futuro de las pensiones: una visión global.
El martes 8 de mayo de 2018 realizamos una conferencia en la Fundación Ramón Areces, en la cual se habló sobre el futuro de las pensiones: una visión global.
Nicholas Barr - Profesor de Economía Pública, London School of Economics. Fundación Ramón Areces
El martes 8 de mayo de 2018 realizamos una conferencia en la Fundación Ramón Areces, en la cual se habló sobre el futuro de las pensiones: una visión global.
El viernes 27 de abril del 2018 se celebró en la Fundación Ramón Areces una Jornada sobre física , en la cual se trataron diversos temas como: Los materiales mecanocalóricos, magnetísmo, biofísica, la energía oscura y instrumentación astronómica.
El viernes 20 de abril organizamos una Jornada sobre la ciencia en el corazón de Europa, en colaboración con Científicos Españoles en Bélgica (CEBE) y realizada en la Fundación Ramón Areces.
Marta Olivares - Investigadora Postdoctoral en Université catholique de Louva...Fundación Ramón Areces
El viernes 20 de abril organizamos una Jornada sobre la ciencia en el corazón de Europa, en colaboración con Científicos Españoles en Bélgica (CEBE) y realizada en la Fundación Ramón Areces.
El viernes 20 de abril organizamos una Jornada sobre la ciencia en el corazón de Europa, en colaboración con Científicos Españoles en Bélgica (CEBE) y realizada en la Fundación Ramón Areces.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
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The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
1. The genetics of obesity
Going beyond common variants and common phenotypes
Ruth Loos
Professor, Preventive Medicine
Director, Genetics of Obesity and Related Metabolic Traits Program
Charles Bronfman Institute for Personalized Medicine
Mindich Child Health and Development Institute
Icahn School of Medicine at Mount Sinai
New York
ruth.loos@mssm.edu
18th Annual International Symposium of the Universite Laval Obesity Research Chair, Montreal, Canada,
3. Outline
• Common variation and common adiposity phenotypes
• Common variation and more refined adiposity phenotypes
• Low-frequency variation and common adiposity phenotypes
4. Waist-to-Hip Ratio
Common variation – common phenotypes
Common DNA
variation (MAF > 5%)
Common
Adiposity traits
~2.5 million variants
mostly non-coding
Body Mass Index
+ Large sample sizes
− Phenotype heterogeneity
5. 0
20
40
60
80
100
120
140
160
180
2007 2008 2009 2010 2011 2012 2013 2015
Cumulativenumberofobesityloci
Childhood Obesity
WHR and BMI tails/ categories
Extreme and early onset obesity
Waist and WHRadjBMI
BMI in African ancestry
BMI in East Asians
BMI in Europeans
Cumulative number of obesity-associated loci
6. Larger GWAS samples size more (common) loci
123,865 individuals of
European descent
from 46 GWAS
103,046 individuals of mainly
European descent
from 43 MetaboChip studies
112,366 individuals of mainly
European descent
from 36 GWAS
339,277 individuals of mainly European decent from 125 studies.
Association of SNPs in 97 loci reach P<5x10-8,
including the 31 established BMI loci, 10 established “other obesity traits” loci and 56 new BMI loci
BMI
Locke et al. Nature (2015)
GANTGANTC O N S O R T I U M
7. Larger GWAS samples size more (common) loci
BMI
Locke et al. Nature (2015)
FTO
8. 77,167 individuals of
European descent
from 32 GWAS
67,326 individuals of mainly
European descent
from 40 MetaboChip studies
65,695 individuals of mainly
European descent
from 25 GWAS
210,088 individuals of mainly European decent from 87 studies.
Association of SNPs in 49 loci reach P<5x10-8,
including the 14 established WHR loci and 35 new WHR loci
WHRadjBMI
Larger GWAS samples size more (common) loci
Shungin et al. Nature (2015)
GANTGANTC O N S O R T I U M
10. 0
20
40
60
80
100
120
140
160
180
2007 2008 2009 2010 2011 2012 2013 2015
Cumulativenumberofobesityloci
Childhood Obesity
WHR and BMI tails/ categories
Extreme and early onset obesity
Waist and WHRadjBMI
BMI in African ancestry
BMI in East Asians
BMI in Europeans
GIANT BMI meta-analysis:
N=339,247
56 new BMI loci
GIANT WHR meta-analysis:
N=211,221
35 new WHR loci
Common variation – common phenotypes 166 loci
11. Locke et al. Nature (In press)
0.000
0.200
0.400
0.600
0.800
1.000
1.200
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Effectonweight(kg)/perBMI-increasingallele
BMI increasing allele
All variants are common and have modest effects
12. From common loci to causal/functional gene/variant
Locke et al. Nature (2015)
13. Analyses to decipher each locus
• Cross-phenotype associations with cardiometabolic traits and diseases
• Cross-ancestry associations
• Fine-mapping analyses
• eQTL analyses for cis-association
• ENCODE annotation to identify regulatory marks
• Pathway analyses (MAGENTA and DEPICT)
14. Tissue enrichment analyses point towards different systems
BMI-associated loci
WHRadjBMI-associated loci
15. Is FTO the obesity gene ?
Adiposity
ER- breast cancer
FTO
Melanoma
17. Common variation – More refined phenotypes
Common DNA
variation (MAF > 5%)
~2.5 million variants
mostly non-coding Leptin levels
Refined adiposity
traits
Body Fat %
- Smaller sample sizes
+ More accurate phenotype
Visceral and
subcutaneous fat
18. 0
20
40
60
80
100
120
140
160
180
2007 2008 2009 2010 2011 2012 2013 2015
Cumulativenumberofobesityloci
Childhood Obesity
WHR and BMI tails/ categories
Extreme and early onset obesity
Waist and WHRadjBMI
BMI in African ancestry
BMI in East Asians
BMI in Europeans
Common variation – common phenotypes 166 loci
19. GIANT BMI meta-analysis:
N=339,247
56 new BMI loci
GIANT WHR meta-analysis:
N=211,221
35 new WHR loci
Common variation – more refined phenotypes 177 loci
0
20
40
60
80
100
120
140
160
180
2007 2008 2009 2010 2011 2012 2013 2015
Cumulativenumberofobesityloci
Circulating Leptin
Bariatric surgery weight loss
VAT/ SAT
Body fat%
Childhood Obesity
WHR and BMI tails/ categories
Extreme and early onset obesity
Waist and WHRadjBMI
BMI in African ancestry
BMI in East Asians
BMI in Europeans
20. Body fat percentage more accurately assesses adiposity
0
10
20
30
40
50
60
15 20 25 30 35 40 45 50 55
BMI (kg.m-2)
BodyfatpercentagebyDEXA(%)
Women
Men
21. 24,582 individuals of 13
MetaboChip studies
37,562 individuals of
from 28 new GWAS
100,706 individuals of mainly European decent from 56 studies.
Association of SNPs in 12 loci reach P<5x10-8,
including the 2 established BF% loci, 6 established BMI loci and 4 new BF% loci
38,562 individuals
from 15 GWAS used
previously
Common variation for body fat percentage
22. 12 loci for body fat percentage
FTO
IRS1
MC4R
TMEM18
COBLL1
SPRY2
TOMM40
TUFM/SH2B1
IGF2BP1
SEC16B
PLA2G6 (M)
CRTC1 (W)
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09
EffectsonBMI(SD/allele)
Effects on body fat % (SD/allele)
23. 0.9
1
1.1
1.2
All Men Women
Per-allelechangeinrisk(OR)
0.9
1
1.1
1.2
All Men Women
-0.25
-0.2
-0.15
-0.1
-0.05
0
All Men Women
Per-allelechangeinbodyfat(%)
-0.15
-0.1
-0.05
0
0.05
0.1
All Men Women
Per-allelechangeinBMI(kg/m2)
-0.1
0
0.1
0.2
0.3
0.4
All Men Women
Per-allelechangeinWHR
The near-IRS1 locus & measures of body composition
N 43,291 24,731 18,560 N 21.832 10,602 11,230N 43,291 24,731 18,560
N 42,551 24,557 17,944 N 26,009 13,518 12,491
Body fat % BMI WHR
Overweight Obesity
Kilpeläinen et al Nature Genetics 2011
24. The near-IRS1 locus and disease risk
P = 1.5x10-5
P = 9.3x10-12
P = 3x10-9
P = 0.?
P = 2.35x10-9
25. The near-IRS1 locus and fat distribution (CT data)
Fat%-decreasing allele ... Men Women
(n = 4,997) (n = 5,560)
Subcutaneous fat (SAT) P = 0.0018 P = 0.063
Visceral fat (VAT) P = 0.95 P = 0.63
VAT/SAT P = 6.1x10-6 P = 0.31
GWAS of CT data Personal communication with Caroline Fox
The ‘body fat% decreasing allele’ leads to …
reduced storage of fat subcutaneously, but not viscerally
ectopic fat deposition ?
insulin resistance and dyslipidemia ?
Kilpeläinen et al Nature Genetics 2011
26. Leptin is secreted in proportion to total fat mass
The Fenland Study: n~5,000 population-based
27. 20,278 individuals of
from 12 GWAS +
MetaboChip
52,339 individuals of European decent from 34 studies.
Association of SNPs in 6 loci reach P<5x10-8
LEP, FTO, CCNL1, GCKR, COBLL1, SLC32A1
32,061 individuals
from 22 GWAS
Common variation for circulating leptin levels
29. Explant knockdown strategy
80 mg
Wash in PBS
AT +
siRNA
Plate in M199 media +10%FBS
1. Collect media for leptin content
1. Extract RNA for expression
12hrs
With or without:
7nM Insulin
25nM Dexamethasone
20 min
Antibiotic-
Antimycotic
PGAT
Change
media
after 20hrs
Electroporation
(n=3/condition)
Puri, et al. J Lip Res. 2007, Lee, et al. AJP-Endocrinol Metab. 2007
Explant knockdown strategy to identify causal gene Jayne Martin
Alicja Skowronski
Yiying Zhang
Charles LeDuc
Amanda Rosenbaum
Rudy Leibel
30. Cobll1 knockdown leads to decreased insulin/dexamethasone-
stimulated Lep secretion
s iC tr s iA d ig
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0
A d ig m R N AArbitraryUnits
****
s iC tr s iA d ig
0
5
1 0
1 5
L e p m R N A
ArbitraryUnits
*
s iC tr s iA d ig
0
1 0
2 0
3 0
S e c re te d L e p tin
ng/ml
*
Near-SLC32A1
0
2
4
6
8
10
-log10(p−value)
0
20
40
60
80
100
Recombinationrate(cM/Mb)
rs6071166
0.2
0.4
0.6
0.8
r2
4 genes
omitted
BPI
LBP
LOC388796
SNORA71B
SNORA71A
SNORA71C
SNORA71D
SNHG11
SNORA39
SNORA60
ADIG
ARHGAP40
SLC32A1
ACTR5
PPP1R16B
FAM83D
DHX35
37 37.2 37.4 37.6
Position on chr20 (Mb)
otted SNPs
Explant knockdown strategy to identify causal gene
ADIG Adipogenin
- Involved in adipogenesis and adipose tissue
development
- Highly expressed in white adipose tissue
- Upregulated in mice on high-fat diet
- Plasma membrane protein
Involved in production of leptin in adipose tissue
31. Waist-to-Hip Ratio
Low frequency variation – common phenotypes
Common
Adiposity traits
Body Mass Index
Low frequency DNA
variation (MAF ≤ 5%)
ExomeChip
~250,00 coding
variants
GANTGANTC O N S O R T I U M
ExomeChip analyses:
~525,000 individuals, predominantly European ancestry
~250,000 SNV’s of which 196,304 variants have a MAF <5%
~20,000 genes
32. Low frequency variation (≤ 5%) and BMI
MC4R
MAF= 0.01%
Effect ~ 8.4 kg/allele
Farooqi et al NEJM 2003
33. Low frequency variation (≤ 5%) and BMI
GPR61
MAF= 3%
Effect ~ 850g/allele
- Highly expressed in the brain
- KO mice gain weight faster and eat more
RAPGEF3 (EPAC1)
MAF= 1 %
Effect ~ 1 kg/allele
- KO mice develop diet-induced obesity,
hyperglycemia, b-cell dysfunction, and other
metabolic defects.
35. Some variants are low-frequency and have intermediate effects
11 SNPs at P < 5x10-7
31 SNPs at P < 10-5
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
0.0% 0.1% 1.0% 10.0%
Effectonweight(kg)/perBMI-increasingallele
Minor alele frequency
GWAS-identified loci
ExomeChip sub-significant
ExomChip Significant
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
0.0% 0.1% 1.0% 10.0%
Effectonweight(kg)/perBMI-increasingallele
Minor alele frequency
GWAS-identified loci
ExomeChip sub-significant
ExomChip Significant
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
0.0% 0.1% 1.0% 10.0%
Effectonweight(kg)/perBMI-increasingallele
Minor alele frequency
GWAS-identified loci
ExomeChip sub-significant
ExomChip Significant
MC4R Y35X & D37V
KSR2 R554Q
36. • GWAS has been successful in identifying >170 genetic variants associated
with adiposity traits. However, identifying the causal genes proves to be
challenging, because
• The vast majority of variants locate in intergenic and intronic regions.
• The majority of adiposity phenotypes studies represent heterogeneous
outcomes.
Conclusions & near future directions
Follow-up analyses aim at identifying regulatory regions that target the “causal”
gene, requires accurate annotation of the whole genome at a tissue-specific level.
Maybe first focussing on the exome only provides an easier way “in”.
These heterogeneous phenotypes are the result of a diverse range of biological causes
Phenotypes that are more refined and closer to the “biology” of the outcome might
help point towards the causal gene
37. GANTGANTC O N S O R T I U M
Collaborators and acknowledgements
Erik
Ingelsson
Kari North
Cecilia
Lindgren
Joel
Hirschhorn
Karen
Mohlke
Mike
Boehnke
Ines Barroso
Cristen
Willer
Peter
Visscher
Goncalo
Abecasis
Elizabeth
Speliotes
Mark
McCarthy
Tuomas Kilpeläinen
Assistant professor,
Novo Nordisk Foundation
Center for Basic Metabolic Research
Copenhagen, Denmark
Rudy LeibelAlicia SkowronskiJayne Martin
Editor's Notes
1
Annotation of sequecing and filtering will provide better power (reduce number of vaiants).
More detailed phenotypes – phenotypes closer to DNA.
75 loci
To identify tissues in which genes within BMI-associated loci are preferentially 186 expressed, we first used large-scale gene expression data to connect genes with tissues, 187 and then tested for specific enrichment of tissues by comparing results with randomly 188 selected loci matched for gene density (implemented as part of DEPICT, see Methods).
We have developed a novel approach that integrates the associated loci with complementary data sets (including 77,840 gene expression microarrays, 169,810 experimentally-derived high-confidence protein-protein interactions, 211,882 gene-phenotype pairs from mouse knock-out studies, and 6,004 gene sets from pathway databases) and identified dozens of genes and pathways that are likely to be causal for one of the two phenotypes. Specifically, we found that pathways related to neuronal regulation (for example glutamate signaling) are likely to play key roles for BMI , while pathways that impact insulin resistance, lipid handling, glycogen levels, and blood pressure were significantly enriched in the WHR analysis. The marked difference in BMI and WHR pathways was further supported by our finding that genes in BMI-associated loci were significantly co-expressed in the central nervous system, while genes encoded in WHR-associated loci were significantly and exclusively co-expressed in adipose tissue.
16
Annotation of sequecing and filtering will provide better power (reduce number of vaiants).
More detailed phenotypes – phenotypes closer to DNA.
23
24
25
Stage 1: 22 GWAS: 32,061 individuals 10 loci
Satge 2: 12 GWAS: 22,000 individuals 6 loci
Using this technique, Adipogenin (Adig), implicated in one of the four novel regions that were found in this GWAS meta-analysis, was analyzed. Adig is a plasma membrane protein primarily expressed in white adipose tissue and has previously been shown to play a role in adipogenesis (Hong YH, et al, Mol Cell Biochem 2005 , Kim JY, et al, Biochem and Biophys Research Communications, 2005). Our results indicate that Adig is also involved in production of leptin in adipose tissue. Add to end note. Hong et al. Title: “Up-regulation of adipogenin, an adipocyte plasma transmembrane protein, during adipogenesis.”
Kim et al. title: “Cloning, expression, and differentiation-dependent regulation of SMAP1 in adipogenesis.”
Annotation of sequecing and filtering will provide better power (reduce number of vaiants).
More detailed phenotypes – phenotypes closer to DNA.