Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization studyBMJ 2017; 356 doi: https://doi.org/10.1136/bmj.j1000 (Published 16 March 2017) Cite this as: BMJ 2017;356:j1000
- Ming Ding, research fellow1,
- Tao Huang, assistant professor1 2 3 4,
- Helle KM Bergholdt, research fellow5 6 7,
- Børge G Nordestgaard, professor7 8 9,
- Christina Ellervik, associate professor7 10 11,
- Lu Qi, professor1 4
- on behalf of the CHARGE Consortium
- 1Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
- 2Epidemiology Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore
- 3Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- 4Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
- 5Department of Clinical Biochemistry, Naestved Hospital, Naestved, Denmark
- 6Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg Frederiksberg, Copenhagen, Denmark
- 7Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- 8Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- 9Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- 10Department of Production, Research and Innovation, Region Sjælland, Sorø, Denmark
- 11Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA, USA
- Correspondence to: L Qi
- Accepted 1 February 2017
Objective To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.
Design Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.
Setting CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.
Participants Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.
Main outcome measures The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.
Results Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval −0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (β=1.35, 95% confidence interval −0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: β=−0.21, 95% confidence interval −0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with −0.11 (95% confidence interval −0.20 to −0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).
Conclusion The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.
Members of the CHARGE Consortium:
Alexis C Frazier-Wood, assistant professor,1 Stella Aslibekyan, assistant professor,2 Kari E North, professor,3 4 Trudy Voortman, research fellow,5 Mariaelisa Graff, research assistant professor,3 Caren E Smith, scientist,6 Chao-Qiang Lai, research geneticist,6 Anette Varbo, doctoral student, assistant professor,7 8 Rozenn N Lemaitre, research associate professor,9 Ester AL de Jonge, research fellow,5 10 Frédéric Fumeron, associate professor,11 12 13 14 Dolores Corella, professor,15 16 Carol A Wang, research officer,17 Anne Tjønneland, research leader,18 Kim Overvad, professor,19 20 Thorkild IA Sørensen, professor,21 22 Mary F Feitosa, associate professor,23 Mary K Wojczynski, assistant professor,23 Mika Kähönen, professor,24 25 Shafqat Ahmad, research fellow,26 27 Frida Renström, research fellow,27 28 Bruce M Psaty, professor,9 14 29 30 David S Siscovick, professor,31 Inês Barroso, senior group leader,32 33 34 Ingegerd Johansson, professor,35 Dena Hernandez, biologist,36 Luigi Ferrucci, scientific director,37 Stefania Bandinelli, geriatrician,38 Allan Linneberg, professor,39 40 Camilla Helene Sandholt, research fellow,21 Oluf Pedersen, professor,21 41 Torben Hansen, professor,21 42 Christina-Alexandra Schulz, doctoral student,43 Emily Sonestedt, associate professor,43 Marju Orho-Melander, professor,43 Tzu-An Chen, senior statistician,1 Jerome I Rotter, professor,44 Mathew A Allison, professor,45 Stephen S Rich, professor,46 Jose V Sorlí, professor,15 16 Oscar Coltell, professor,16 47 Craig E Pennell, professor,17 Peter R Eastwood, professor,48 Albert Hofman, professor,5 49 Andre G Uitterlinden, professor,10 MCarola Zillikens, associate professor,10 Frank JA van Rooij, research associate,5 Audrey Y Chu, research fellow,50 Lynda M Rose, associate professor,50 Paul M Ridker, professor,50 51 Jorma Viikari, professor,52 53 Olli Raitakari, project coordinator professor,54 55 Terho Lehtimäki, professor,56 57 Vera Mikkilä, associate professor,55 58 Walter C Willett, professor,26 49 59 Yujie Wang, biostatistician,3 Katherine L Tucker, professor,60 Jose M Ordovas, senior scientist,6 61 62 Tuomas O Kilpeläinen, associate professor,21 Michael A Province, professor,23 Paul W Franks, professor,26 27 63 Donna K Arnett, professor,2 Toshiko Tanaka, staff scientist,37 Ulla Toft, associate professor,39 Ulrika Ericson, associate researcher,43 Oscar H Franco, professor,5 CHARGE consortium, Dariush Mozaffarian, professor,64 Frank B Hu, professor,26 49 59 Daniel I Chasman, associate professor,50 65 66
1. USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA; 2. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA; 3. Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA; 4. Carolina Center for Genome, Sciences University of North Carolina, Chapel Hill, NC, USA; 5. Department of Epidemiology Erasmus MC, University Medical Center, Rotterdam, Netherlands; 6. Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University Boston, MA, USA; 7. Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 8. Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; 9. Department of Medicine, University of Washington, WA, USA; 10. Department of Internal Medicine Erasmus MC, University Medical Center, Rotterdam, Netherlands; 11. INSERM UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; 12. Univ Paris Diderot Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; 13. Sorbonne Universités UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; 14. Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris; 15. Department of Preventive Medicine and Public Health, University of Valencia, Valencia, Spain; 16. CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; 17. School of Women’s and Infants’ Health, University of Western Australia, Australia; 18. Danish Cancer Society Research Center, Copenhagen, Denmark; 19. Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus C, Denmark; 20. Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; 21. Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 22. Institute of Preventive Medicine Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark; 23. Department of Genetics Washington University School of Medicine, Saint Louis, MO, USA; 24. Department of Clinical Physiology, Tampere University Hospital, Finland; 25. Department of Clinical Physiology, University of Tampere School of Medicine, Finland; 26. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA; 27. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; 28. Department of Biobank Research, Umeå University, Umeå, Sweden; 29. Department of Epidemiology, University of Washington, WA, USA; 30. Department of Health Sciences, University of Washington, WA, USA; 31. New York Academy of Medicine, New York, NY, USA; 32. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; 33. NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK; 34. University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK; 35. Department of Biobank Research, Umeå University, Umeå, Sweden; 36. Laboratory of Neurogenetics National Institute on Aging, Bethesda MD, USA; 37. Translational Gerontology Branch, Baltimore, MD, USA; 38. Geriatric Unit, Local Health Tuscany Center (LHTC), Florence, Italy; 39. Research Centre for Prevention and Health, the Capital Region of Denmark, Copenhagen, Denmark; 40. Department of Clinical Experimental Research Rigshospitalet, Glostrup, Denmark; 41. Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark; 42. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; 43. Department of Clinical Sciences in Malmö, Lund University, Sweden; 44. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, USA; 45. Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA; 46. Center for Public Health Genomics, 3232 West Complex, University of Virginia, Charlottesville, VA, USA; 47. Department of Computer Languages and Systems, University Jaume I, Castellon, Spain; 48. Centre for Sleep Science, School of Anatomy Physiology and Human Biology, University of Western Australia, Australia; 49. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; 50. Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA USA; 51. Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical Schoo, Boston, MA, USA; 52. Division of Medicine, Turku University Hospital, Finland; 53. Department of Medicine, University of Turku, Finland; 54. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Finland; 55. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland; 56. Department of Clinical Chemistry Fimlab Laboratories, Tampere University Hospital, Finland; 57. Department of Clinical Chemistry, University of Tampere School of Medicine, Finland; 58. Department of Food and Environmental Sciences, University of Helsinki, Finland; 59. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 60. Department of Biomedical and Nutritional Sciences, Center for Population Health, University of Massachusetts Lowell, Lowell, MA, USA; 61. Department of Epidemiology and Population Genetics, Centro Nacional Investigación Cardiovasculares, Madrid, Spain; 62. Instituto Madrileño de Estudios Avanzados en Alimentación Madrid, Spain; 63. Department of Public Health and Clinical Medicine Section for Medicine, Umeå University, Umeå, Sweden; 64. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA; 65. Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston MA, USA; 66. Broad Institute of MIT and Harvard, Cambridge MA, USA
The authors of the GLACIER Study acknowledge the funding agencies supporting the Northern Sweden Diet Database and the Västerbotten Intervention Project, including the Swedish Research Council. The authors of the YFS gracefully acknowledge the expert technical assistance in the statistical analyses by Ville Aalto, Irina Lisinen, and Mika Helminen. The authors of the Raine study are grateful to the Raine participants and their families, and to the Raine research staff for cohort coordinaion and data collection. This work was supported by resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The authors also gratefully acknowledge the NH&MRC for their long term funding to the study over the past 25 years and also the following institutes for providing funding for core management of the Raine study: University of Western Australia (UWA); Curtin University; Raine Medical Research Foundation; UWA Faculty of Medicine, Dentistry, and Health Sciences; Telethon Kids Institute, Women’s and Infant’s Research Foundation (King Edward Memorial Hospital); and Edith Cowan University. We acknowledge the assistance of the Western Australian DNA Bank (National Health and Medical Research Council of Australia National Enabling Facility); the Raine study participants for their ongoing participation; the Raine study team for study coordination and data collection; the UWA Centre for Science for use of its facility; and the Sleep Study Technicians. The authors of the ARIC study thank the staff and participants for their important contributions. Dr Dolores Corella acknowledges the collaboration of the Real Colegio Complutense at Harvard University, Cambridge. MA, USA.
Contributors: LQ obtained funding from the National Institutes of Health. MD, TH, HKB, CE, and LQ designed the study. MD and TH collected the data. MD, TH, and HKB provided statistical expertise. MD analyzed the data and wrote the first draft of the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript. MD, TH, HKB, BGN, CE, and LQ are the guarantors of this investigation and contribute equally to this work.
Funding: Funding: LQ is recipient of the National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024), the National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK078616), the Boston Obesity Nutrition Research Center (DK46200), the United States–Israel Binational Science Foundation grant (2011036), and the American Heart Association Scientist Development Award (0730094N) for the Mendelian randomization study. The CGPS is was funded by the Danish Council for Independent Research; Medical Sciences (FSS); Herlev Hospital, Copenhagen University Hospital; Copenhagen County Foundation; and Chief Physician Johan Boserup and Lise Boserup’s Fund, Denmark. The GESUS was funded by the Region Zealand Foundation, Naestved Hospital Foundation. Edith and Henrik Henriksens Memorial Scholarship, Johan and Lise Boserup Foundation, TrygFonden, Johannes Fog’s Foundation, Region Zealand, Naestved Hospital, National Board of Health, and Local Government Denmark Foundation. The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, the Donald W Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The NHS and the HPFS was supported by grants UM1 CA186107, P01 CA87969, R01 CA49449, R01 HL034594, R01 HL088521, UM1 CA167552, R01 HL35464, HL073168, CA87969, CA49449, CA055075, HL34594, HL088521, U01HG004399, DK080140, P30, U01CA137088, U54CA155626, DK58845, DK098311, U01HG004728, EY015473, CA134958, DK70756, and DK46200 from the National Institutes of Health, with additional support for genotyping from Merck Research Laboratories, North Wales, PA. LRP is supported by the Arthur Ashley Williams Foundation and a Harvard ophthalmology scholar award (Harvard Medical School) from the Harvard Glaucoma Center of Excellence. ATC is a Damon Runyon Cancer Foundation clinical investigator. The funding sources had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant No UL1RR025005, a component of the National Institutes of Health and NIH roadmap for medical research. The Inter99 study was funded by the Danish Research Councils, Health Foundation, Danish Centre for Evaluation and Health Technology Assessment, Copenhagen County, Danish Heart Foundation, Ministry of Health and Prevention, Association of Danish Pharmacies, Augustinus Foundation, Novo Nordisk, Velux Foundation, Becket Foundation, and Ib Henriksens Foundation. The D.E.S.I.R. study has been supported by INSERM contracts with CNAMTS, Lilly, Novartis Pharma, and Sanofi-Aventis; by INSERM (Réseaux en Santé Publique, Interactions entre les déterminants de la santé, Cohortes Santé TGIR 2008), the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, CNIEL, ONIVINS, Société Francophone du Diabète, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, Topcon. The funding sources had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The D.E.S.I.R. Study Group: INSERM CESP U1018: B Balkau, P Ducimetière, E Eschwège; INSERM U367: F. Alhenc-Gelas; CHU d’Angers: A Girault; Bichat Hospital: F Fumeron, M Marre, R Roussel; CHU de Rennes: F Bonnet; CNRS UMR8090, Lille: S Cauchi P Froguel; Centres d’Examens de Santé: Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, Le Mans, Orléans, Tours; Institute de Recherche Médecine Générale: J Cogneau; General practitioners of the region; Institute inter-Regional pour la Santé: C Born, E Caces, N Copin, JG Moreau, O Lantieri, F Rakotozafy, J Tichet, S Vol. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (No 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project No 050-060-810. The MDCS was initiated and planned in collaboration with the International Agency for Research on Cancer, the Swedish Cancer Society, and Swedish Medical Research Council and the Faculty of Medicine Lund University, Sweden. The study is also funded by Region Skåne, City of Malmö, Påhlsson Foundation and the Swedish Heart and Lung Foundation.
The GLACIER Study was funded by project grants from the Swedish Heart-Lung Foundation, the Swedish Diabetes Association, the Påhlsson’s Foundation, Region Skåne, the Swedish Research Council, the Umeå Medical Research Foundation, Novo Nordisk, The Heart Foundation of Northern Sweden (all to PWF), and Wellcome Trust WT098051. The MESA study was supported by contracts HHSN268201500003I, N01-HC-95159,N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR. The FamHS was supported by grants DK089256 and HL117078 from the National Institutes of Health. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The YFS has been financially supported by the Academy of Finland: grants 286284 (TL), 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Kuopio, Tampere and Turku University Hospital Medical Funds (grant X51001 for T.L.); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research (T.L.); Finnish Cultural Foundation; Tampere Tuberculosis Foundation (TL); Emil Aaltonen Foundation (TL); and Yrjö Jahnsson Foundation (TL). The DCH and the DIOGENES cohorts were a part of the research program of the UNIK: Food, Fitness and Pharma for Health and Disease (see www.foodfitnesspharma.ku.dk). The UNIK project was supported by the Danish Ministry of Science, Technology and Innovation. Tuomas O Kilpeläinen was supported by the Danish Council for Independent Research (DFF– 333-00124 and Sapere Aude program grant DFF–1331-00730B). The PREDIMED-VALENCIA study was supported by the Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economía y Competitividad (projects G03/140, CIBER 06/03, RD06/0045 PI07-0954, CNIC-06, PI11/02505, SAF2009-12304, AGL2010-22319-C03-03 and PRX14/00527), Fondo Europeo de Desarrollo Regional, by the University Jaume I (Project P1-1B2013-54) and by the Generalitat Valenciana (AP111/10, AP-042/11, BEST/2015/087, GVACOMP2011-151, ACOMP/2011/145, ACOMP/2012/190 and ACOMP/2013/159.
The BPRHS was supported by the National Institutes of Health grants P01 AG023394 and P50 HL105185. The GOLDN Study was supported by National Heart, Lung, and Blood Institute (NHLBI) grant No U01HL072524 (Genetic and Environmental Determinants of Triglycerides), NHLBI R01 HL091357 (Genomewide Association Study of Lipid Response to Fenofibrate and Dietary Fat), NHLBI grant Nos HL54776 and HL078885; and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture, Agriculture Research Service. The Raine Study was supported by the National Health and Medical Research Council of Australia (grant Nos 403981 and 003209) and the Canadian Institutes of Health Research (grant No MOP-82893). The 22 year Raine Study follow-up was funded by NHMRC project grants 1027449, 1044840 and 1021855. Funding was also provided by Safework Australia. The InCHIANTI study baseline (1998-2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (contracts: 263 MD 9164 and 263 MD 821336). The sponsors have no role in: the study design; the collection, analysis, or interpretation of data; the writing of the report; or in the decision to submit the article for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and the Harvard TH Chan School of Public Health. The completion of the self administered questionnaire was considered to imply informed consent.
Data sharing: No additional data available.
Transparency: The lead authors (the manuscript’s guarantors) affirm 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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