1. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019; 139:e56–528.
2. Organisation for Economic Cooperation and Development (OECD). Cardiovascular Disease and Diabetes: Policies for Better Health and Quality of Care. Paris: OECD Publishing;2015. DOI:
10.1787/9789264233010-en.
3. Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology. Int J Epidemiol. 2016; 45:1866–1886.
4. Buttar HS, Li T, Ravi N. Prevention of cardiovascular diseases: Role of exercise, dietary interventions, obesity and smoking cessation. Exp Clin Cardiol. 2005; 10:229–249.
5. Jee YH, Emberson J, Jung KJ, et al. Cohort profile: the Korean Cancer Prevention Study-II (KCPS-II) Biobank. Int J Epidemiol. 2018; 47:385–386f.
6. O'Donnell CJ, Elosua R. Cardiovascular risk factors. Insights from Framingham Heart Study. Rev Esp Cardiol. 2008; 61:299–310.
8. Bell S, Daskalopoulou M, Rapsomaniki E, et al. Association between clinically recorded alcohol consumption and initial presentation of 12 cardiovascular diseases: population based cohort study using linked health records. BMJ. 2017; 356:j909.
9. Klatsky AL, Armstrong MA, Friedman GD, Sidney S. Alcohol drinking and risk of hospitalization for ischemic stroke. Am J Cardiol. 2001; 88:703–706.
10. Klatsky AL, Friedman GD, Siegelaub AB. Alcohol use and cardiovascular disease: the Kaiser-Permanente experience. Circulation. 1981; 64:III 32–41.
11. The Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the pooling project. The pooling project research group. J Chronic Dis. 1978; 31:201–306.
12. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of lipids on cardiovascular health: JACC Health Promotion Series. J Am Coll Cardiol. 2018; 72:1141–1156.
13. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364:937–952.
14. Robertson TL, Kato H, Rhoads GG, et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California. Incidence of myocardial infarction and death from coronary heart disease. Am J Cardiol. 1977; 39:239–243.
15. National Heart Lung and Blood Institute. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984; 251:365–374.
16. Anderson TW, Rubin H. Estimation of the parameters of a single equation in a complete system of stochastic equations. Ann Math Stat. 1949; 20:46–63.
17. Gofman JW, Young W, Tandy R. Ischemic heart disease, atherosclerosis, and longevity. Circulation. 1966; 34:679–697.
18. Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. Ann Intern Med. 1979; 90:85–91.
19. Salonen JT, Salonen R, Seppänen K, Rauramaa R, Tuomilehto J. HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. Circulation. 1991; 84:129–139.
20. Rosenson RS, Otvos JD, Freedman DS. Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial. Am J Cardiol. 2002; 90:89–94.
21. Kosmas CE, Martinez I, Sourlas A, et al. High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease. Drugs Context. 2018; 7:212525.
22. Castelli WP, Doyle JT, Gordon T, et al. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation. 1977; 55:767–772.
23. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011; 123:2292–2333.
24. Jeong SM, Choi S, Kim K, et al. Effect of change in total cholesterol levels on cardiovascular disease among young adults. J Am Heart Assoc. 2018; 7:e008819.
26. Jee SH, Jang Y, Oh DJ, et al. A coronary heart disease prediction model: the Korean Heart Study. BMJ Open. 2014; 4:e005025.
27. Klatsky AL, Friedman GD, Siegelaub AB. Alcohol consumption before myocardial infarction. Results from the Kaiser-Permanente epidemiologic study of myocardial infarction. Ann Intern Med. 1974; 81:294–301.
28. Mukamal K, Lazo M. Alcohol and cardiovascular disease. BMJ. 2017; 356:j1340.
29. Fernández-Solà J. Cardiovascular risks and benefits of moderate and heavy alcohol consumption. Nat Rev Cardiol. 2015; 12:576–587.
31. Mukamal K. Alcohol intake and noncoronary cardiovascular diseases. Ann Epidemiol. 2007; 17:S8–12.
32. Yoon YS, Oh SW, Baik HW, Park HS, Kim WY. Alcohol consumption and the metabolic syndrome in Korean adults: the 1998 Korean National Health and Nutrition Examination Survey. Am J Clin Nutr. 2004; 80:217–224.
34. Doyle JT, Dawber TR, Kannel WB, Heslin AS, Kahn HA. Cigarette smoking and coronary heart disease. Combined experience of the Albany and Framingham studies. N Engl J Med. 1962; 266:796–801.
35. Rosenberg L, Palmer JR, Shapiro S. Decline in the risk of myocardial infarction among women who stop smoking. N Engl J Med. 1990; 322:213–217.
36. National Center for Chronic Disease Prevention and Health Promotion (US). How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention;2010.
37. Jee SH, Suh I, Kim IS, Appel LJ. Smoking and atherosclerotic cardiovascular disease in men with low levels of serum cholesterol: the Korea Medical Insurance Corporation Study. JAMA. 1999; 282:2149–2155.
38. Jee Y, Jung KJ, Lee S, Back JH, Jee SH, Cho SI. Smoking and atherosclerotic cardiovascular disease risk in young men: the Korean Life Course Health Study. BMJ Open. 2019; 9:e024453.
41. Engeland A, Bjørge T, Søgaard AJ, Tverdal A. Body mass index in adolescence in relation to total mortality: 32-year follow-up of 227,000 Norwegian boys and girls. Am J Epidemiol. 2003; 157:517–523.
42. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006; 113:898–918.
43. Kachur S, Lavie CJ, de Schutter A, Milani RV, Ventura HO. Obesity and cardiovascular diseases. Minerva Med. 2017; 108:212–228.
44. Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol. 2009; 6:399–409.
45. Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol. 2007; 49:2129–2138.
47. Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol. 2009; 53:1925–1932.
48. Jee SH, Sull JW, Park J, et al. Body-mass index and mortality in Korean men and women. N Engl J Med. 2006; 355:779–787.
49. Choi S, Kim K, Kim SM, et al. Association of obesity or weight change with coronary heart disease among young adults in South Korea. JAMA Intern Med. 2018; 178:1060–1068.
50. Cozlea DL, Farcas DM, Nagy A, et al. The impact of C reactive protein on global cardiovascular risk on patients with coronary artery disease. Curr Health Sci J. 2013; 39:225–231.
51. de Ferranti S, Rifai N. C-reactive protein and cardiovascular disease: a review of risk prediction and interventions. Clin Chim Acta. 2002; 317:1–15.
52. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001; 103:1194–1197.
53. Mendall MA, Strachan DP, Butland BK, et al. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J. 2000; 21:1584–1590.
54. Berlin JA, Colditz GA. A meta-analysis of physical activity in the prevention of coronary heart disease. Am J Epidemiol. 1990; 132:612–628.
55. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation. 2007; 116:2110–2118.
56. Carnethon MR. Physical activity and cardiovascular disease: how much is enough? Am J Lifestyle Med. 2009; 3:44S–49S.
57. Kim Y, Sharp S, Hwang S, Jee SH. Exercise and incidence of myocardial infarction, stroke, hypertension, type 2 diabetes and site-specific cancers: prospective cohort study of 257 854 adults in South Korea. BMJ Open. 2019; 9:e025590.
58. Kannel WB, Sorlie P, Gordon T. Labile hypertension: a faulty concept? The Framingham study. Circulation. 1980; 61:1183–1187.
59. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002; 360:1903–1913.
60. Kjeldsen SE. Hypertension and cardiovascular risk: general aspects. Pharmacol Res. 2018; 129:95–99.
61. Lawes CM, Bennett DA, Parag V, et al. Blood pressure indices and cardiovascular disease in the Asia Pacific region: a pooled analysis. Hypertension. 2003; 42:69–75.
62. Kim SJ, Lee J, Jee SH, et al. Cardiovascular risk factors for incident hypertension in the prehypertensive population. Epidemiol Health. 2010; 32:e2010003.
64. Fox CS, Coady S, Sorlie PD, et al. Trends in cardiovascular complications of diabetes. JAMA. 2004; 292:2495–2499.
65. Goldschmid MG, Barrett-Connor E, Edelstein SL, Wingard DL, Cohn BA, Herman WH. Dyslipidemia and ischemic heart disease mortality among men and women with diabetes. Circulation. 1994; 89:991–997.
66. Wilson PW, McGee DL, Kannel WB. Obesity, very low density lipoproteins, and glucose intolerance over fourteen years: the Framingham Study. Am J Epidemiol. 1981; 114:697–704.
67. Kahn R, Buse J, Ferrannini E, Stern M. American Diabetes Association. European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005; 28:2289–2304.
68. Ueshima H. Explanation for the Japanese paradox: prevention of increase in coronary heart disease and reduction in stroke. J Atheroscler Thromb. 2007; 14:278–286.
69. NIPPON DATA80 Research Group. Risk assessment chart for death from cardiovascular disease based on a 19-year follow-up study of a Japanese representative population. Circ J. 2006; 70:1249–1255.
70. Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation. 2008; 118:2702–2709.
72. Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007; 316:1491–1493.
74. Wang X, Yang B, Sun H, Zhang A. Pattern recognition approaches and computational systems tools for ultra performance liquid chromatography-mass spectrometry-based comprehensive metabolomic profiling and pathways analysis of biological data sets. Anal Chem. 2012; 84:428–439.
76. Shah SH, Newgard CB. Integrated metabolomics and genomics: systems approaches to biomarkers and mechanisms of cardiovascular disease. Circ Cardiovasc Genet. 2015; 8:410–419.
79. Liu YT, Jia HM, Chang X, Ding G, Zhang HW, Zou ZM. The metabolic disturbances of isoproterenol induced myocardial infarction in rats based on a tissue targeted metabonomics. Mol Biosyst. 2013; 9:2823–2834.
81. Park JY, Lee SH, Shin MJ, Hwang GS. Alteration in metabolic signature and lipid metabolism in patients with angina pectoris and myocardial infarction. PLoS One. 2015; 10:e0135228.
83. Smith GD, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003; 32:1–22.
88. Zhao Q, Wang J, Spiller W, Bowden J, Small DS. Two-sample instrumental variable analyses using heterogeneous samples. Stat Sci. 2019; 34:317–333.
89. Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017; 26:2333–2355.
90. Sanderson E, Davey Smith G, Windmeijer F, Bowden J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol. 2019; 48:713–727.
92. Davies NM, von Hinke Kessler Scholder S, Farbmacher H, Burgess S, Windmeijer F, Smith GD. The many weak instruments problem and Mendelian randomization. Stat Med. 2015; 34:454–468.
95. Spiller W, Slichter D, Bowden J, Davey Smith G. Detecting and correcting for bias in Mendelian randomization analyses using gene-by-environment interactions. Int J Epidemiol. 2019; 48:702–712.
99. Valdes-Marquez E, Parish S, Clarke R, et al. Relative effects of LDL-C on ischemic stroke and coronary disease: a Mendelian randomization study. Neurology. 2019; 92:e1176–87.
100. Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012; 60:2631–2639.
102. Holmes MV, Asselbergs FW, Palmer TM, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. 2015; 36:539–550.
103. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012; 380:572–580.
104. Haase CL, Tybjærg-Hansen A, Qayyum AA, Schou J, Nordestgaard BG, Frikke-Schmidt R. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab. 2012; 97:E248–56.
105. Burgess S, Freitag DF, Khan H, Gorman DN, Thompson SG. Using multivariable Mendelian randomization to disentangle the causal effects of lipid fractions. PLoS One. 2014; 9:e108891.
106. Burgess S, Harshfield E. Mendelian randomization to assess causal effects of blood lipids on coronary heart disease: lessons from the past and applications to the future. Curr Opin Endocrinol Diabetes Obes. 2016; 23:124–130.
108. Cho Y, Shin SY, Won S, Relton CL, Davey Smith G, Shin MJ. Alcohol intake and cardiovascular risk factors: a Mendelian randomisation study. Sci Rep. 2015; 5:18422.
109. Holmes MV, Dale CE, Zuccolo L, et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ. 2014; 349:g4164.
110. Chen L, Smith GD, Harbord RM, Lewis SJ. Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. PLoS Med. 2008; 5:e52.
111. Jee YH, Jung KJ, Park YB, Spiller W, Jee SH. Causal effect of alcohol consumption on hyperuricemia using a Mendelian randomization design. Int J Rheum Dis. 2019; [Epub ahead of print].
112. Frayling TM, Stoneman CE. Mendelian randomisation in type 2 diabetes and coronary artery disease. Curr Opin Genet Dev. 2018; 50:111–120.
114. Geng T, Smith CE, Li C, Huang T. Childhood BMI and adult type 2 diabetes, coronary artery diseases, chronic kidney disease, and cardiometabolic traits: a Mendelian randomization analysis. Diabetes Care. 2018; 41:1089–1096.
115. Lyall DM, Celis-Morales C, Ward J, et al. Association of body mass index with cardiometabolic disease in the UK Biobank: a Mendelian randomization study. JAMA Cardiol. 2017; 2:882–889.
116. Hägg S, Fall T, Ploner A, et al. Adiposity as a cause of cardiovascular disease: a Mendelian randomization study. Int J Epidemiol. 2015; 44:578–586.
119. Dale CE, Fatemifar G, Palmer TM, et al. Causal associations of adiposity and body fat distribution with coronary heart disease, stroke subtypes, and type 2 diabetes mellitus: a Mendelian randomization analysis. Circulation. 2017; 135:2373–2388.
121. Ligthart S, de Vries PS, Uitterlinden AG, et al. Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein. PLoS One. 2015; 10:e0118859.
122. C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC). Wensley F, Gao P, et al. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ. 2011; 342:d548.
123. Casas JP, Shah T, Cooper J, et al. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol. 2006; 35:922–931.
124. Kardys I, de Maat MP, Uitterlinden AG, Hofman A, Witteman JC. C-reactive protein gene haplotypes and risk of coronary heart disease: the Rotterdam Study. Eur Heart J. 2006; 27:1331–1337.
125. Ross S, D'Mello M, Anand SS, et al. Effect of bile acid sequestrants on the risk of cardiovascular events: a Mendelian randomization analysis. Circ Cardiovasc Genet. 2015; 8:618–627.
127. Larsson SC, Scott RA, Traylor M, et al. Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes: Mendelian randomization study. Neurology. 2017; 89:454–460.
128. Davey Smith G. Does schizophrenia influence cannabis use? How to report the influence of disease liability on outcomes in Mendelian randomization studies. TARG Blog [Internet]. Bristol: University of Bristol;2019. cited 2019. Available from
https://targ.blogs.bristol.ac.uk/2019/01/07/.
129. Lieb W, Jansen H, Loley C, et al. Genetic predisposition to higher blood pressure increases coronary artery disease risk. Hypertension. 2013; 61:995–1001.
130. Åsvold BO, Bjørngaard JH, Carslake D, et al. Causal associations of tobacco smoking with cardiovascular risk factors: a Mendelian randomization analysis of the HUNT Study in Norway. Int J Epidemiol. 2014; 43:1458–1470.
132. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006; 354:1264–1272.
133. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 2016; 375:2144–2153.
134. Rosenson RS, Hegele RA, Fazio S, Cannon CP. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol. 2018; 72:314–329.
135. Takeuchi F, McGinnis R, Bourgeois S, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet. 2009; 5:e1000433.
136. Cha PC, Mushiroda T, Takahashi A, et al. Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Hum Mol Genet. 2010; 19:4735–4744.
137. Perera MA, Cavallari LH, Limdi NA, et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet. 2013; 382:790–796.
138. Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018; 3:619–627.
139. AIM-HIGH Investigators. Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365:2255–2267.
140. HPS2-THRIVE Collaborative Group. Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014; 371:203–212.
141. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; 376:1713–1722.
142. Carter AR, Gill D, Davies NM, et al. Understanding the consequences of education inequality on cardiovascular disease: mendelian randomisation study. BMJ. 2019; 365:l1855.