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

Fall, Tove, Hägg, Sara, Maegi, Reedik, Ploner, Alexander, Fischer, Krista, Horikoshi, Momoko, Sarin, Antti-Pekka, Thorleifsson, Gudmar, Ladenvall, Claes, Kals, Mart, Kuningas, Maris, Draisma, Harmen H. M., Ried, Janina S., van Zuydam, Natalie R., Huikari, Ville, Mangino, Massimo, Sonestedt, Emily, Benyamin, Beben, Nelson, Christopher P., Rivera, Natalia V., Kristiansson, Kati, Shen, Huei-yi, Havulinna, Aki S., Dehghan, Abbas, Donnelly, Louise A., Kaakinen, Marika, Nuotio, Marja-Liisa, Robertson, Neil, de Bruijn, Renee F. A. G., Ikram, M. Arfan, Amin, Najaf, Balmforth, Anthony J., Braund, Peter S., Doney, Alexander S. F., Doering, Angela, Elliott, Paul, Esko, Tõnu, Franco, Oscar H., Gretarsdottir, Solveig, Hartikainen, Anna-Liisa, Heikkilä, Kauko, Herzig, Karl-Heinz, Holm, Hilma, Hottenga, Jouke Jan, Hyppönen, Elina, Illig, Thomas, Isaacs, Aaron, Isomaa, Bo, Karssen, Lennart C., Kettunen, Johannes, Koenig, Wolfgang, Kuulasmaa, Kari, Laatikainen, Tiina, Laitinen, Jaana, Lindgren, Cecilia, Lyssenko, Valeriya, Läärä, Esa, Rayner, Nigel W., Männistö, Satu, Pouta, Anneli, Rathmann, Wolfgang, Rivadeneira, Fernando, Ruokonen, Aimo, Savolainen, Markku J., Sijbrands, Eric J. G., Small, Kerrin S., Smit, Jan H., Steinthorsdottir, Valgerdur, Syvänen, Ann-Christine, Taanila, Anja, Tobin, Martin D., Uitterlinden, Andre G., Willems, Sara M., Willemsen, Gonneke, Witteman, Jacqueline, Perola, Markus, Evans, Alun, Ferrières, Jean, Virtamo, Jarmo, Kee, Frank, Tregouet, David-Alexandre, Arveiler, Dominique, Amouyel, Philippe, Ferrario, Marco M., Brambilla, Paolo, Hall, Alistair S., Heath, Andrew C., Madden, Pamela A. F., Martin, Nicholas G., Montgomery, Grant W., Whitfield, John B., Jula, Antti, Knekt, Paul, Oostra, Ben, van Duijn, Cornelia M., Penninx, Brenda W. J. H., Smith, George Davey, Kaprio, Jaakko, Samani, Nilesh J., Gieger, Christian, Peters, Annette, Wichmann, H.-Erich, Boomsma, Dorret I., de Geus, Eco J. C., Tuomi, TiinaMaija, Power, Chris, Hammond, Christopher J., Spector, Tim D., Lind, Lars, Orho-Melander, Marju, Palmer, Colin Neil Alexander, Morris, Andrew D., Groop, Leif, Järvelin, Marjo-Riitta, Salomaa, Veikko, Vartiainen, Erkki, Hofman, Albert, Ripatti, Samuli, Metspalu, Andres, Thorsteinsdottir, Unnur, Stefansson, Kari, Pedersen, Nancy L., McCarthy, Mark I., Ingelsson, Erik and Prokopenko, Inga (2013) The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis. PLoS Medicine, 10 6: e1001474.1-e1001474.15. doi:10.1371/journal.pmed.1001474

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Author Fall, Tove
Hägg, Sara
Maegi, Reedik
Ploner, Alexander
Fischer, Krista
Horikoshi, Momoko
Sarin, Antti-Pekka
Thorleifsson, Gudmar
Ladenvall, Claes
Kals, Mart
Kuningas, Maris
Draisma, Harmen H. M.
Ried, Janina S.
van Zuydam, Natalie R.
Huikari, Ville
Mangino, Massimo
Sonestedt, Emily
Benyamin, Beben
Nelson, Christopher P.
Rivera, Natalia V.
Kristiansson, Kati
Shen, Huei-yi
Havulinna, Aki S.
Dehghan, Abbas
Donnelly, Louise A.
Kaakinen, Marika
Nuotio, Marja-Liisa
Robertson, Neil
de Bruijn, Renee F. A. G.
Ikram, M. Arfan
Amin, Najaf
Balmforth, Anthony J.
Braund, Peter S.
Doney, Alexander S. F.
Doering, Angela
Elliott, Paul
Esko, Tõnu
Franco, Oscar H.
Gretarsdottir, Solveig
Hartikainen, Anna-Liisa
Heikkilä, Kauko
Herzig, Karl-Heinz
Holm, Hilma
Hottenga, Jouke Jan
Hyppönen, Elina
Illig, Thomas
Isaacs, Aaron
Isomaa, Bo
Karssen, Lennart C.
Kettunen, Johannes
Koenig, Wolfgang
Kuulasmaa, Kari
Laatikainen, Tiina
Laitinen, Jaana
Lindgren, Cecilia
Lyssenko, Valeriya
Läärä, Esa
Rayner, Nigel W.
Männistö, Satu
Pouta, Anneli
Rathmann, Wolfgang
Rivadeneira, Fernando
Ruokonen, Aimo
Savolainen, Markku J.
Sijbrands, Eric J. G.
Small, Kerrin S.
Smit, Jan H.
Steinthorsdottir, Valgerdur
Syvänen, Ann-Christine
Taanila, Anja
Tobin, Martin D.
Uitterlinden, Andre G.
Willems, Sara M.
Willemsen, Gonneke
Witteman, Jacqueline
Perola, Markus
Evans, Alun
Ferrières, Jean
Virtamo, Jarmo
Kee, Frank
Tregouet, David-Alexandre
Arveiler, Dominique
Amouyel, Philippe
Ferrario, Marco M.
Brambilla, Paolo
Hall, Alistair S.
Heath, Andrew C.
Madden, Pamela A. F.
Martin, Nicholas G.
Montgomery, Grant W.
Whitfield, John B.
Jula, Antti
Knekt, Paul
Oostra, Ben
van Duijn, Cornelia M.
Penninx, Brenda W. J. H.
Smith, George Davey
Kaprio, Jaakko
Samani, Nilesh J.
Gieger, Christian
Peters, Annette
Wichmann, H.-Erich
Boomsma, Dorret I.
de Geus, Eco J. C.
Tuomi, TiinaMaija
Power, Chris
Hammond, Christopher J.
Spector, Tim D.
Lind, Lars
Orho-Melander, Marju
Palmer, Colin Neil Alexander
Morris, Andrew D.
Groop, Leif
Järvelin, Marjo-Riitta
Salomaa, Veikko
Vartiainen, Erkki
Hofman, Albert
Ripatti, Samuli
Metspalu, Andres
Thorsteinsdottir, Unnur
Stefansson, Kari
Pedersen, Nancy L.
McCarthy, Mark I.
Ingelsson, Erik
Prokopenko, Inga
Title The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis
Journal name PLoS Medicine   Check publisher's open access policy
ISSN 1549-1277
Publication date 2013-06-25
Sub-type Article (original research)
DOI 10.1371/journal.pmed.1001474
Open Access Status DOI
Volume 10
Issue 6
Start page e1001474.1
End page e1001474.15
Total pages 15
Place of publication United States
Publisher Public Library of Science
Collection year 2014
Language eng
Formatted abstract
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.

Editors' Summary Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Globally, both the incidence of CVD (the number of new cases in a population every year) and its prevalence (the proportion of the population with CVD) are increasing, particularly in low- and middle-income countries. This increasing burden of CVD is occurring in parallel with a global increase in the incidence and prevalence of obesity—having an unhealthy amount of body fat (adiposity)—and of metabolic diseases—conditions such as diabetes in which metabolism (the processes that the body uses to make energy from food) is disrupted, with resulting high blood sugar and damage to the blood vessels.
Why Was This Study Done? Epidemiological studies—investigations that record the patterns and causes of disease in populations—have reported an association between adiposity (indicated by an increased body mass index [BMI], which is calculated by dividing body weight in kilograms by height in meters squared) and cardiometabolic traits such as coronary heart disease, stroke, heart failure (a condition in which the heart is incapable of pumping sufficient amounts of blood around the body), diabetes, high blood pressure (hypertension), and high blood cholesterol (dyslipidemia). However, observational studies cannot prove that adiposity causes any particular cardiometabolic trait because overweight individuals may share other characteristics (confounding factors) that are the real causes of both obesity and the cardiometabolic disease. Moreover, it is possible that having CVD or a metabolic disease causes obesity (reverse causation). For example, individuals with heart failure cannot do much exercise, so heart failure may cause obesity rather than vice versa. Here, the researchers use “Mendelian randomization” to examine whether adiposity is causally related to various cardiometabolic traits. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Thus, an investigation of the associations between rs9939609 and cardiometabolic traits can indicate whether obesity is causally related to these traits.
What Did the Researchers Do and Find? The researchers analyzed the association between rs9939609 (the “instrumental variable,” or IV) and BMI, between rs9939609 and 24 cardiometabolic traits, and between BMI and the same traits using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent. They then quantified the strength of the causal association between BMI and the cardiometabolic traits by calculating “IV estimators.” Higher BMI showed a causal relationship with heart failure, metabolic syndrome (a combination of medical disorders that increases the risk of developing CVD), type 2 diabetes, dyslipidemia, hypertension, increased blood levels of liver enzymes (an indicator of liver damage; some metabolic disorders involve liver damage), and several other cardiometabolic traits. All the IV estimators were similar to the BMI–cardiovascular trait associations (observational estimates) derived from the same individuals, with the exception of diabetes, where the causal estimate was higher than the observational estimate, probably because the observational estimate is based on a single BMI measurement, whereas the causal estimate considers lifetime changes in BMI.
What Do These Findings Mean? Like all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. Nevertheless, these findings provide support for many previously suspected and biologically plausible causal relationships, such as that between adiposity and hypertension. They also provide new insights into the causal effect of obesity on liver enzyme levels and on heart failure. In the latter case, these findings suggest that a one-unit increase in BMI might increase the incidence of heart failure by 17%. In the US, this corresponds to 113,000 additional cases of heart failure for every unit increase in BMI at the population level. Although additional studies are needed to confirm and extend these findings, these results suggest that global efforts to reduce the burden of obesity will likely also reduce the occurrence of CVD and metabolic disorders.
Keyword Body-mass index
Impaired glucose-tolerance
Genome-wide association
FTO gene
Diabetes prevention
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2014 Collection
School of Medicine Publications
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