基金：
In this pooled analysis of 97 prospective cohort studies, we estimated that nearly half of excess risk for coronary heart disease and three-quarters of excess risk for stroke due to high BMI were mediated through three metabolic risk factors: blood pressure, cholesterol, and glucose. The most important mediator was blood pressure, especially for stroke, accounting for two-thirds of the excess risk. Compared with having healthy weight, being overweight or obese was associated with an increased risk of coronary heart disease and stroke, with obesity having a larger effect than overweight. Our results for the overall association between BMI and coronary heart disease or stroke are consistent with those of other large pooled analyses of prospective cohorts. 2,3,24 Previous studies mostly analysed all mediators combined, and did not assess the role of other combinations of mediators. A meta-analysis 18 of 21 cohorts (including 16 analysed here) reported that 45% of excess risk of coronary heart disease was mediated through blood pressure and total cholesterol, compared with 39% in our analysis (both effects reported for 5 kg/m 2 higher BMI). Results of another pooled analysis 3 of 58 cohorts (including 15 analysed here) showed that roughly 60% of the excess risk of coronary heart disease and 70% of ischaemic stroke were due to the same three mediators, compared with 46% for coronary heart disease and 76% for stroke in our analysis. Our lower estimates for coronary heart disease might be the result of a larger number of cohorts that included only fatal coronary heart disease (almost half of our cohorts used only fatal coronary heart disease compared with 9% in the study by Wormser and colleagues 3 ) because PERM tended to be lower when fatal events were analysed ( table 4 ). Our lower estimates for coronary heart disease could also be explained by the use of blood glucose measurements versus diabetes as the metric of mediator. The slightly higher estimates for stroke might be due to the larger number of Asian cohorts in our analysis (34% of our cohorts were from Asia compared with 7% in the study by Wormser and colleagues 3 ), or the stroke subtypes analysed (we used total stroke whereas Wormser and colleagues 3 used ischaemic stroke). Our finding that both overweight and obesity were associated with increased risk of coronary heart disease and stroke differed from reports by Flegal and colleagues, 28 who recorded no effects for overweight on either cardiovascular disease mortality in one cohort, or on all-cause mortality in a meta-analysis. 29 Flegal and colleagues' findings for cardiovascular disease 28 might have differed from ours because of inadequate adjustment for pre-existing diseases and their inadequate control of confounding. 30,31 Our results are not directly comparable with those for all-cause mortality. We noted that metabolic factors mediate a larger proportion of the excess risk for overweight individuals than do those for obese individuals (although the 95% CIs overlapped). This finding suggests that clinical and public health interventions that control blood pressure, cholesterol, and glucose can largely (in coronary heart disease) or fully (in stroke) address the excess risk of coronary heart disease and stroke in overweight individuals. Obese individuals also benefit from interventions on mediators but will continue to have significantly raised risk. Several pathways link adiposity and excess weight to cardiovascular disease via the mediators analysed in this study. Adiposity can raise blood pressure through increased peripheral vascular resistance and renal salt retention, the latter itself due to higher activity of sympathetic nervous system, leptin concentrations, angiotensin-aldosterone activity, and hyperinsulinaemia. 5,32 Adiposity is also associated with dyslipidaemia, and systemic inflammatory state, which could contribute to the development of insulin resistance and diabetes. 6 Our results also suggest that the association between adiposity and cardiovascular disease is not completely explained by the three mediators in our analysis. The unexplained risk might be caused by other pathways such as endothelial dysfunction, increase in thrombogenic factors, and the remaining effect of increased sympathetic activity and systemic inflammation not related to risk factors analysed here. 6 These other pathways might play a more important part in obese individuals than in overweight individuals. It would be interesting to probe and quantify the role of these other pathways in subsequent studies, including in relation to overweight versus obese status, although fewer cohorts collect comparable data for these other variables compared with the well known metabolic mediators that we analysed. Panel Research in context Systematic Review We did a systematic review by searching PubMed and Embase from their inception up to March 23, 2010, using search terms listed in the appendix (pp 2–4) . We invited the corresponding authors of eligible cohorts to join the Collaborating Group. We analysed data from 97 prospective cohort studies to estimate the effects of high body-mass index (BMI) on coronary heart disease and stroke, with and without adjustment for selected metabolic factors (blood pressure, serum cholesterol, and glucose). We pooled hazard ratios (HRs) across cohorts and quantified how much of the excess risk of BMI is mediated through any combination of three metabolic factors. Interpretation We found that about half of the excess risk of BMI on coronary heart disease and three-quarters of the excess risk of BMI on stroke was mediated by blood pressure, glucose, and cholesterol collectively. The most important mediator was blood pressure, which mediated a third of the excess risk of BMI on coronary heart disease and two-thirds for stroke. A larger proportion of risk might be mediated for overweight compared with obesity. Interventions that reduce high blood pressure, cholesterol, and glucose might address a substantial proportion of the effect of high BMI on cardiovascular disease. Maintenance of optimum bodyweight is needed to achieve the full benefits. Our study is the largest pooling analysis of multiple cardiovascular disease risk factors, with 1·8 million participants, and 57 161 coronary heart disease and 31 093 stroke events. This large sample size allowed us to study the extent of mediation, and how it varies by cohort characteristics. The cohorts covered Asian and western populations, and therefore, showed the role of BMI and the mediators of its effects in these diverse populations. The consistent stratified analysis suggested the important role of blood pressure as a mediator in the effect of BMI on stroke in Asian populations, in whom high blood pressure and large stroke burden have made this risk factor the leading cause of disease burden. 16,33 Our study has some limitations. First, although we consistently adjusted for age, sex, and smoking as the minimum set of confounders, our results might still be affected by unmeasured and residual confounding. For instance, only a few cohorts were adjusted for diet and physical activity, which are risk factors for coronary heart disease and stroke and are associated with increased BMI. Confounders might have been measured with error, which leads to residual confounding (eg, smoking and socioeconomic status). When we restricted the pooling to cohorts that had adjusted for additional confounders, PERM for the three mediators did not change significantly: it was 6 percentage points higher for coronary heart disease and 1 percentage point lower for stroke than for cohorts with minimum set of confounders, and 95% CIs overlapped. Our analysis did not allow for interactions between BMI and mediators, which might exist. 34 The mediators were not measured consistently across cohorts because of variability in laboratory methods or metrics of mediators. Sensitivity analyses showed that our results were robust to the choice of metrics used for mediators. Additionally, we could not analyse stroke subtypes separately because most cohorts had not reported the stroke outcome by subtype. Finally, despite the large number of cohorts included in the analysis, we could not access data from all eligible cohorts, especially some with enrolment decades ago. Our findings have implications for clinical prevention of cardiovascular disease as well as for public health programmes. As a clinical example, consider a 70-year-old non-smoking man who does not have diabetes, is 174 cm tall and weighs 100 kg (ie, has a BMI of 33 kg/m 2 ), with a systolic blood pressure of 147 mm Hg, total cholesterol of 5·05 mmol/L, and HDL cholesterol of 0·93 mmol/L. This person represents roughly the 80th percentile of age, BMI, and cholesterol of adult men, and 90th percentile of blood pressure among adult men with BMI of 30 kg/m 2 or more in the US National Health and Nutrition Examination Survey in 2007–08. According to the Framingham risk score, this man's predicted 10-year risk of coronary heart disease is 25%. 35 With the assumption that the results of our observational analysis are indicative of the true benefits of losing excess weight, if this patient lost 15 kg of weight through a hypothetical intervention (ie, 5 kg/m 2 lower BMI), his new estimated 10 year coronary heart disease risk would be 19·7% (25% minus [25% divided by 1·27], because the HR for coronary heart disease per 5 kg/m 2 BMI is 1·27), which is 5 percentage points lower. Alternatively, if he receives drugs to lower his blood pressure and cholesterol to levels that are expected based on a 15 kg weight loss, his 10 year risk of coronary heart disease would only decrease by 2 percentage points (5% times 39%, because the estimated PERM by blood pressure and cholesterol for coronary heart disease is 39% per 5 kg/m 2 higher BMI), as he only receives the benefits of reductions in these two risk factors. Despite the potentially large benefits of weight loss, interventions have had small long-term success, especially at the population level, 7,8 leading to a worldwide rise in overweight and obesity. 14 By contrast, effective clinical and lifestyle interventions are available to control blood pressure and serum cholesterol, 36–39 with evidence that these risk factors have been successfully reduced, in individual patients and whole populations. 16,17,40,41 For example, blood pressure, the most important mediator of the association between BMI and cardiovascular disease, has fallen substantially in high-income countries, central Europe, and parts of Latin America. 16 Serum cholesterol has also fallen in western countries, but has increased in east and southeast Asia. 17 In the USA, decreases in blood pressure and cholesterol have been even larger in overweight and obese individuals, possibly because of more aggressive management. 42 Therefore, control of blood pressure and cholesterol might help to lessen the cardiovascular effects of the global obesity epidemic. The most important step to leverage this potential is to continue past efforts for the reduction of blood pressure and cholesterol, and to try to replicate these efforts in Asia where blood pressure remains high, 16 serum cholesterol has increased, 17 and stroke is a common cause of death. Despite this potential, and some past successes, further reduction of blood pressure and cholesterol needs major improvements in both primary care and public health programmes. 43 The coverage of blood pressure and lipid-lowering drugs is low in most low-income and middle-income countries, even in patients with cardiovascular disease, and social inequalities in coverage exist. 44,45 To increase diagnosis and treatment will need well developed national guidelines that include these activities in the primary care system, with emphasis on improvement of access in disadvantaged social and economic groups. 44–46 Interventions related to diet that lower the intake of salt, saturated and trans fats, and processed carbohydrates, and increase the consumption of fruits, vegetables, unsaturated fats, and whole grains, can improve the metabolic risk profile even when total calories remain unchanged, 47–50 but access to these interventions needs to be improved worldwide. 43,51 Additionally, adiposity increases the risk of diabetes, and prevalence of blood glucose and diabetes has increased worldwide. 52 Clinical interventions for glycaemic management are not as effective as those for blood pressure and cholesterol. 53 Therefore, reliance on control of the metabolic mediators might be only a partial and temporary response to the obesity epidemic. Rather, creative and bold strategies are needed that can curb and reverse rising adiposity so that the full benefits for cardiovascular disease and diabetes reduction can be achieved. Correspondence to: Goodarz Danaei, Department of Global Health and Population, Harvard School of Public Health, Boston, MA 02115, USA [email protected] Contributors GD and ME developed the study concept and analytical strategy. YL and KH did the systematic review, pooled analysis, and prepared results. YL, KH, and Cohort Collaborating Group analysed cohort data. EBR and MW contributed to the design of the study and interpretation of results. YL, KH, ME, and GD wrote the first draft of the report. All other Collaborating Group members commented on the report draft and have seen and approved of the final text. ME and GD oversaw the research. GD is the study guarantor. The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects) Writing and Pooling Group: Yuan Lu (Department of Global Health and Population, Harvard School of Public Health, Boston, USA), Kaveh Hajifathalian (Department of Global Health and Population, Harvard School of Public Health, Boston, USA), Majid Ezzati (MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK), Mark Woodward (The George Institute for Global Health, Australia), Eric B Rimm (Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA), Goodarz Danaei * * Corresponding author. (Department of Global Health and Population and Department of Epidemiology, Harvard School of Public Health, Boston, USA). Cohort Collaborating Group † : † Cohort Collaborating Group members were listed by alphabetical order of last name. Age 40-programme linked with National Cause of Death Register: Randi Selmer (Norwegian Institute of Public Health, Norway), Bjorn H Strand (Norwegian Institute of Public Health, Norway). Asia Pacific Cohort Study Collaboration (Data were analysed by the Writing Group on behalf of APCSC for those cohorts that are not separately listed below): Executive Committee: X Fang, D F Gu, R Huxley, Y Imai, H C Kim, T H Lam, W H Pan, A Rodgers, I Suh, H Ueshima, M Woodward Participating Studies and Principal Collaborators: Aito Town Study: H Maegawa, A Okayama, H Ueshima; Akabane Study: N Aoki, M Nakamura; Anzhen 02 Cohort Study: Z S Wu; Beijing Anzhen Cohort Study: Z S Wu, C H Yao; Australian Longitudinal Study of Aging: M Luszcz; Australian National Heart Foundation: T A Welborn; Beijing Aging Study: Z Tang; Beijing Iron and Steel Worker Cohort Study: L S Liu, J X Xie; Blood Donors' Health Study: S Ameratunga, S MacMahon, R Norton, G Whitlock; Busselton Health Study (phase I): M W Knuiman, M L Divitini; Canberra-Queanbeyan Longitudinal Study of the Elderly: H Christensen; Capital Iron and Steel Company Study: X G Wu; Capital Iron and Steel Company Hospital Cohort: X H Yu, J Zhou; Civil Service Workers Study: A Tamakoshi; The CardioVascular Disease risk FACtors Two-township Study: W H Pan; East Beijing Cohort Study: L Q Chen, G L Shan, Z L Wu; Electrical Generating Authority of Thailand Study: P Sritara; Fangshan Cohort Study: X F Duan, D F Gu; Fletcher Challenge Heart and Health Study: R Jackson, S MacMahon, R Norton, G Whitlock; Guangzhou Study: Y H Li; Guangzhou Occupational Cohort Study: C Q Jiang, T H Lam; Hisayama Study (phase I): H Arima, M Iida, Y Kiyohara; Health Risks and Quality of Life in the Hong Kong Elderly: S C Ho, J Woo; Huashan Study: Z Hong, M S Huang, B Zhou; The Kinmen Neurological Disorders Survey: J L Fuh; Konan Health and Nutrition Study: S R Choudhury, Y Kita, H Ueshima; Korean Medical Insurance Corporation Study: S H Jee, I S Kim, I Suh; Melbourne Collaborative Study (MCCS): G G Giles; Miyama Cohort Study: T Hashimoto, K Sakata; Newcastle Study: A Dobson; Ohasama Study: Y Imai, T Ohkubo, A Hozawa; Perth Risk Factors Survey: K Jamrozik, M Hobbs, R Broadhurst; Saitama Cohort Study: K Nakachi; Seven Cities Cohort Study: X H Fang, S C Li, Q D Yang; Shanghai Factory Workers Study: Z M Chen; Shibata Cohort Study: H Tanaka; Shigaraki Town Study: Y Kita, A Nozaki, H Ueshima; Shirakawa Study: H Horibe, Y Matsutani, M Kagaya; Singapore Heart: K Hughes, J Lee; Singapore NHS92: S K Chew, D Heng; Six Chinese Cohorts Study: H Y Zhang, B F Zhou; Tanno - Soubetsu Study: K Shimamoto, S Saitoh; Tianjin Study: Z Z Li, H Y Zhang; Abdominal Aortic Aneurysm Screening Program: K Jamrozik, P Norman; Xi'an Study: Y He, T H Lam; Yunnan Tin Miner Cohort Study: S X Yao. Atherosclerosis Risk in Communities Study (ARIC) : Emily D Parker (HealthPartners Institute for Education and Research, Minneapolis, USA), Mark A Pereira (University of Minnesota, Minneapolis, USA), June Stevens (University of North Carolina at Chapel Hill, USA). ATTICA Study: Demosthenes B Panagiotakos (Harokopio University of Athens, Greece), Christos Pitsavos (University of Athens, Greece). Beijing Iron and Steel Worker Cohort Study: John R Attia (School of Medicine and Public Health, University of Newcastle, and Hunter Medical Research Institute, Australia), Catherine A D'Este (School of Medicine and Public Health, University of Newcastle, and Hunter Medical Research Institute, Australia), Xiaofei Zhang (Second Hospital Affiliated Zhejiang University College of Medine, China; Cardiovascular Institute and Fu Wai Hospital, Peking Union Medical College, China). Belgian Interuniversity Research on Nutrition and Health (BIRNH): Els Clays (Department of Public Health, Ghent University, Ghent, Belgium), Dirk A O De Bacquer (Department of Public Health, Ghent University, Belgium), Koen Van Herck (Department of Public Health, Ghent University, Ghent, Belgium). Busselton Health Study (BHS): Mark L Divitini (The University of Western Australia, Perth, Australia), Matthew W Knuiman (The University of Western Australia, Perth, Australia). Canada Nutrition Database: Howard I Morrison (Public Health Agency of Canada, Canada), Feng Wang (Public Health Agency of Canada, Canada). CardioVascular Disease risk FACtors Two-township Study (CVDFACTS): Shao-Yuan Chuang (Division of Preventive Medicine and Health Services Research, Institute of Population Health Sciences, National Health Research Institutes, Maoli, Taiwan-), Wen-Harn Pan (Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Division of Preventive Medicine and Health Services Research, Institute of Population Health Sciences, National Health Research Institutes, Maoli, Taiwan), Wen-Ting Yeh (Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan). China Prospective Study (CPS): Zhengming Chen (Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK), Margaret C Smith (Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK), Maigeng Zhou (National Centre for Chronic and Noncommunicable Disease Control and Prevention, Chinese Centre for Disease Control and Prevention, Beijing, China). Chinese Multi-Provincial Cohort Study (CMCS): Wei Wang (Department of Epidemiology, Capital Medical University Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China), Xiao-ting Zhang (Department of Epidemiology, Capital Medical University Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China), Dong Zhao (Department of Epidemiology, Capital Medical University Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China). Cohort of Norway (CONOR) (except Tromso and HUNT studies): Randi Selmer (Norwegian Institute of Public Health, Norway), Bjorn H Strand (Norwegian Institute of Public Health, Norway), Stein Emil Vollset (Norwegian Institute of Public Health and University of Bergen, Norway). Cohort study from Porto Alegre, southern Brazil: Sandra C Fuchs (Postgraduate Studies Program in Cardiology, Universidade Federal do Rio Grande do Sul, School of Medicine, Porto Alegre, Brazil), Flavio D Fuchs (Hospital de Clinicas de Porto Alegre, Division of Cardiology, and the National Institute for Science and Technology for Health Technology Assessment (IATS), Brazil), Leila B Moreira (Postgraduate Studies Program in Cardiology, Universidade Federal do Rio Grande do Sul, School of Medicine, Porto Alegre, Brazil). Corfu Cohort, Seven Countries Study: Ismene A Dontas (University of Athens, Greece), Cleo A Dontas (Corfu General Hospital, Greece). Crete Cohort, Seven Countries Study : Anthony G Kafatos (University of Crete, Greece), Joanna Moschandreas (University of Crete, Greece). Crevalcore, Montegiorgio and Rome Cohort, Seven Countries Study : Mariapaola Lanti (Association for Cardiac Research, Rome, Italy), Alessandro Menotti (Association for Cardiac Research, Rome, Italy). Dalmatia and Slavonia Cohort, Seven Countries Study : Daan Kromhout (Division of Human Nutrition, Wageningen University, The Netherlands), Alessandro Menotti (Association for Cardiac Research, Rome, Italy). Danish Diet, Cancer and Health study: Majken K Jensen (Department of Nutrition, Harvard School of Public Health, Boston), Kim Overvad (Section for Epidemiology, Department of Public Health, Aarhus University, Denmark; Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark), Anne Tjonneland (Danish Cancer Society, Copenhagen, Denmark). Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment (DETECT) : Jens Klotsche (Institute of Clinical Psychology and Psychotherapy/Centre of Clinical Epidemiology and Longitudinal Studies (CELOS), Technische Universitaet Dresden, Germany), Hans-Ulrich Wittchen (Institute of Clinical Psychology and Psychotherapy/Centre of Clinical Epidemiology and Longitudinal Studies (CELOS), Technische Universitaet Dresden, Germany) Diabetes Intervention Study: Sabine Fischer (Medical Clinic III, Technical University Dresden, Germany), Markolf Hanefeld (Centre for Clinical Studies, GWT, Technical University Dresden, Germany), Uta Schwanebeck (Coordination Centre for Clinical Trials, University of Technology, Germany). Dubbo Study of the Elderly: Leon A Simons (University of NSW and St Vincents Hospital, Sydney, Australia), Judith Simons (St Vincents Hospital, Sydney, Australia). Duesseldorf Obesity Mortality Study (DOMS): Ralf Bender (IQWiG, Cologne, Germany), Silke Matthies (Department of Mathematics and Technology, RheinAhrCampus, Koblenz University of Applied Sciences, Remagen, Germany). East and West Finland Cohort, Seven Countries Study, Phase I: Aulikki Nissinen (National Institute for Health and Welfare, Department of Chronic Disease Prevention, Finland), Hanna K Tolonen (National Institute for Health and Welfare, Department of Chronic Disease Prevention, Chronic Disease Epidemiology and Prevention Unit), Jaakko Tuomilehto (Centre for Vascular Prevention, Danube-University Krems, Krems, Austria; Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; Instituto de Investigacion Sanitaria del Hospital Universario La Paz (IdiPAZ), Madrid, Spain; King Abdulaziz University, Jeddah, Saudi Arabia). East and West Finland Cohort, Seven Countries Study, Phase II: Aulikki Nissinen (National Institute for Health and Welfare, Department of Chronic Disease Prevention, Finland), Jaakko Tuomilehto (Centre for Vascular Prevention, Danube-University Krems, Krems, Austria; Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; Instituto de Investigacion Sanitaria del Hospital Universario La Paz (IdiPAZ), Madrid, Spain; King Abdulaziz University, Jeddah, Saudi Arabia). EURODIAB Prospective Complications Study: Nish Chaturvedi (National Heart and Lung Institute, Imperial College, London, UK), John H Fuller (Epidemiology and Public Health, Royal Free and University College London Medical School, London, UK), Sabita S Soedamah-Muthu (Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands). European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE): Dirk AO De Bacquer (Department of Public Health, Ghent University, Ghent, Belgium), Kornelia Kotseva (Department of Cardiovascular Medicine, National Heart and Lung Institute, Imperial College London, UK), David A Wood (Department of Cardiovascular Medicine, National Heart and Lung Institute, Imperial College London, UK). EUROSTROKE: Michiel L Bots (Julius Centre For Health Sciences and Primary care, UMC Utrecht, The Netherlands), Karel G M Moons (Julius Centre For Health Sciences and Primary care, UMC Utrecht, The Netherlands). Finnish Mobile Clinic Health Examination Survey (FMC): Markku Heliovaara (National Institute for Health and Welfare, Finland), Paul B Knekt (National Institute for Health and Welfare, Finland), Harri Rissanen (National Institute for Health and Welfare, Finland) General Post Office Study (GPO): Jane E Ferrie (Department of Epidemiology and Public Health, University College London, UK), Martin J Shipley (Department of Epidemiology and Public Health, University College London, UK), George Davey Smith (School of Social and Community Medicine, University of Bristol, UK). Goteborg BEDA study: Saga Johansson (AstraZeneca R&D, Molndal, Sweden), Georgios Lappas (Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden), Annika Rosengren (Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden). Health Risks and Quality of Life in the Hong Kong Elderly: Aprille Sham (The Chinese University of Hong Kong, Hong Kong), Jean Woo (The Chinese University of Hong Kong, Hong Kong), Ruby HY Yu (The Chinese University of Hong Kong, Hong Kong). Hisayama Study: Jun Hata (Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan), Yutaka Kiyohara (Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan), Toshiharu Ninomiya (Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan). Jichi Medical School-Ambulatory blood pressure monitoring (JMS-ABPM), wave 1: Satoshi Hoshide (Department of Cardiology, Jichi Medical University School of Medicine, Tochigi, Japan), Kazuomi Kario (Department of Cardiology, Jichi Medical University School of Medicine, Tochigi, Japan). Kaunas Rotterdam Intervention Study (KRIS): Daiva Rastenyte (Department of Neurology, Medical Academy of Lithuanian University of Health Sciences, Lithuania), Abdonas Tamosiunas (Department of Population studies of Institute of Cardiology, Medical Academy of Lithuanian University of Health Sciences, Lithuania). LIFE Study: Giovanni de Simone (Department of Translational Medical Sciences, Federico II University, Naples, Italy), Richard B Devereux (Department of Medicine, The New York Presbyterian Hospital, Weill-Cornell Medical College, New York, USA), Eva Gerdts (Department of Clinical Science, University of Bergen, Bergen, Norway). Long term Intervention with Pravastatin in Ischaemic Disease (LIPID): David M Colquhoun (University of Queensland, Greenslopes and Wesley Private Hospitals, Australia), Anthony C Keech (NHMRC Clinical Trials Centre, University of Sydney, Australia), Adrienne C Kirby (NHMRC Clinical Trials Centre, University of Sydney, Australia). Management of Elevated Cholesterol in Primary Prevention Group of Adult Japanese (MEGA): Kyoichi Mizuno (Nippon Medical School of Medicine, Tokyo, Japan), Haruo Nakamura (Mitsukoshi Health and Welfare Foundation, Tokyo, Japan), Shinichiro Uchiyama (Tokyo Women's Medical University, Tokyo, Japan). Melbourne Collaborative Study (MCCS): Julie K Bassett (Cancer Council Victoria, Cancer Epidemiology Centre, Melbourne, Australia), Graham G Giles (Cancer Council Victoria, Cancer Epidemiology Centre, Melbourne, Australia), Allison M Hodge (Cancer Council Victoria, Cancer Epidemiology Centre, Melbourne, Australia). Multifactor Primary Prevention Study: Georgios Lappas (Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden), Annika Rosengren (Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden), Lars Wilhelmsen (Department of Medicine, University of Gothenburg, Sweden). National Heart Foundation Risk Factor Prevalence Study: Satvinder S Dhaliwal (School of Public Health, Curtin University, Western Australia, Australia), Timothy A Welborn (University of Western Australia, Australia) NIPPON DATA80: Yasuyuki Nakamura (Kyoto Women's University, Kyoto, Japan), Akira Okayama (The First Institute for Health Promotion and Health Care, Japan Anti-Tuberculosis Association, Tokyo, Japan), Hirotsugu Ueshima (Shiga University of Medical Science, Otsu, Shiga, Japan). NIPPON DATA90: Aya Kadota (Osaka Kyoiku University, Kashiwara, Osaka, Japan), Tomonori Okamura (Keio University, Tokyo, Tokyo, Japan), Hirotsugu Ueshima (Shiga University of Medical Science, Otsu, Shiga, Japan). Nord-Trondelag Health Study 1 (HUNT 1): Marie S Sandvei (Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway; Nordland Hospital Bodø, Bodø, Norway), Lars J Vatten (Department of Community Medicine and General Practice, Norwegian University of Science and Technology, Trondheim, Norway), Anne Vik (Department of Neuroscience, Norwegian University of Science and Technology and Department of Neurosurgery, Trondheim University Hospital,, Trondheim, Norway). Nord-Trondelag Health Study 2 (HUNT 2): Bjorn Morkedal (Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway), Pal R Romundstad (Department of Community Medicine and General Practice, Norwegian University of Science and Technology, Trondheim, Norway), Marie S Sandvei (Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway; Nordland Hospital Bodø, Bodø, Norway). Northern Manhattan Study (NOMAS): Mitchell SV Elkind (Department of Neurology, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA), Hannah Gardener (University of Miami Miller School of Medicine, Department of Neurology, Miami, USA), Ralph L Sacco (Departments of Neurology and Public Health Sciences, University of Miami Miller School of Medicine, Miami, USA) Norwegian Counties Study (NCS): Randi Selmer (Norwegian Institute of Public Health, Norway), Bjorn H Strand (Norwegian Institute of Public Health, Norway). Prediction of cerebrovascular and cardiovascular events in patients with subclinical carotid atherosclerosis : the role of C-reactive protein : Antonino Mignano (Operative Unit of Cardiology AOUP “Paolo Giaccone” Palermo, Italy), Salvatore Novo (Operative Unit of Cardiology AOUP “Paolo Giaccone” Palermo, Italy), Manfredi Rizzo (Department of Internal Medicine and Clinical Specialties, University of Palermo, Italy). Prospective Cardiovascular Münster Study (PROCAM): Gerd Assmann (Assmann Foundation for Prevention, Münster, Germany), Helmut Schulte (Assmann Foundation for Prevention, Münster, Germany). Prospective Study of Women in Gothenburg : Lauren Lissner (Department of Public Health and Community Medicine, University of Gothenburg, Sweden), Ingmar Skoog (Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden), Valter Sundh (Department of Public Health and Community Medicine, University of Gothenburg, Sweden). Risk of ischaemic heart disease in Zaragoza (ZACARIS): Alejandro Marin (Centro De Salud Zaragoza Norte Zaragoza, Spain), Maria Jose Medrano (National Centre for Epidemiology, Carlos III Institute of Health (ISCIII), Madrid, Spain). Rotterdam Study (RS): Albert Hofman (Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands), Maris Kuningas (Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands), Bruno H Stricker (Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands). Secondary Manifestations of ARTerial Disease (SMART): Yolanda van der Graaf (Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, The Netherlands), Frank LJ Visseren (Vascular Medicine University Medical Centre Utrecht, The Netherlands). Singapore Cardiovascular Cohort Study : Jeannette JM Lee (Saw Swee Hock School of Public Health, National University of Singapore, Singapore). Study of Multifactorial Prevention of Ischemic Heart Disease: Daiva Rastenyte (Department of Neurology, Medical Academy of Lithuanian University of Health Sciences, Lithuania), Abdonas Tamosiunas (Department of Population studies of Institute of Cardiology, Medical Academy of Lithuanian University of Health Sciences, Lithuania). Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA): Wanda Bemelmans (National Institute for Public Health and the Environment, Bilthoven, The Netherlands), Lisette C P G M de Groot (Wageningen University, Wageningen, The Netherlands), Ellen L de Hollander (Wageningen University, Wageningen, the Netherlands and National Institute for Public Health and the Environment, Bilthoven, The Netherlands). Tanushimaru and Ushibuka Cohort, Seven Countries Study: Hisashi Adachi (Department of Community Medicine, Kurume University School of Medicine, Kurume, Japan), Yuji Hirai (Department of Internal Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Kurume, Japan). Tehran Lipid and Glucose Study (TLGS): Fereidoun Azizi (Endocrine Research Centre, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran), Farzad Hadaegh (Prevention of Metabolic Disorders Research Centre, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran), Davood Khalili (Prevention of Metabolic Disorders Research Centre, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran). Tromso Study: Ellisiv B Mathiesen (Department of Clinical Medicine, University of Tromso, Tromso, Norway), Inger Njolstad (Department of Community Medicine, University of Tromso, Tromso, Norway), Tom Wilsgaard (Department of Community Medicine, University of Tromso, Tromso, Norway). Turkish Adult Risk Factor Study (TARF): Gunay Can (Department of Public Health, Cerrahpasa Medical Faculty, Istanbul University, Turkey), Altan Onat (Emeritus, Cerrahpasa Medical Faculty, Istanbul University, Turkey). Uppsala Longitudinal Study of Adult Men (ULSAM): Johan Arnlov (Department of Public Health and Caring Sciences, Uppsala University, Sweden), Johan Sundstrom (Department of Medical Sciences, Uppsala University, Sweden). US Railroad Cohort, Seven Countries Study: Henry W Blackburn (University of Minnesota School of Public Health, USA), David R Jacobs (University of Minnesota School of Public Health, USA). Ventimiglia di Sicilia Heart Study: Maurizio R Averna (Department of Biomedicine, Internal Medicine and Medical Specialties, University of Palermo, Italy), Angelo B Cefalu (Department of Biomedicine, Internal Medicine and Medical Specialties, University of Palermo, Italy), Davide Noto (Department of Biomedicine, Internal Medicine and Medical Specialties, University of Palermo, Italy). Vorarlberg Health Monitoring & Promotion Programme (VHM&PP): Hans Concin (Agency for Preventive and Social Medicine, Bregenz, Austria), Gabriele Nagel (Institute for Epidemiology and medical biometry, University of Ulm, Germany, and Agency for Preventive and Social Medicine, Bregenz, Austria), Hanno Ulmer (Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Austria). Western Collaborative Group Study (WCGS): Ruth E Krasnow (Centre for Health Sciences, SRI International, Menlo Park, USA), Gary E Swan (Centre for Health Sciences, SRI International, Menlo Park, USA) Whitehall II Study : Mika Kivimaki (Department of Epidemiology and Public Health, University College London, UK), Martin J Shipley (Department of Epidemiology and Public Health, University College London, UK). Whitehall I Study: G David Batty (Department of Epidemiology and Public Health, University College London, UK), Martin J Shipley (Department of Epidemiology and Public Health, University College London, UK). Zrenjanin, Belgrade and Velika Krsna Cohort, Seven Countries Study: Natasa Milic (School of Medicine, University of Belgrade, Serbia), Miodrag C Ostojic (School of Medicine, University of Belgrade, Serbia), Biljana Parapid (Division of Cardiology, Clinical Centre of Serbia, Belgrade, Serbia). Zutphen cohort, Seven Countries Study, Phase I: Johanna M Geleijnse (Division of Human Nutrition, Wageningen University, The Netherlands), Daan Kromhout (Division of Human Nutrition, Wageningen University, The Netherlands), Eveline Waterham (Division of Human Nutrition, Wageningen University, The Netherlands). Zutphen cohort, Seven Countries Study, Phase II: Edith J Feskens (Division of Human Nutrition, Wageningen University, The Netherlands), Daan Kromhout (Division of Human Nutrition, Wageningen University, The Netherlands), Eveline Waterham (Division of Human Nutrition, Wageningen University, The Netherlands). Conflicts of interest The members of the Writing and Pooling Group declare that they have no conflicts of interest. Acknowledgments We thank Zhou Zhou for her help with the systematic reviews and Sanne AE Peters for assistance with the APCSC data. This report was prepared using Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, Framingham Offspring Study, Honolulu Heart Program, Multi-Ethnic Study of Atherosclerosis, Multiple risk factor intervention trial, Puerto Rico Heart Health Program, Women's Health Initiative: Clinical Trials, Women's Health Initiative: Observational Study research materials obtained from the NHLBI Biological Specimen and Data Repository Information Coordinating Centre. The study was funded by the UK Medical Research Council, National Institute for Health Research Comprehensive Biomedical Research Centre at Imperial College Healthcare NHS Trust, National Institute of Health grant RO1 DK090435 , UK Medical Research Council, National Institute for Health Research Comprehensive Biomedical Research Centre at Imperial College Healthcare NHS Trust, Lown Scholars in Residence Program on cardiovascular disease prevention, and Harvard Global Health Institute Doctoral Research Grant. This paper is dedicated to the memory of Gary Whitlock, epidemiologist and scholar.
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