New evidence supports a causal relationship between adiposity and heart failure, and between adiposity and increased liver enzymes, according to a study published this week in PLOS Medicine. The study, conducted by Inga Prokopenko, Erik Ingelsson, and colleagues from the ENGAGE (European Network for Genetic and Genomic Epidemiology) Consortium, also provides additional support for several previously shown causal associations such as those between adiposity and type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension.
The authors investigated whether adiposity is causally related to various cardiometabolic traits using a Mendelian randomization analysis, in which the variation in genes associated with conditions is used to assess the causal relationship between conditions. 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. Using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent, the authors measured the strength of the causal association between BMI and cardiometabolic traits and found that higher BMI had a causal relationship with heart failure, type 2 diabetes, metabolic syndrome, dyslipidemia, hypertension, increased blood levels of liver enzymes, and several other cardiometabolic traits.
As with all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. The authors report, "The present study addressing the role of BMI in 24 traits in up to 198,502 individuals provides novel insights in the causal effect of obesity on heart failure and increased liver enzymes levels."
They also say that this study "provides robust support to the causal relationship between obesity and a number of cardiometabolic traits reported previously. These results support global public prevention efforts for obesity in order to decrease cost and suffering from [type 2 diabetes] and heart failure."
Funding: ENGAGE (European Network for Genetic and Genomic Epidemiology) Consortium, the European Community's Seventh Framework Programme grant FP7-HEALTH-F4-2007 (201413); Academy of Finland (104781, 120315, 129418, 139635, 141054), Center of Excellence in Complex Disease Genetics (213506, 129680), and SALVE research program (129418, 129494); Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498); Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921); Avera Institute, Sioux Falls, South Dakota (USA); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); Biotechnology and Biological Sciences Research Council (BBSRC); British Heart Foundation; Center for Medical Systems Biology (CSMB, NOW Genomics); Center of Excellence in Genomics (EXCEGEN); Chronic Disease Research Foundation (CDRF); City of Malmö; Crafoord Foundation; Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London; Development Fund of University of Tartu (SP1GVARENG); Diabetes Programme at the Lund University; Erasmus MC; Erasmus University Rotterdam; Estonian Government (SF0180142s08); Estonian Research Roadmap through Estonian Ministry of Education and Research (3.2.0304.11-0312); Estonian Science Foundation (EstSF ETF9353); EU 5th Framework Programme GenomEUtwin Project (QLG2-CT-2002-01254, EU/QLRT-2001-01254); EU Framework Programme 7 funding stream (IMI SUMMIT); EUR Fellowship; European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-0164, FP6 STRP 018947, LSHG-CT-2006- 019473); European Community's Seventh Framework Program (FP7/2007-2013, CEED3 223211); European Community's Sixth Framework Programme Cardiogenics project (LSHM-CT-2006-037593); European Foundation for the Study of Diabetes (EFSD); European Science Council (ERC Advanced, 230374); European Science Foundation (ESF, EU/QLRT-2001-01254); European Union (EU/WLRT-2001-01254); EUROSPAN (European Special Populations Research Network); Faculty of Medicine, Lund University; Fellowship Schemes NBIC/BioAssist/RK (2008.024); Finnish Diabetes Research Society; Finnish Foundation for Cardiovascular Research; Folkha¨lsan Research Foundation; Foundation for Life and Health in Finland; Foundation for the US National Institutes of Health; French Institute of Health and Medical Research (U258); Genetic Association Information Network (GAIN); German Federal Ministry of Education and Research (BMBF); German National Genome Research Network (NGFNPlus, 01GS0834); German Research Center for Environmental Health; Guide Dogs for the blind Association(GDBA); Health Administration of Regione Lombardia (9783/1986, 41795/1993, 31737/1997, 17155/2004); Health Informatics Centre; Helmholtz Zentrum München; High Performance Computing Center of University of Tartu; International Agency for Research on Cancer; Internationale Stichting Alzheimer Onderzoek (ISAO); Jakobstad Hospital; K Medical Research Council; Knut and Alice Wallenberg Foundation; LMUinnovativ; Manpei Suzuki Diabetes Foundation; Medical Research Council, UK (G0500539, G0600705, PrevMetSyn/SALVE); Medical Society of Finland; Ministry of Education, Culture and Science, The Netherlands; Ministry of Health Welfare and Sports, The Netherlands; Munich Center of Health Sciences (MC Health); Municipality of Rotterdam; National Cancer Institute (N01-RC-37004); MyEuropia Research Training Network; National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit; National Health and Medical Research Council (NHMRC); National Eye Institute via an NIH/CIDR genotyping project (R01EY018246-01-1 PI: Terri Young); National Institute of Aging (NIA); Netherlands Brain Foundation (HersenStichting Nederland); Netherlands Consortium for Healthy Aging (NCHA); (050-060-810); Netherlands Genomics Initiative (NGI); Netherlands Heart Foundation; Netherlands Organization for Health Research and Development (ZonMw) (10-000-1002, 904-61 090, 985-10-002, 904-61-193, 480-04-004, 400-05-717); Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911-03-012, vici, 918-76-619, veni, 916.12.154, Addiction 31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192); Netherlands Scientific Organization (904-61-090, 904-61-193, 480-04-004, 400-05- 717, I 480-05-003); Neuroscience Campus Amsterdam (NCA); NHLBI (5R01HL087679-02); Novo Nordisk Foundation; Närpes Research Foundation; Ollqvist Foundation; Pfizer Global Research Awards for Nicotine Dependence (GRAND); Pfizer Pharmaceuticals; Påhlsson Foundation; Region Skåne; Research Institute for Diseases in the Elderly (014-93-015; RIDE; RIDE2); Royal Swedish Academy of Sciences; Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Seventh Framework Programme ENGAGE project (HEALTH-F4-2007-201413); Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; STAMPEED program (1RL1MH083268-01); Swedish Cancer Society; Swedish Cultural Foundation in Finland; Swedish Diabetes Foundation; Swedish Diabetes Research Society; Swedish Foundation for Strategic Research (SSF; ICA08-0047); Swedish Heart and Lung Foundation; Swedish Medical Research Council; Swedish Ministry for Higher Education; Swedish Research Council for Medicine and Health (Linné grant 349-2008-6589, a strategic SFO grant, Exodiab 2009-1039, M-2005-1112, 2009-2298); Swedish Research Council for Infrastructures; Swedish Society of Medicine; US NIH (AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA15416, AA17688, DA12854, MH66206, R01D0042157-01A, AG028555, AG08724, AG04563, AG10175, AG08861, R01HL089650-02, DK U01-066134, 5R01MH63706:02, RO1 MH059160, 1RC2MH089951-01, 1RC2 MH089995-01); University Hospital Oulu; University of Dundee; University of Ulm; Uppsala University; Uppsala University Hospital; US National Heart, Lung and Blood Institute; US Public Health Service contracts (N01-CN-45165, N01-RC-45035); Vasa and Närpes Health centers; Wellcome Trust (Biomedical Collections Grant GR072960); Wellcome Trust Sanger Institute; VU University's Institute for Health and Care Research (EMGO+); TDS is an NIHR senior Investigator and is holder of an ERC Advanced Principal Investigator award; CJH is an NIHR Senior Research Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: TF has received honoraria by MSD for lecturing. GT, SG, VS, UT, and KS are employees of deCODE Genetics/Amgen, a biotechnology company. OHF is the recipient of a grant from Pfizer Nutrition to establish a new center of ageing research: ErasmusAGE. KH received funding via the Finnish Academy (grant number 129418). JK holds grants from the EU FP7 (funding the present research and other projects), US NIH, the Academy of Finland, and several Finnish Foundations. JK consulted for Pfizer Inc. in 2012 on nicotine dependence. LG, GDS, and MM are members of the Editorial Board of PLOS Medicine. All other authors have declared that no competing interests exist.
Citation: Fall T, Hägg S, Mägi R, Ploner A, Fischer K, et al. (2013) The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis. PLoS Med 10(6): e1001474. doi:10.1371/journal.pmed.1001474
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CONTACTS:
Inga Prokopenko, PhD
Senior Lecturer in Human Genomics
Imperial College London
Department of Genomics of Common Disease, School of Public Health
Burlington Danes Building, Room E305
Hammersmith Hospital
Du Cane Road
London, W12 0NN
UNITED KINGDOM
+44 20 759 46501
i.prokopenko@imperial.ac.uk
Wellcome Trust Centre for Human Genetics
University of Oxford, Oxford, UK
and
Erik Ingelsson, MD, PhD, FAHA
Professor of Molecular Epidemiology
Department of Medical Sciences
Molecular Epidemiology and Science for Life Laboratory
UCR/MTC
Dag Hammarskjölds väg 14B
Uppsala Science Park
SE-752 37 Uppsala
Sweden
+46 70 7569422
erik.ingelsson@medsci.uu.se
Department of Medical Epidemiology and Biostatistics
Karolinska Institutet
Stockholm, Sweden
Journal
PLoS Medicine