The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.

<h4>Background</h4>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 cardi...

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Autores principales:	Tove Fall, Sara Hägg, Reedik Mägi, Alexander Ploner, Krista Fischer, Momoko Horikoshi, Antti-Pekka Sarin, Gudmar Thorleifsson, Claes Ladenvall, Mart Kals, Maris Kuningas, Harmen H M Draisma, Janina S Ried, Natalie R van Zuydam, Ville Huikari, Massimo Mangino, Emily Sonestedt, Beben Benyamin, Christopher P Nelson, Natalia V Rivera, Kati Kristiansson, Huei-Yi Shen, Aki S Havulinna, Abbas Dehghan, Louise A Donnelly, Marika Kaakinen, Marja-Liisa Nuotio, Neil Robertson, Renée F A G de Bruijn, M Arfan Ikram, Najaf Amin, Anthony J Balmforth, Peter S Braund, Alexander S F Doney, Angela Döring, Paul Elliott, Tõnu Esko, Oscar H Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkilä, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hyppönen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Lennart C Karssen, Johannes Kettunen, Wolfgang Koenig, Kari Kuulasmaa, Tiina Laatikainen, Jaana Laitinen, Cecilia Lindgren, Valeriya Lyssenko, Esa Läärä, Nigel W Rayner, Satu Männistö, Anneli Pouta, Wolfgang Rathmann, Fernando Rivadeneira, Aimo Ruokonen, Markku J Savolainen, Eric J G Sijbrands, Kerrin S Small, Jan H Smit, Valgerdur Steinthorsdottir, Ann-Christine Syvänen, Anja Taanila, Martin D Tobin, Andre G Uitterlinden, Sara M Willems, Gonneke Willemsen, Jacqueline Witteman, Markus Perola, Alun Evans, Jean Ferrières, Jarmo Virtamo, Frank Kee, David-Alexandre Tregouet, Dominique Arveiler, Philippe Amouyel, Marco M Ferrario, Paolo Brambilla, Alistair S Hall, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, John B Whitfield, Antti Jula, Paul Knekt, Ben Oostra, Cornelia M van Duijn, Brenda W J H Penninx, George Davey Smith, Jaakko Kaprio, Nilesh J Samani, Christian Gieger, Annette Peters, H Erich Wichmann, Dorret I Boomsma, Eco J C de Geus, TiinaMaija Tuomi, Chris Power, Christopher J Hammond, Tim D Spector, Lars Lind, Marju Orho-Melander, Colin Neil Alexander Palmer, Andrew D Morris, Leif Groop, Marjo-Riitta Järvelin, Veikko Salomaa, Erkki Vartiainen, Albert Hofman, Samuli Ripatti, Andres Metspalu, Unnur Thorsteinsdottir, Kari Stefansson, Nancy L Pedersen, Mark I McCarthy, Erik Ingelsson, Inga Prokopenko, European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R
Acceso en línea:	https://doaj.org/article/b5132a1a19434786853b884448f17682
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institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R
spellingShingle	Medicine R Tove Fall Sara Hägg Reedik Mägi Alexander Ploner Krista Fischer Momoko Horikoshi Antti-Pekka Sarin Gudmar Thorleifsson Claes Ladenvall Mart Kals Maris Kuningas Harmen H M Draisma Janina S Ried Natalie R van Zuydam Ville Huikari Massimo Mangino Emily Sonestedt Beben Benyamin Christopher P Nelson Natalia V Rivera Kati Kristiansson Huei-Yi Shen Aki S Havulinna Abbas Dehghan Louise A Donnelly Marika Kaakinen Marja-Liisa Nuotio Neil Robertson Renée F A G de Bruijn M Arfan Ikram Najaf Amin Anthony J Balmforth Peter S Braund Alexander S F Doney Angela Döring Paul Elliott Tõnu Esko Oscar H Franco Solveig Gretarsdottir Anna-Liisa Hartikainen Kauko Heikkilä Karl-Heinz Herzig Hilma Holm Jouke Jan Hottenga Elina Hyppönen Thomas Illig Aaron Isaacs Bo Isomaa Lennart C Karssen Johannes Kettunen Wolfgang Koenig Kari Kuulasmaa Tiina Laatikainen Jaana Laitinen Cecilia Lindgren Valeriya Lyssenko Esa Läärä Nigel W Rayner Satu Männistö Anneli Pouta Wolfgang Rathmann Fernando Rivadeneira Aimo Ruokonen Markku J Savolainen Eric J G Sijbrands Kerrin S Small Jan H Smit Valgerdur Steinthorsdottir Ann-Christine Syvänen Anja Taanila Martin D Tobin Andre G Uitterlinden Sara M Willems Gonneke Willemsen Jacqueline Witteman Markus Perola Alun Evans Jean Ferrières Jarmo Virtamo Frank Kee David-Alexandre Tregouet Dominique Arveiler Philippe Amouyel Marco M Ferrario Paolo Brambilla Alistair S Hall Andrew C Heath Pamela A F Madden Nicholas G Martin Grant W Montgomery John B Whitfield Antti Jula Paul Knekt Ben Oostra Cornelia M van Duijn Brenda W J H Penninx George Davey Smith Jaakko Kaprio Nilesh J Samani Christian Gieger Annette Peters H Erich Wichmann Dorret I Boomsma Eco J C de Geus TiinaMaija Tuomi Chris Power Christopher J Hammond Tim D Spector Lars Lind Marju Orho-Melander Colin Neil Alexander Palmer Andrew D Morris Leif Groop Marjo-Riitta Järvelin Veikko Salomaa Erkki Vartiainen Albert Hofman Samuli Ripatti Andres Metspalu Unnur Thorsteinsdottir Kari Stefansson Nancy L Pedersen Mark I McCarthy Erik Ingelsson Inga Prokopenko European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
description	<h4>Background</h4>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.<h4>Methods and findings</h4>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).<h4>Conclusions</h4>We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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author	Tove Fall Sara Hägg Reedik Mägi Alexander Ploner Krista Fischer Momoko Horikoshi Antti-Pekka Sarin Gudmar Thorleifsson Claes Ladenvall Mart Kals Maris Kuningas Harmen H M Draisma Janina S Ried Natalie R van Zuydam Ville Huikari Massimo Mangino Emily Sonestedt Beben Benyamin Christopher P Nelson Natalia V Rivera Kati Kristiansson Huei-Yi Shen Aki S Havulinna Abbas Dehghan Louise A Donnelly Marika Kaakinen Marja-Liisa Nuotio Neil Robertson Renée F A G de Bruijn M Arfan Ikram Najaf Amin Anthony J Balmforth Peter S Braund Alexander S F Doney Angela Döring Paul Elliott Tõnu Esko Oscar H Franco Solveig Gretarsdottir Anna-Liisa Hartikainen Kauko Heikkilä Karl-Heinz Herzig Hilma Holm Jouke Jan Hottenga Elina Hyppönen Thomas Illig Aaron Isaacs Bo Isomaa Lennart C Karssen Johannes Kettunen Wolfgang Koenig Kari Kuulasmaa Tiina Laatikainen Jaana Laitinen Cecilia Lindgren Valeriya Lyssenko Esa Läärä Nigel W Rayner Satu Männistö Anneli Pouta Wolfgang Rathmann Fernando Rivadeneira Aimo Ruokonen Markku J Savolainen Eric J G Sijbrands Kerrin S Small Jan H Smit Valgerdur Steinthorsdottir Ann-Christine Syvänen Anja Taanila Martin D Tobin Andre G Uitterlinden Sara M Willems Gonneke Willemsen Jacqueline Witteman Markus Perola Alun Evans Jean Ferrières Jarmo Virtamo Frank Kee David-Alexandre Tregouet Dominique Arveiler Philippe Amouyel Marco M Ferrario Paolo Brambilla Alistair S Hall Andrew C Heath Pamela A F Madden Nicholas G Martin Grant W Montgomery John B Whitfield Antti Jula Paul Knekt Ben Oostra Cornelia M van Duijn Brenda W J H Penninx George Davey Smith Jaakko Kaprio Nilesh J Samani Christian Gieger Annette Peters H Erich Wichmann Dorret I Boomsma Eco J C de Geus TiinaMaija Tuomi Chris Power Christopher J Hammond Tim D Spector Lars Lind Marju Orho-Melander Colin Neil Alexander Palmer Andrew D Morris Leif Groop Marjo-Riitta Järvelin Veikko Salomaa Erkki Vartiainen Albert Hofman Samuli Ripatti Andres Metspalu Unnur Thorsteinsdottir Kari Stefansson Nancy L Pedersen Mark I McCarthy Erik Ingelsson Inga Prokopenko European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium
author_facet	Tove Fall Sara Hägg Reedik Mägi Alexander Ploner Krista Fischer Momoko Horikoshi Antti-Pekka Sarin Gudmar Thorleifsson Claes Ladenvall Mart Kals Maris Kuningas Harmen H M Draisma Janina S Ried Natalie R van Zuydam Ville Huikari Massimo Mangino Emily Sonestedt Beben Benyamin Christopher P Nelson Natalia V Rivera Kati Kristiansson Huei-Yi Shen Aki S Havulinna Abbas Dehghan Louise A Donnelly Marika Kaakinen Marja-Liisa Nuotio Neil Robertson Renée F A G de Bruijn M Arfan Ikram Najaf Amin Anthony J Balmforth Peter S Braund Alexander S F Doney Angela Döring Paul Elliott Tõnu Esko Oscar H Franco Solveig Gretarsdottir Anna-Liisa Hartikainen Kauko Heikkilä Karl-Heinz Herzig Hilma Holm Jouke Jan Hottenga Elina Hyppönen Thomas Illig Aaron Isaacs Bo Isomaa Lennart C Karssen Johannes Kettunen Wolfgang Koenig Kari Kuulasmaa Tiina Laatikainen Jaana Laitinen Cecilia Lindgren Valeriya Lyssenko Esa Läärä Nigel W Rayner Satu Männistö Anneli Pouta Wolfgang Rathmann Fernando Rivadeneira Aimo Ruokonen Markku J Savolainen Eric J G Sijbrands Kerrin S Small Jan H Smit Valgerdur Steinthorsdottir Ann-Christine Syvänen Anja Taanila Martin D Tobin Andre G Uitterlinden Sara M Willems Gonneke Willemsen Jacqueline Witteman Markus Perola Alun Evans Jean Ferrières Jarmo Virtamo Frank Kee David-Alexandre Tregouet Dominique Arveiler Philippe Amouyel Marco M Ferrario Paolo Brambilla Alistair S Hall Andrew C Heath Pamela A F Madden Nicholas G Martin Grant W Montgomery John B Whitfield Antti Jula Paul Knekt Ben Oostra Cornelia M van Duijn Brenda W J H Penninx George Davey Smith Jaakko Kaprio Nilesh J Samani Christian Gieger Annette Peters H Erich Wichmann Dorret I Boomsma Eco J C de Geus TiinaMaija Tuomi Chris Power Christopher J Hammond Tim D Spector Lars Lind Marju Orho-Melander Colin Neil Alexander Palmer Andrew D Morris Leif Groop Marjo-Riitta Järvelin Veikko Salomaa Erkki Vartiainen Albert Hofman Samuli Ripatti Andres Metspalu Unnur Thorsteinsdottir Kari Stefansson Nancy L Pedersen Mark I McCarthy Erik Ingelsson Inga Prokopenko European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium
author_sort	Tove Fall
title	The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
title_short	The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
title_full	The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
title_fullStr	The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
title_full_unstemmed	The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
title_sort	role of adiposity in cardiometabolic traits: a mendelian randomization analysis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/b5132a1a19434786853b884448f17682
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spelling	oai:doaj.org-article:b5132a1a19434786853b884448f176822021-11-18T05:42:33ZThe role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.1549-12771549-167610.1371/journal.pmed.1001474https://doaj.org/article/b5132a1a19434786853b884448f176822013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23824655/?tool=EBIhttps://doaj.org/toc/1549-1277https://doaj.org/toc/1549-1676<h4>Background</h4>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.<h4>Methods and findings</h4>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).<h4>Conclusions</h4>We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.Tove FallSara HäggReedik MägiAlexander PlonerKrista FischerMomoko HorikoshiAntti-Pekka SarinGudmar ThorleifssonClaes LadenvallMart KalsMaris KuningasHarmen H M DraismaJanina S RiedNatalie R van ZuydamVille HuikariMassimo ManginoEmily SonestedtBeben BenyaminChristopher P NelsonNatalia V RiveraKati KristianssonHuei-Yi ShenAki S HavulinnaAbbas DehghanLouise A DonnellyMarika KaakinenMarja-Liisa NuotioNeil RobertsonRenée F A G de BruijnM Arfan IkramNajaf AminAnthony J BalmforthPeter S BraundAlexander S F DoneyAngela DöringPaul ElliottTõnu EskoOscar H FrancoSolveig GretarsdottirAnna-Liisa HartikainenKauko HeikkiläKarl-Heinz HerzigHilma HolmJouke Jan HottengaElina HyppönenThomas IlligAaron IsaacsBo IsomaaLennart C KarssenJohannes KettunenWolfgang KoenigKari KuulasmaaTiina LaatikainenJaana LaitinenCecilia LindgrenValeriya LyssenkoEsa LääräNigel W RaynerSatu MännistöAnneli PoutaWolfgang RathmannFernando RivadeneiraAimo RuokonenMarkku J SavolainenEric J G SijbrandsKerrin S SmallJan H SmitValgerdur SteinthorsdottirAnn-Christine SyvänenAnja TaanilaMartin D TobinAndre G UitterlindenSara M WillemsGonneke WillemsenJacqueline WittemanMarkus PerolaAlun EvansJean FerrièresJarmo VirtamoFrank KeeDavid-Alexandre TregouetDominique ArveilerPhilippe AmouyelMarco M FerrarioPaolo BrambillaAlistair S HallAndrew C HeathPamela A F MaddenNicholas G MartinGrant W MontgomeryJohn B WhitfieldAntti JulaPaul KnektBen OostraCornelia M van DuijnBrenda W J H PenninxGeorge Davey SmithJaakko KaprioNilesh J SamaniChristian GiegerAnnette PetersH Erich WichmannDorret I BoomsmaEco J C de GeusTiinaMaija TuomiChris PowerChristopher J HammondTim D SpectorLars LindMarju Orho-MelanderColin Neil Alexander PalmerAndrew D MorrisLeif GroopMarjo-Riitta JärvelinVeikko SalomaaErkki VartiainenAlbert HofmanSamuli RipattiAndres MetspaluUnnur ThorsteinsdottirKari StefanssonNancy L PedersenMark I McCarthyErik IngelssonInga ProkopenkoEuropean Network for Genetic and Genomic Epidemiology (ENGAGE) consortiumPublic Library of Science (PLoS)articleMedicineRENPLoS Medicine, Vol 10, Iss 6, p e1001474 (2013)

The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.

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