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The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis
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نویسنده
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fall t. ,hägg s. ,mägi r. ,ploner a. ,fischer k. ,horikoshi m. ,sarin a.-p. ,thorleifsson g. ,ladenvall c. ,kals m. ,kuningas m. ,draisma h.h.m. ,ried j.s. ,van zuydam n.r. ,huikari v. ,mangino m. ,sonestedt e. ,benyamin b. ,nelson c.p. ,rivera n.v. ,kristiansson k. ,shen h.-y. ,havulinna a.s. ,dehghan a. ,donnelly l.a. ,kaakinen m. ,nuotio m.-l. ,robertson n. ,de bruijn r.f.a.g. ,ikram m.a. ,amin n. ,balmforth a.j. ,braund p.s. ,doney a.s.f. ,döring a. ,elliott p. ,esko t. ,franco o.h. ,gretarsdottir s. ,hartikainen a.-l. ,heikkilä k. ,herzig k.-h. ,holm h. ,hottenga j.j. ,hyppönen e. ,illig t. ,isaacs a. ,isomaa b. ,karssen l.c. ,kettunen j. ,koenig w. ,kuulasmaa k. ,laatikainen t. ,laitinen j. ,lindgren c. ,lyssenko v. ,läärä e. ,rayner n.w. ,männistö s. ,pouta a. ,rathmann w. ,rivadeneira f. ,ruokonen a. ,savolainen m.j. ,sijbrands e.j.g. ,small k.s. ,smit j.h. ,steinthorsdottir v. ,syvänen a.-c. ,taanila a. ,tobin m.d. ,uitterlinden a.g. ,willems s.m. ,willemsen g. ,witteman j. ,perola m. ,evans a. ,ferrières j. ,virtamo j. ,kee f. ,tregouet d.-a. ,arveiler d. ,amouyel p. ,ferrario m.m. ,brambilla p. ,hall a.s. ,heath a.c. ,madden p.a.f. ,martin n.g. ,montgomery g.w. ,whitfield j.b. ,jula a. ,knekt p. ,oostra b. ,van duijn c.m. ,penninx b.w.j.h. ,davey smith g. ,kaprio j. ,samani n.j. ,gieger c. ,peters a. ,wichmann h.-e. ,boomsma d.i. ,de geus e.j.c. ,tuomi t.m. ,power c. ,hammond c.j. ,spector t.d. ,lind l. ,orho-melander m. ,palmer c.n.a. ,morris a.d. ,groop l. ,järvelin m.-r. ,salomaa v. ,vartiainen e. ,hofman a. ,ripatti s. ,metspalu a. ,thorsteinsdottir u. ,stefansson k. ,pedersen n.l. ,mccarthy m.i. ,ingelsson e. ,prokopenko i.
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منبع
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plos medicine - 2013 - دوره : 10 - شماره : 6
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چکیده
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Background:the association between adiposity and cardiometabolic traits is well known from epidemiological studies. whilst the causal relationship is clear for some of these traits,for others it is not. we aimed to determine whether adiposity is causally related to various cardiometabolic traits using the mendelian randomization approach.methods and findings:we used the adiposity-associated variant rs9939609 at the fto locus as an instrumental variable (iv) for body mass index (bmi) in a mendelian randomization design. thirty-six population-based studies of individuals of european descent contributed to the analyses.age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and bmi (n = 198,502),(ii) rs9939609 and 24 traits,and (iii) bmi and 24 traits. the causal effect of bmi on the outcome measures was quantified by iv estimators. the estimators were compared to the bmi-trait associations derived from the same individuals. in the iv analysis,we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio,1.19 per bmi-unit increase; 95% ci,1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes,metabolic syndrome,dyslipidemia,and hypertension (odds ratio for iv estimator,1.1-1.4; all p<0.05). for quantitative traits,our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure,fasting insulin,2-h post-load glucose from the oral glucose tolerance test,c-reactive protein,triglycerides,and high-density lipoprotein cholesterol levels (all p<0.05). the estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes,where the causal estimate was larger than the observational estimate (p = 0.001).conclusions:we provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.please see later in the article for the editors' summary. © 2013 fall et al.
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آدرس
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molecular epidemiology and science for life laboratory,department of medical sciences,uppsala university,uppsala,sweden,department of medical epidemiology and biostatistics,karolinska institutet,stockholm, Sweden, molecular epidemiology and science for life laboratory,department of medical sciences,uppsala university,uppsala,sweden,department of medical epidemiology and biostatistics,karolinska institutet,stockholm, Sweden, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,estonian genome center,university of tartu,tartu, Estonia, department of medical epidemiology and biostatistics,karolinska institutet,stockholm, Sweden, estonian genome center,university of tartu,tartu, Estonia, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology and metabolism,university of oxford,oxford, United Kingdom, institute for molecular medicine finland,university of helsinki,helsinki, Finland, decode genetics,reykjavik, Iceland, department of clinical sciences,diabetes and endocrinology,lund university diabetes centre,lund university and skåne university hospital,malmö, Sweden, estonian genome center,university of tartu,tartu, Estonia, department of epidemiology,erasmus medical center,rotterdam, Netherlands, department of biological psychology,vu university amsterdam,amsterdam,netherlands,the emgo institute for health and care research,amsterdam, Netherlands, institute of genetic epidemiology,helmholtz zentrum münchen-german research center for environmental health,neuherberg, Germany, medical research institute,ninewells hospital and medical school,university of dundee,dundee, United Kingdom, institute of health sciences,university of oulu,oulu, Finland, department of twin research and genetic epidemiology,king's college london, United Kingdom, diabetes and cardiovascular diseases genetic epidemiology research unit,department of clinical sciences,skåne university hospital,lund university,malmö, Sweden, queensland institute of medical research,herston,australia,queensland brain institute,university of queensland,st lucia, Australia, department of cardiovascular sciences,university of leicester,leicester,united kingdom,national institute for health research,leicester cardiovascular biomedical research unit,glenfield hospital,leicester, United Kingdom, ircss multimedica,milan,italy,institute of genetics and biomedical research,consiglio nazionale delle ricerche,milan,italy,department of genetic epidemiology,erasmus medical center,rotterdam, Netherlands, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, institute for molecular medicine finland,university of helsinki,helsinki,finland,public health genomics unit,national institute for health and welfare,helsinki, Finland, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, department of epidemiology,erasmus medical center,rotterdam,netherlands,netherlands consortium for healthy ageing,netherlands genomics initiative,leiden, Netherlands, medical research institute,ninewells hospital and medical school,university of dundee,dundee, United Kingdom, institute of health sciences,university of oulu,oulu,finland,biocenter oulu,university of oulu,oulu, Finland, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology and metabolism,university of oxford,oxford, United Kingdom, department of epidemiology,erasmus medical center,rotterdam,netherlands,department of neurology,erasmus medical center,rotterdam, Netherlands, department of epidemiology,erasmus medical center,rotterdam,netherlands,department of neurology,erasmus medical center,rotterdam,netherlands,department of radiology,erasmus medical center,rotterdam, Netherlands, department of genetic epidemiology,erasmus medical center,rotterdam, Netherlands, division of epidemiology,leeds institute of genetics,health and therapeutics,school of medicine,university of leeds,leeds, United Kingdom, department of cardiovascular sciences,university of leicester,leicester, United Kingdom, medical research institute,ninewells hospital and medical school,university of dundee,dundee, United Kingdom, institute of epidemiology i,helmholtz zentrum münchen-german research center for environmental health,neuherberg,germany,institute of epidemiology ii,helmholtz zentrum münchen-german research center for environmental health,neuherberg, Germany, mrc-hpa centre for environment and health,department of epidemiology and biostatistics,school of public health,imperial college london,london, United Kingdom, estonian genome center,university of tartu,tartu, Estonia, department of epidemiology,erasmus medical center,rotterdam,netherlands,netherlands consortium for healthy ageing,netherlands genomics initiative,leiden, Netherlands, decode genetics,reykjavik, Iceland, department of obstetrics and gynaecology,institute of clinical sciences,university of oulu,oulu, Finland, department of public health,hjelt institute,university of helsinki,helsinki, Finland, biocenter oulu,university of oulu,oulu,finland,institute of biomedicine,university of oulu,oulu,finland,department of psychiatry,kuopio university hospital,kuopio, Finland, decode genetics,reykjavik, Iceland, department of biological psychology,vu university amsterdam,amsterdam,netherlands,the emgo institute for health and care research,amsterdam, Netherlands, centre for paediatric epidemiology and biostatistics,medical research council centre for the epidemiology of child health,university college london institute of child health,london, United Kingdom, hannover unified biobank,hannover medical school,hannover,germany,research unit of molecular epidemiology,helmholtz zentrum münchen-german research center for environmental health,neuherberg, Germany, department of genetic epidemiology,erasmus medical center,rotterdam, Netherlands, department of social services and health care,jakobstad,finland,folkhälsan research centre,helsinki, Finland, department of genetic epidemiology,erasmus medical center,rotterdam, Netherlands, institute for molecular medicine finland,university of helsinki,helsinki,finland,department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, department of internal medicine ii-cardiology,university of ulm medical center,ulm, Germany, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, finnish institute of occupational health,helsinki, Finland, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, department of clinical sciences,diabetes and endocrinology,lund university diabetes centre,lund university and skåne university hospital,malmö,sweden,steno diabetes center,gentofte, Denmark, department of mathematical sciences,university of oulu,oulu, Finland, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology and metabolism,university of oxford,oxford,united kingdom,wellcome trust sanger institute,hinxton, United Kingdom, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, department of obstetrics and gynaecology,institute of clinical sciences,university of oulu,oulu,finland,department of children,young people and families,national institute for health and welfare,oulu, Finland, institute of biometrics and epidemiology,german diabetes center,düsseldorf university,düsseldorf, Germany, netherlands consortium for healthy ageing,netherlands genomics initiative,leiden,netherlands,department of internal medicine,erasmus medical center,rotterdam, Netherlands, institute of diagnostics,university of oulu,oulu, Finland, biocenter oulu,university of oulu,oulu,finland,department of internal medicine,institute of clinical medicine,university of oulu,oulu, Finland, department of internal medicine,erasmus medical center,rotterdam, Netherlands, department of twin research and genetic epidemiology,king's college london, United Kingdom, the emgo institute for health and care research,amsterdam,netherlands,neuroscience campus amsterdam,amsterdam,netherlands,department of psychiatry,vu university medical center,amsterdam, Netherlands, decode genetics,reykjavik, Iceland, molecular medicine and science for life laboratory,department of medical sciences,uppsala university,uppsala, Sweden, institute of health sciences,university of oulu,oulu, Finland, department of health sciences,university of leicester,leicester, United Kingdom, department of internal medicine,erasmus medical center,rotterdam, Netherlands, department of genetic epidemiology,erasmus medical center,rotterdam, Netherlands, department of biological psychology,vu university amsterdam,amsterdam,netherlands,the emgo institute for health and care research,amsterdam, Netherlands, department of epidemiology,erasmus medical center,rotterdam,netherlands,netherlands consortium for healthy ageing,netherlands genomics initiative,leiden, Netherlands, estonian genome center,university of tartu,tartu,estonia,department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, centre for public health,queen's university of belfast,belfast, Ireland, department of cardiology,toulouse university school of medicine,rangueil hospital,toulouse, France, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, centre of excellence for public health northern ireland,queen's university of belfast,belfast, Ireland, institute of cardiometabolism and nutrition,inserm umr s937,pierre and marie curie university,paris, France, department of epidemiology and public health,university of strasbourg,strasbourg, France, institut pasteur de lille,inserm u744,université lille nord de france,lille, France, epidemiology and preventive medicine research centre,department of clinical and experimental medicine,university of insubria,varese, Italy, department of experimental medicine,university of milano-bicocca,monza, Italy, division of epidemiology,leeds institute of genetics,health and therapeutics,school of medicine,university of leeds,leeds, United Kingdom, washington university school of medicine,st louis,mo, United States, washington university school of medicine,st louis,mo, United States, queensland institute of medical research,herston, Australia, queensland institute of medical research,herston, Australia, queensland institute of medical research,herston, Australia, population studies unit,department of chronic disease prevention,national institute for health and welfare,turku, Finland, department of health,functional capacity and welfare,national institute for health and welfare,helsinki, Finland, department of clinical genetics,erasmus medical center,rotterdam, Netherlands, department of genetic epidemiology,erasmus medical center,rotterdam,netherlands,netherlands genomic initiative,leiden,netherlands,centre for medical systems biology,leiden, Netherlands, the emgo institute for health and care research,amsterdam,netherlands,department of psychiatry,vu university medical center,amsterdam, Netherlands, mrc centre for integrative epidemiology unit,university of bristol,bristol, United Kingdom, institute for molecular medicine finland,university of helsinki,helsinki,finland,department of public health,hjelt institute,university of helsinki,helsinki,finland,department of mental health and substance abuse services,national institute for health and welfare,helsinki, Finland, department of cardiovascular sciences,university of leicester,leicester,united kingdom,national institute for health research,leicester cardiovascular biomedical research unit,glenfield hospital,leicester, United Kingdom, institute of genetic epidemiology,helmholtz zentrum münchen-german research center for environmental health,neuherberg, Germany, institute of epidemiology ii,helmholtz zentrum münchen-german research center for environmental health,neuherberg,germany,munich heart alliance,munich, Germany, institute of epidemiology i,helmholtz zentrum münchen-german research center for environmental health,neuherberg,germany,institute of medical informatics,biometry and epidemiology,chair of epidemiology,ludwig-maximilians-universität,munich,germany,klinikum grosshadern,munich, Germany, department of biological psychology,vu university amsterdam,amsterdam,netherlands,the emgo institute for health and care research,amsterdam,netherlands,neuroscience campus amsterdam,amsterdam, Netherlands, department of biological psychology,vu university amsterdam,amsterdam,netherlands,the emgo institute for health and care research,amsterdam,netherlands,neuroscience campus amsterdam,amsterdam, Netherlands, folkhälsan research centre,helsinki,finland,department of medicine,helsinki university central hospital,helsinki, Finland, centre for paediatric epidemiology and biostatistics,medical research council centre for the epidemiology of child health,university college london institute of child health,london, United Kingdom, department of twin research and genetic epidemiology,king's college london, United Kingdom, department of twin research and genetic epidemiology,king's college london, United Kingdom, department of medical sciences,uppsala university,uppsala, Sweden, department of clinical sciences,diabetes and endocrinology,lund university diabetes centre,lund university and skåne university hospital,malmö, Sweden, medical research institute,ninewells hospital and medical school,university of dundee,dundee, United Kingdom, medical research institute,ninewells hospital and medical school,university of dundee,dundee, United Kingdom, institute for molecular medicine finland,university of helsinki,helsinki,finland,department of clinical sciences,diabetes and endocrinology,lund university diabetes centre,lund university and skåne university hospital,malmö, Sweden, institute of health sciences,university of oulu,oulu,finland,biocenter oulu,university of oulu,oulu,finland,department of children,young people and families,national institute for health and welfare,oulu,finland,department of epidemiology and biostatistics,imperial college london,london, United Kingdom, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, division of welfare and health promotion,national institute for health and welfare,helsinki, Finland, department of epidemiology,erasmus medical center,rotterdam,netherlands,netherlands consortium for healthy ageing,netherlands genomics initiative,leiden, Netherlands, institute for molecular medicine finland,university of helsinki,helsinki,finland,department of chronic disease prevention,national institute for health and welfare,helsinki,finland,wellcome trust sanger institute,hinxton, United Kingdom, estonian genome center,university of tartu,tartu, Estonia, decode genetics,reykjavik,iceland,faculty of medicine,university of iceland,reykjavík, Iceland, decode genetics,reykjavik,iceland,faculty of medicine,university of iceland,reykjavík, Iceland, department of medical epidemiology and biostatistics,karolinska institutet,stockholm, Sweden, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology and metabolism,university of oxford,oxford,united kingdom,oxford national institute for health research biomedical research centre,churchill hospital,oxford, United Kingdom, molecular epidemiology and science for life laboratory,department of medical sciences,uppsala university,uppsala,sweden,department of medical epidemiology and biostatistics,karolinska institutet,stockholm,sweden,wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology and metabolism,university of oxford,oxford,united kingdom,department of genomics of common disease,school of public health,imperial college london,london, United Kingdom
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Authors
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