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FTO genotype and weight loss: systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials

BMJ 2016; 354 doi: (Published 20 September 2016) Cite this as: BMJ 2016;354:i4707

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  1. Katherine M Livingstone, postdoctoral research fellow1 2,
  2. Carlos Celis-Morales, research associate1 3,
  3. George D Papandonatos, associate professor4,
  4. Bahar Erar, doctoral student4,
  5. Jose C Florez, chief of the Diabetes Unit, member of the Center for Human Genetic Research, and associate professor5 6,
  6. Kathleen A Jablonski, associate research professor7,
  7. Cristina Razquin, research associate8 9,
  8. Amelia Marti, professor of human physiology9 10,
  9. Yoriko Heianza, postdoctoral fellow11,
  10. Tao Huang, postdoctoral fellow11 12,
  11. Frank M Sacks, professor13,
  12. Mathilde Svendstrup, research fellow14 15,
  13. Xuemei Sui, assistant professor graduate director16,
  14. Timothy S Church, professor17,
  15. Tiina Jääskeläinen, postdoctoral fellow18 19,
  16. Jaana Lindström, adjunct professor20,
  17. Jaakko Tuomilehto, professor21 22,
  18. Matti Uusitupa, professor emeritus18,
  19. Tuomo Rankinen, associate professor human genomics23,
  20. Wim H M Saris, professor of human nutrition24,
  21. Torben Hansen, professor14,
  22. Oluf Pedersen, scientific director14,
  23. Arne Astrup, head of department, senior consultant, and professor25,
  24. Thorkild I A Sørensen, professor of metabolic epidemiology, director, chief physician in clinical epidemiology, and professor of clinical epidemiology14 26,
  25. Lu Qi, professor11 13,
  26. George A Bray, professor17,
  27. Miguel A Martinez-Gonzalez, professor of preventive medicine and public health9 10,
  28. J Alfredo Martinez, professor of human nutrition and scientific director9 10 27,
  29. Paul W Franks, professor13 28,
  30. Jeanne M McCaffery, associate professor of psychiatry and human behaviour29,
  31. Jose Lara, senior lecturer1 30,
  32. John C Mathers, professor of human nutrition1
  1. 1Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
  2. 2Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Victoria, Australia
  3. 3BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, UK
  4. 4Department of Biostatistics, Brown University School of Public Health, Providence, RI, USA
  5. 5Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
  6. 6Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
  7. 7George Washington University Department of Epidemiology and Biostatistics The Biostatistics Center, Rockville, MD, USA
  8. 8Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
  9. 9CIBER Fisiopatologia de la Obesidad y Nutricion and PREDIMED Network from Instituto de Salud Carlos III Spanish Government, Spain
  10. 10Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
  11. 11Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
  12. 12Epidemiology Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  13. 13Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  14. 14Novo Nordisk Foundation Centre for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  15. 15Danish Diabetes Academy, Odense, Denmark
  16. 16Department of Exercise Science, University of South Carolina, Columbia, SC, USA
  17. 17Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
  18. 18Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
  19. 19Department of Medical and Clinical Genetics, University of Helsinki, Finland
  20. 20Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
  21. 21Dasman Diabetes Institute, Dasman, Kuwait City, Kuwait
  22. 22Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
  23. 23Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
  24. 24Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre +, Maastricht, Netherlands
  25. 25Department of Nutrition, Exercise and Sports, Copenhagen University, Rolighedsvej 30, Frederiksberg C, Denmark
  26. 26Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Denmark
  27. 27Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain
  28. 28Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
  29. 29The Miriam Hospital and the Alpert School of Medicine, Brown University, Providence, USA
  30. 30Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK
  1. Correspondence to: J C Mathers john.mathers{at}
  • Accepted 17 August 2016


Objective To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials.

Design Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials.

Data sources Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015.

Eligibility criteria for study selection Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity.

Results We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category.

Conclusions We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions.

Systematic review registration PROSPERO CRD42015015969.


  • We thank Shakir Chowdhury for his assistance with the literature search.

  • Contributors: KML, CCM, JL, and JCM designed the research. KML, CCM, GDP, and JCM wrote the paper. KML, CCM, and GDP performed the meta-analysis for all studies. All authors contributed towards the statistical analysis, critically reviewed the manuscript during the writing process, and approved the final version to be published. KML and CCM contributed equally so are joint first authors. JL and JCM are joint last authors. KML and JCM are the guarantors for the study.

  • Funding: KML is funded by the Alfred Deakin postdoctoral research fellowship. CCM was supported by the UK Research Councils’ Lifelong Health and Wellbeing Initiative in partnership with the Department of Health (MR/K025090/1).

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from companies for the submitted work; no relationships with companies that might have an interest in the submitted work in the previous three years; no spouses, partners, or children have no financial relationships that may be relevant to the submitted work; no non-financial interests that may be relevant to the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

  • Transparency: The lead author (JCM) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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