Evidence map›Paper›PMID 25378557›Full record

ArticleHuman molecular genetics2015

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Jodie N Painter, Tracy A O'Mara, Jyotsna Batra, Timothy Cheng, Felicity A Lose, Joe Dennis, Kyriaki Michailidou, Jonathan P Tyrer, Shahana Ahmed, Kaltin Ferguson and 109 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 9 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed, 9 pooled it
0.9field-weighted citation impact, top 26% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

34 citing papers in PubMed, 9 syntheses or guidelines pooled it, 7 citations in OpenAlex.

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  5. Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2016
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

119 authors at 20 institutions in 19 countries.

Jodie N PainterQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Tracy A O'MaraQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Jyotsna BatraAustralian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation, and School of Biomedical Science and.
Timothy ChengWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Felicity A LoseQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Joe DennisCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
Kyriaki MichailidouCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
Jonathan P TyrerCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Shahana AhmedCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Kaltin FergusonQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Catherine S HealeyCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Susanne KaufmannQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Kristine M HillmanQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Carina WalpoleAustralian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation, and School of Biomedical Science and.
Leire MoyaAustralian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation, and School of Biomedical Science and.
Pamela PollockInstitute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia.
Angela JonesWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Kimberley HowarthWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Lynn MartinWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Maggie GormanWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Shirley HodgsonDepartment of Clinical Genetics, St George's Hospital Medical School, London, UK.
National Study of Endometrial Cancer Genetics Group (NSECG)
CHIBCHA Consortium
Ma Magdalena Echeverry De PolancoGrupo de Investigación Citogenética, Filogenia y Evolución de Poblaciones, Universidad del Tolima, Ibagué, Tolima, Colombia.
Monica SansDepartment of Biological Anthropology, College of Humanities and Educational Sciences, University of the Republic, Magallanes, Montevideo, Uruguay.
Angel CarracedoGrupo de Medicina Xenómica, Fundación Galega de Medicina Xenómica (SERGAS) and CIBERER, Universidade de Santiago de Compostela, Santiago de Compostela, Spain, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, KSA.
Sergi Castellvi-BelGenetic Predisposition to Colorectal Cancer Group, Gastrointestinal & Pancreatic Oncology Team, IDIBAPS/CIBERehd/Hospital Clínic, Centre Esther Koplowitz (CEK), Barcelona, Spain.
Augusto Rojas-MartinezUniversidad Autónoma de Nuevo León, Pedro de Alba s/n, San Nicolás de Los Garza, Nuevo León, Mexico.
Erika SantosHospital A.C. Camargo, São Paulo, Brazil.
Manuel R TeixeiraDepartment of Genetics, Portuguese Oncology Institute, Porto, Portugal, Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
Luis Carvajal-CarmonaWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Grupo de Investigación Citogenética, Filogenia y Evolución de Poblaciones, Universidad del Tolima, Ibagué, Tolima, Colombia, Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
Xiao-Ou ShuDepartment of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Jirong LongDepartment of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Wei ZhengDepartment of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Yong-Bing XiangDepartment of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
Australian National Endometrial Cancer Study Group (ANECS)
Grant W MontgomeryQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Penelope M WebbQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Rodney J ScottHunter Medical Research Institute and, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia, Centre for Information Based Medicine and School of Biomedical Science and Pharmacy.
Mark McEvoyCentre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health.
John AttiaHunter Medical Research Institute and, Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health.
Elizabeth HollidayHunter Medical Research Institute and, Centre for Information Based Medicine and School of Medicine and Public Health.
Nicholas G MartinQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Dale R NyholtQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Anjali K HendersQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Peter A FaschingDivision of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Alexander HeinUniversity Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Matthias W BeckmannUniversity Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Stefan P RennerUniversity Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Thilo DörkGynaecology Research Unit and.
Peter HillemannsClinics of Gynaecology and Obstetrics, Hannover Medical School, Hannover, Germany.
Matthias DürstDept. of Gynaecology, Friedrich Schiller University Jena, Jena, Germany.
Ingo RunnebaumDept. of Gynaecology, Friedrich Schiller University Jena, Jena, Germany.
Diether LambrechtsVesalius Research Center, VIB, Leuven, Belgium, Department of Oncology, Laboratory for Translational Genetics.
Lieve CoenegrachtsDivision of Gynaecological Oncology, Department of Oncology, University Hospital Leuven, KU Leuven, Belgium.
Stefanie SchrauwenDivision of Gynaecological Oncology, Department of Oncology, University Hospital Leuven, KU Leuven, Belgium.
Frederic AmantDivision of Gynaecological Oncology, Department of Oncology, University Hospital Leuven, KU Leuven, Belgium.
Boris WinterhoffDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology.
Sean C DowdyDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology.
Ellen L GoodeDivision of Epidemiology, Department of Health Science Research and.
Attila TeomanDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology.
Helga B SalvesenDepartment of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
Jone TrovikDepartment of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
Tormund S NjolstadDepartment of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
Henrica M J WernerDepartment of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
Katie AshtonHunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia, Faculty of Health, Centre for Information Based Medicine and the Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy and.
Tony ProiettoFaculty of Health, School of Medicine and Public Health, University of Newcastle, NSW, Australia.
Geoffrey OttonFaculty of Health, School of Medicine and Public Health, University of Newcastle, NSW, Australia.
Gerasimos TzortzatosDepartment of Women's and Children's Health.
Miriam MintsDepartment of Women's and Children's Health.
Emma ThamDepartment of Molecular Medicine and Surgery and.
RENDOCAS
Per HallDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Kamila CzeneDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Jianjun LiuHuman Genetics, Genome Institute of Singapore, Singapore.
Jingmei LiHuman Genetics, Genome Institute of Singapore, Singapore.
John L HopperCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and.
Melissa C SoutheyDepartment of Pathology, Genetic Epidemiology Laboratory, The University of Melbourne, Melbourne, VIC, Australia.
Australian Ovarian Cancer Study (AOCS)
Arif B EkiciInstitute of Human Genetics, University Hospital, Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Matthias RuebnerUniversity Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Nicola JohnsonBreakthrough Breast Cancer Research Centre.
Julian PetoLondon School of Hygiene and Tropical Medicine, London, UK.
Barbara BurwinkelMolecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Molecular Epidemiology, C080.
Frederik MarmeMolecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
Hermann BrennerDivision of Clinical Epidemiology and Aging Research, German Cancer Consortium (DKTK), Heidelberg, Germany.
Aida K DieffenbachDivision of Clinical Epidemiology and Aging Research, German Cancer Consortium (DKTK), Heidelberg, Germany.
Alfons MeindlDivision of Tumor Genetics, Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany.
Hiltrud BrauchDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Stuttgart, University of Tuebingen, Germany.
GENICA Network
Annika LindblomDepartment of Molecular Medicine and Surgery and.
Jeroen DepreeuwVesalius Research Center, VIB, Leuven, Belgium.
Matthieu MoisseVesalius Research Center, VIB, Leuven, Belgium.
Jenny Chang-ClaudeDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Anja RudolphDepartment of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
Fergus J CouchDepartments of Laboratory Medicine and Pathology, and Health Science Research, Mayo Clinic, Rochester, MN, USA.
Janet E OlsonDivision of Epidemiology, Department of Health Science Research and.
Graham G GilesCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, VIC, Australia, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
Fiona BruinsmaCancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, VIC, Australia.
Julie M CunninghamDepartments of Laboratory Medicine and Pathology, and Health Science Research, Mayo Clinic, Rochester, MN, USA.
Brooke L FridleyDepartment of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
Anne-Lise Børresen-DaleDepartment of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway, Faculty of Medicine, The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
Vessela N KristensenDepartment of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway, Faculty of Medicine, The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway, Division of Medicine, Department of Clinical Molecular Oncology, Akershus University Hospital, Ahus, Norway.
Angela CoxDepartment of Oncology, Sheffield Cancer Research Centre, University of Sheffield, Sheffield, UK.
Anthony J SwerdlowDivision of Genetics and Epidemiology and, Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
Nicholas OrrDivision of Breast Cancer Research, Institute of Cancer Research, London, UK.
Manjeet K BollaCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
Qin WangCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
Rachel Palmieri WeberDepartment of Community and Family Medicine, Duke University School of Medicine, Durham, NC, USA.
Zhihua ChenDivision of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
Mitul ShahCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Juliet D FrenchQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Paul D P PharoahCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Alison M DunningCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Ian TomlinsonWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Douglas F EastonCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Stacey L EdwardsQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Deborah J ThompsonCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Amanda B SpurdleQIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia, amanda.spurdle@qimrberghofer.edu.au.
QIMR Berghofer Medical Research Institute · AUUniversity of Cambridge · GBCentre for Human Genetics · GBFriedrich-Alexander-Universität Erlangen-Nürnberg · DEHaukeland University Hospital · NOGerman Cancer Research Center · DEGynecologic Oncology Group · USKU Leuven · BEProstate Cancer Research · GBVanderbilt University Medical Center · USCancer Council Victoria · AUFriedrich Schiller University Jena · DEGenome Institute of Singapore · SGHealth and Human Development (2HD) Research Network · CMHunter Medical Research Institute · AUInstitute of Cancer Research · GBJohn Hunter Hospital · AUKarolinska University Hospital · SEMayo Clinic in Florida · USUniversity of Newcastle Australia · AU

Funding

Women's Cancer ProgramP30CA015083 · NCI · MAYO CLINIC ROCHESTER · PI Felicity Enders · 1985 to 2026
$151.3M
Use of microfluidic tumor cultures to enable clinical trials of therapies for ovarian cancerP50CA136393 · NCI · MAYO CLINIC ROCHESTER · PI Zhenkun Lou · 2009 to 2026
$37.0M
Epidemiologic StudiesU19CA148065 · NCI · HARVARD SCHOOL OF PUBLIC HEALTH · PI AHSAN, HABIBUL, BRUGGE, JOAN SIEFERT · 2010 to 2014
$10.6M
Epidemiological and Clinical Translational Studies Post Genome-Wide AssociationU19CA148537 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI EASTON, DOUGLAS FREDERICK, EELES, ROSALIND · 2010 to 2014
$10.4M
Ovarian cancer GWAS discovery, expansion and replication (N2 - Project #1)U19CA148112 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI SELLERS, THOMAS A · 2010 to 2014
$10.2M
Shanghai Womens Health StudyUM1CA182910 · NCI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI ZHENG, WEI · 2014 to 2018
$5.9M
Shanghai Breast Cancer StudyR01CA064277 · NCI · VANDERBILT UNIVERSITY · PI SHU, XIAO-OU · 1996 to 2012
$4.8M
A genome-wide association study for breast cancer in BRCA1 mutation carriersR01CA128978 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH · 2008 to 2012
$4.8M
MOLECULAR EPIDEMIOLOGIC STUDY OF BREAST CANCERR01CA090899 · NCI · VANDERBILT UNIVERSITY · PI ZHENG, WEI · 2000 to 2009
$3.5M
Consortium Study to Identify Breast Cancer Susceptibility LociR01CA148667 · NCI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI LONG, JIRONG, ZHENG, WEI · 2011 to 2015
$3.3M
Genetic Variation in the NF-kappaB Pathway and Ovarian Cancer EtiologyR01CA122443 · NCI · MAYO CLINIC ROCHESTER · PI GOODE, ELLEN L. · 2007 to 2012
$2.7M
Soyfood, Gene Polymorphisms and Endometrial Cancer RiskR01CA092585 · NCI · VANDERBILT UNIVERSITY · PI SHU, XIAO-OU · 2001 to 2010
$2.3M
Cancer Research UK 10124Cancer Research UK 16459Cancer Research UK 16561Cancer Research UK 16563Cancer Research UK 16565Cancer Research UK C12292/A11174Cancer Research UK C1281/A12014Cancer Research UK C1287/A10118Cancer Research UK C1287/A 10710Cancer Research UK C1287/A12014Cancer Research UK C490/A10124Cancer Research UK C5047/A10692Cancer Research UK C5047/A15007Cancer Research UK C5047/A8384CIHRMedical Research Council G0000934NCI NIH HHS 1U19 CA148065NCI NIH HHS 1U19 CA148112NCI NIH HHS 1U19 CA148537NCI NIH HHS CA128978NCI NIH HHS P30 CA015083NCI NIH HHS P50 CA136393NCI NIH HHS R01 CA064277NCI NIH HHS R01 CA090899NCI NIH HHS R01 CA 092585NCI NIH HHS R01 CA092585NCI NIH HHS R01 CA122443NCI NIH HHS R01 CA128978NCI NIH HHS R01 CA148667NCI NIH HHS R01 CA64277NCI NIH HHS R01 CA90899NCI NIH HHS U19 CA148065NCI NIH HHS U19 CA148112NCI NIH HHS U19 CA148537NCI NIH HHS UM1 CA182910Wellcome Trust 068545/Z/02Wellcome Trust 085475Wellcome Trust 090532
6 · The paper itself

Abstract

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

Indexed as

Chromosome MappingGenetic LociAllelesCase-Control StudiesCell Line, TumorComputational BiologyDatabases, GeneticEndometrial NeoplasmsEpigenesis, GeneticFemaleGenetic VariationGenome-Wide Association StudyGenotypeHaplotypesHepatocyte Nuclear Factor 1-betaHumansHepatocyte Nuclear Factor 1-betaHNF1B protein, humanRNA, Messenger

Identifiers

PMID25378557
PMCPMC4321445
OpenAlexW1519041492

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LicenceCC BY
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.