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The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
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.
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).
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
ppublish 2013/06
received 2012/12/03
accepted 2013/05/14
epublish 2013/06/25
entrez 2013/07/05 06:00
pubmed 2013/07/05 06:00
medline 2014/03/22 06:00
Fall T Fall Tove T Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Hägg S Hägg Sara S
Mägi R Mägi Reedik R
Ploner A Ploner Alexander A
Fischer K Fischer Krista K
Horikoshi M Horikoshi Momoko M
Sarin AP Sarin Antti-Pekka AP
Thorleifsson G Thorleifsson Gudmar G
Ladenvall C Ladenvall Claes C
Kals M Kals Mart M
Kuningas M Kuningas Maris M
Draisma HH Draisma Harmen H M HH
Ried JS Ried Janina S JS
van Zuydam NR van Zuydam Natalie R NR
Huikari V Huikari Ville V
Mangino M Mangino Massimo M
Sonestedt E Sonestedt Emily E
Benyamin B Benyamin Beben B
Nelson CP Nelson Christopher P CP
Rivera NV Rivera Natalia V NV
Kristiansson K Kristiansson Kati K
Shen HY Shen Huei-Yi HY
Havulinna AS Havulinna Aki S AS
Dehghan A Dehghan Abbas A
Donnelly LA Donnelly Louise A LA
Kaakinen M Kaakinen Marika M
Nuotio ML Nuotio Marja-Liisa ML
Robertson N Robertson Neil N
de Bruijn RF de Bruijn Renée F A G RF
Ikram MA Ikram M Arfan MA
Amin N Amin Najaf N
Balmforth AJ Balmforth Anthony J AJ
Braund PS Braund Peter S PS
Doney AS Doney Alexander S F AS
Döring A Döring Angela A
Elliott P Elliott Paul P
Esko T Esko Tõnu T
Franco OH Franco Oscar H OH
Gretarsdottir S Gretarsdottir Solveig S
Hartikainen AL Hartikainen Anna-Liisa AL
Heikkilä K Heikkilä Kauko K
Herzig KH Herzig Karl-Heinz KH
Holm H Holm Hilma H
Hottenga JJ Hottenga Jouke Jan JJ
Hyppönen E Hyppönen Elina E
Illig T Illig Thomas T
Isaacs A Isaacs Aaron A
Isomaa B Isomaa Bo B
Karssen LC Karssen Lennart C LC
Kettunen J Kettunen Johannes J
Koenig W Koenig Wolfgang W
Kuulasmaa K Kuulasmaa Kari K
Laatikainen T Laatikainen Tiina T
Laitinen J Laitinen Jaana J
Lindgren C Lindgren Cecilia C
Lyssenko V Lyssenko Valeriya V
Läärä E Läärä Esa E
Rayner NW Rayner Nigel W NW
Männistö S Männistö Satu S
Pouta A Pouta Anneli A
Rathmann W Rathmann Wolfgang W
Rivadeneira F Rivadeneira Fernando F
Ruokonen A Ruokonen Aimo A
Savolainen MJ Savolainen Markku J MJ
Sijbrands EJ Sijbrands Eric J G EJ
Small KS Small Kerrin S KS
Smit JH Smit Jan H JH
Steinthorsdottir V Steinthorsdottir Valgerdur V
Syvänen AC Syvänen Ann-Christine AC
Taanila A Taanila Anja A
Tobin MD Tobin Martin D MD
Uitterlinden AG Uitterlinden Andre G AG
Willems SM Willems Sara M SM
Willemsen G Willemsen Gonneke G
Witteman J Witteman Jacqueline J
Perola M Perola Markus M
Evans A Evans Alun A
Ferrières J Ferrières Jean J
Virtamo J Virtamo Jarmo J
Kee F Kee Frank F
Tregouet DA Tregouet David-Alexandre DA
Arveiler D Arveiler Dominique D
Amouyel P Amouyel Philippe P
Ferrario MM Ferrario Marco M MM
Brambilla P Brambilla Paolo P
Hall AS Hall Alistair S AS
Heath AC Heath Andrew C AC
Madden PA Madden Pamela A F PA
Martin NG Martin Nicholas G NG
Montgomery GW Montgomery Grant W GW
Whitfield JB Whitfield John B JB
Jula A Jula Antti A
Knekt P Knekt Paul P
Oostra B Oostra Ben B
van Duijn CM van Duijn Cornelia M CM
Penninx BW Penninx Brenda W J H BW
Smith GD Smith George Davey GD
Kaprio J Kaprio Jaakko J
Samani NJ Samani Nilesh J NJ
Gieger C Gieger Christian C
Peters A Peters Annette A
Wichmann HE Wichmann H Erich HE
Boomsma DI Boomsma Dorret I DI
de Geus EJ de Geus Eco J C EJ
Tuomi T Tuomi TiinaMaija T
Power C Power Chris C
Hammond CJ Hammond Christopher J CJ
Spector TD Spector Tim D TD
Lind L Lind Lars L
Orho-Melander M Orho-Melander Marju M
Palmer CN Palmer Colin Neil Alexander CN
Morris AD Morris Andrew D AD
Groop L Groop Leif L
Järvelin MR Järvelin Marjo-Riitta MR
Salomaa V Salomaa Veikko V
Vartiainen E Vartiainen Erkki E
Hofman A Hofman Albert A
Ripatti S Ripatti Samuli S
Metspalu A Metspalu Andres A
Thorsteinsdottir U Thorsteinsdottir Unnur U
Stefansson K Stefansson Kari K
Pedersen NL Pedersen Nancy L NL
McCarthy MI McCarthy Mark I MI
Ingelsson E Ingelsson Erik E
Prokopenko I Prokopenko Inga I
European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium
TITLE: PLoS medicine
YEAR: 2013
ISSN: 1549-1676
ISSNTYPE: Electronic
COUNTRY: United States
ISSNLINKING: 1549-1277
NLMUNIQUEID: 101231360
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
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British Heart Foundation United Kingdom
Adiposity genetics
Body Mass Index genetics
Cardiovascular Diseases metabolism
Case-Control Studies metabolism
Confounding Factors (Epidemiology) metabolism
Genetic Association Studies metabolism
Humans metabolism
Mendelian Randomization Analysis metabolism
Meta-Analysis as Topic metabolism
Polymorphism, Single Nucleotide genetics
Proteins genetics
Quantitative Trait, Heritable genetics
0 FTO protein, human
0 Proteins
PMC3692470 NLM