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Science China Life Sciences

, Volume 62, Issue 6, pp 758–770 | Cite as

Mendelian randomization studies on atherosclerotic cardiovascular disease: evidence and limitations

  • Qin HuEmail author
  • Panpan Hao
  • Qiji Liu
  • Mei Dong
  • Yaoqin Gong
  • Cheng Zhang
  • Yun ZhangEmail author
Review

Abstract

Epidemiological research has revealed a galaxy of biomarkers, such as genes, molecules or traits, which are associated with increased risk of atherosclerotic cardiovascular diseases (ASCVD). However, the etiological basis remains poorly characterized. Mendelian randomization (MR) involves the use of observational genetic data to ascertain the roles of disease-associated risk factors and, in particular, differentiate those reflecting the presence or severity of a disease from those contributing causally to a disease. Over the past decade, MR has evolved into a fruitful approach to clarifying the causal relation of a biomarker with ASCVD and to verifying potential therapeutic targets for ASCVD. In this review, we selected high-quality MR studies on ASCVD, examined the causal relationship of a series of biomarkers with ASCVD, and elucidated the role of MR in validating biomarkers as a therapeutic target by comparing the results from MR studies and randomized clinical trials (RCTs) for the treatment of ASCVD. The good agreement between the results derived by MR and RCTs suggests that MR could be performed as a screening process before novel drug development. However, when designing and interpreting a MR study, the assumptions and limitations inherent in this approach should be taken into account. Novel methodological developments, such as sensitivity analysis, will help to strengthen the validity of MR studies.

Mendelian randomization atherosclerotic cardiovascular disease causality therapeutic target 

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Notes

Acknowledgements

This work was supported by the State Key Program of National Natural Science of China (81530014), the National Natural Science Foundation of China (81370410, 81425004, 81770442, 81571689) and the Taishan Scholars Program of Shandong province, China.

Supplementary material

11427_2019_9537_MOESM1_ESM.jpg (129 kb)
Supplementary material, approximately 129 KB.
11427_2019_9537_MOESM2_ESM.docx (13 kb)
Legend to Supplemental Figure 1
11427_2019_9537_MOESM3_ESM.docx (16 kb)
Supplemental Table 1. Consistency between RCTs and MRs in identifying causal risk factors for ASCVD

References

  1. Ahmad, O.S., Morris, J.A., Mujammami, M., Forgetta, V., Leong, A., Li, R., Turgeon, M., Greenwood, C.M.T., Thanassoulis, G., Meigs, J.B., et al. (2015). A Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease. Nat Commun 6, 7060.CrossRefGoogle Scholar
  2. Au Yeung, S.L., Lin, S.L., Li, A.M., and Schooling, C.M. (2016). Birth weight and risk of ischemic heart disease: A Mendelian randomization study. Sci Rep 6, 38420.CrossRefGoogle Scholar
  3. Benn, M., Tybjaerg-Hansen, A., McCarthy, M.I., Jensen, G.B., Grande, P., and Nordestgaard, B.G. (2012). Nonfasting glucose, ischemic heart disease, and myocardial infarction. J Am Coll Cardiol 59, 2356–2365.CrossRefGoogle Scholar
  4. Bergholdt, H.K.M., Nordestgaard, B.G., Varbo, A., and Ellervik, C. (2015). Milk intake is not associated with ischaemic heart disease in observational or Mendelian randomization analyses in 98529 Danish adults. Int J Epidemiol 44, 587–603.CrossRefGoogle Scholar
  5. Bochud, M., and Rousson, V. (2010). Usefulness of Mendelian randomization in observational epidemiology. Int J Environ Res Public Health 7, 711–728.CrossRefGoogle Scholar
  6. Borges, M.C., Lawlor, D.A., de Oliveira, C., White, J., Horta, B.L., and Barros, A.J.D. (2016). Role of adiponectin in coronary heart disease risk. Circ Res 119, 491–499.CrossRefGoogle Scholar
  7. Brendum-Jacobsen, P., Benn, M., Afzal, S., and Nordestgaard, B.G. (2015). No evidence that genetically reduced 25-hydroxyvitamin D is associated with increased risk of ischaemic heart disease or myocardial infarction: a Mendelian randomization study. Int J Epidemiol 44, 651–661.CrossRefGoogle Scholar
  8. Burgess, S., Freitag, D.F., Khan, H., Gorman, D.N., and Thompson, S.G. (2014). Using multivariable mendelian randomization to disentangle the causal effects of lipid fractions. PLoS ONE 9, e108891.CrossRefGoogle Scholar
  9. Burgess, S., Timpson, N.J., Ebrahim, S., and Davey Smith, G. (2015). Mendelian randomization: where are we now and where are we going? Int J Epidemiol 44, 379–388.CrossRefGoogle Scholar
  10. Burgess, S., and Harshfield, E. (2016). Mendelian randomization to assess causal effects of blood lipids on coronary heart disease. Curr Opin Endocrinol Diabetes Obes 23, 124–130.CrossRefGoogle Scholar
  11. Burgess, S., Bowden, J., Fall, T., Ingelsson, E., and Thompson, S.G. (2017). Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology 28, 30–42.CrossRefGoogle Scholar
  12. Björkegren, J.L.M., Kovacic, J.C., Dudley, J.T., and Schadt, E.E. (2015). Genome-wide significant loci: How important are they? J Am Coll Cardiol 65, 830–845.CrossRefGoogle Scholar
  13. C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC). (2011). Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 342, d548..CrossRefGoogle Scholar
  14. Cannon, C.P., Blazing, M.A., Giugliano, R.P., McCagg, A., White, J.A., Theroux, P., Darius, H., Lewis, B.S., Ophuis, T.O., Jukema, J.W., et al. (2015). Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 372, 2387–2397.CrossRefGoogle Scholar
  15. Casas, J.P., Ninio, E., Panayiotou, A., Palmen, J., Cooper, J.A., Ricketts, S. L., Sofat, R., Nicolaides, A.N., Corsetti, J.P., Fowkes, F.G.R., et al. (2010). PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10494 cases and 15624 controls of European ancestry. Circulation 121, 2284–2293.CrossRefGoogle Scholar
  16. Codd, V., Nelson, C.P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J.L., Hottenga, J.J., Fischer, K., Esko, T., Surakka, I., et al. (2013). Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet 45, 422–427.CrossRefGoogle Scholar
  17. Cole, C.B., Nikpay, M., Stewart, A.F.R., and McPherson, R. (2016). Increased genetic risk for obesity in premature coronary artery disease. Eur J Hum Genet 24, 587–591.CrossRefGoogle Scholar
  18. CRP CHD Genetics Collaboration. (2008). Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomisation. Eur J Epidemiol 23, 531–540.CrossRefGoogle Scholar
  19. Dale, C.E., Fatemifar, G., Palmer, T.M., White, J., Prieto-Merino, D., Zabaneh, D., Engmann, J.E.L., Shah, T., Wong, A., Warren, H.R., et al. (2017). Causal associations of adiposity and body fat distribution with coronary heart disease, stroke subtypes, and type 2 diabetes mellitus. Circulation 135, 2373–2388.CrossRefGoogle Scholar
  20. Davey Smith, G., and Hemani, G. (2014). Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23, R89–R98.CrossRefGoogle Scholar
  21. Do, R., Willer, C.J., Schmidt, E.M., Sengupta, S., Gao, C., Peloso, G.M., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., et al. (2013). Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 45, 1345–1352.CrossRefGoogle Scholar
  22. Elliott, P., Chambers, J.C., Zhang, W., Clarke, R., Hopewell, J.C., Peden, J. F., Erdmann, J., Braund, P., Engert, J.C., Bennett, D., et al. (2009). Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 302, 37–48.CrossRefGoogle Scholar
  23. Ference, B.A., Yoo, W., Alesh, I., Mahajan, N., Mirowska, K.K., Mewada, A., Kahn, J., Afonso, L., Williams Sr, K.A., and Flack, J.M. (2012). Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary Heart disease. J Am Coll Cardiol 60, 2631–2639.CrossRefGoogle Scholar
  24. Ference, B.A., Majeed, F., Penumetcha, R., Flack, J.M., and Brook, R.D. (2015). Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both. J Am Coll Cardiol 65, 1552–1561.CrossRefGoogle Scholar
  25. Ference, B.A., Robinson, J.G., Brook, R.D., Catapano, A.L., Chapman, M. J., Neff, D.R., Voros, S., Giugliano, R.P., Davey Smith, G., Fazio, S., et al. (2016). Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 375, 2144–2153.CrossRefGoogle Scholar
  26. Fernández-Solà, J. (2015). Cardiovascular risks and benefits of moderate and heavy alcohol consumption. Nat Rev Cardiol 12, 576–587.CrossRefGoogle Scholar
  27. Fisher, E., Stefan, N., Saar, K., Drogan, D., Schulze, M.B., Fritsche, A., Joost, H.G., Haring, H.U., Hubner, N., Boeing, H., et al. (2009). Association of AHSG gene polymorphisms with fetuin-A plasma levels and cardiovascular diseases in the EPIC-Potsdam Study. Circ Cardiovasc Genet 2, 607–613.CrossRefGoogle Scholar
  28. Frikke-Schmidt, R., Nordestgaard, B.G., Stene, M.C.A., Sethi, A.A., Remaley, A.T., Schnohr, P., Grande, P., and Tybjaerg-Hansen, A. (2008). Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 299, 2524–2532.CrossRefGoogle Scholar
  29. Gaudet, D., Alexander, V.J., Baker, B.F., Brisson, D., Tremblay, K., Singleton, W., Geary, R.S., Hughes, S.G., Viney, N.J., Graham, M.J., et al. (2015). Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 373, 438–447.CrossRefGoogle Scholar
  30. Gill, D., Del Greco M., F., Walker, A.P., Srai, S.K.S., Laffan, M.A., and Minelli, C. (2017). The effect of iron status on risk of coronary artery disease. Arterioscler Thromb Vasc Biol 37, 1788–1792.CrossRefGoogle Scholar
  31. Grundy, S.M., Cleeman, J.I., Merz, C.N.B., Brewer, H.B., Clark, L.T., Hunninghake, D.B., Pasternak, R.C., Smith, S.C., Stone, N.J., Stone, N. J., et al. (2004). Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110, 227–239.CrossRefGoogle Scholar
  32. Guardiola, M., Exeter, H.J., Perret, C., Folkersen, L., Van’t Hooft, F., Eriksson, P., Franco-Cereceda, A., Paulsson-Berne, G., Palmen, J., Li, K.W., et al. (2015). PLA2G10 gene variants, sPLA2 activity, and coronary heart disease risk. Circ Cardiovasc Genet 8, 356–362.CrossRefGoogle Scholar
  33. Haase, C.L., Tybjœrg-Hansen, A., Ali Qayyum, A., Schou, J., Nordestgaard, B.G., and Frikke-Schmidt, R. (2012). LCAT, HDL cholesterol and ischemic cardiovascular disease: A Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab 97, E248–E256.CrossRefGoogle Scholar
  34. Hägg, S., Fall, T., Ploner, A., Mägi, R., Fischer, K., Draisma, H.H.M., Kals, M., de Vries, P.S., Dehghan, A., Willems, S.M., et al. (2015). Adiposity as a cause of cardiovascular disease: a Mendelian randomization study. Int J Epidemiol 44, 578–586.CrossRefGoogle Scholar
  35. Han, C., Liu, F., Yang, X., Chen, J., Li, J., Cao, J., Li, Y., Shen, C., Yu, L., Liu, Z., et al. (2018). Ideal cardiovascular health and incidence of atherosclerotic cardiovascular disease among Chinese adults: the China-PAR project. Sci China Life Sci 61, 504–514.CrossRefGoogle Scholar
  36. Helgadottir, A., Gretarsdottir, S., Thorleifsson, G., Hjartarson, E., Sigurdsson, A., Magnusdottir, A., Jonasdottir, A., Kristjansson, H., Sulem, P., Oddsson, A., et al. (2016). Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat Genet 48, 634–639.CrossRefGoogle Scholar
  37. Hingorani, A.D., and Casas, J.P. (2012). The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis. Lancet 379, 1214–1224.CrossRefGoogle Scholar
  38. HPS3/TIMI55-REVEAL Collaborative. (2017). Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 377, 1217–1227.CrossRefGoogle Scholar
  39. Holmes, M.V., Asselbergs, F.W., Palmer, T.M., Drenos, F., Lanktree, M.B., Nelson, C.P., Dale, C.E., Padmanabhan, S., Finan, C., Swerdlow, D.I., et al. (2015). Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 36, 539–550.CrossRefGoogle Scholar
  40. Holmes, M.V., Dale, C.E., Zuccolo, L., Silverwood, R.J., Guo, Y., Ye, Z., Prieto-Merino, D., Dehghan, A., Trompet, S., Wong, A., et al. (2014). Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ 349, g4164.CrossRefGoogle Scholar
  41. IL6R Genetics Consortium Emerging Risk Factors Collaboration. (2012). Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 9822, 1205–1213.Google Scholar
  42. Jang, Y., Waterworth, D., Lee, J.E., Song, K., Kim, S., Kim, H.S., Park, K. W., Cho, H.J., Oh, I.Y., Park, J.E., et al. (2011). Carriage of the V279F null allele within the gene encoding Lp-PLA2 is protective from coronary artery disease in South Korean males. PLoS ONE 6, e18208.CrossRefGoogle Scholar
  43. Keavney, B., Danesh, J., Parish, S., Palmer, A., Clark, S., Youngman, L., Delépine, M., Lathrop, M., Peto, R., and Collins, R. (2006). Fibrinogen and coronary heart disease: test of causality by ‘Mendelian randomization’. Int J Epidemiology 35, 935–943.CrossRefGoogle Scholar
  44. Jansen, H., Samani, N.J., and Schunkert, H. (2014). Mendelian randomization studies in coronary artery disease. Eur Heart J 35, 1917–1924.CrossRefGoogle Scholar
  45. Jiang, H., Liu, Y., Zhang, Y., and Chen, Z.Y. (2011). Association of plasma brain-derived neurotrophic factor and cardiovascular risk factors and prognosis in angina pectoris. Biochem Biophys Res Commun 415, 99–103.CrossRefGoogle Scholar
  46. Jørgensen, A.B., Frikke-Schmidt, R., West, A.S., Grande, P., Nordestgaard, B.G., and Tybjœrg-Hansen, A. (2013). Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 34, 1826–1833.CrossRefGoogle Scholar
  47. Kaess, B.M., Preis, S.R., Lieb, W., Beiser, A.S., Yang, Q., Chen, T.C., Hengstenberg, C., Erdmann, J., Schunkert, H., Seshadri, S., et al. (2015). Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community. J Am Heart Assoc 4, e001544.CrossRefGoogle Scholar
  48. Kamstrup, P.R., Tybjaerg-Hansen, A., Steffensen, R., and Nordestgaard, B. G. (2009). Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301, 2331–2339.CrossRefGoogle Scholar
  49. Kastelein, J.J.P., Akdim, F., Stroes, E.S.G., Zwinderman, A.H., Bots, M.L., Stalenhoef, A.F.H., Visseren, F.L.J., Sijbrands, E.J.G., Trip, M.D., Stein, E.A., et al. (2008). Simvastatin with or without Ezetimibe in familial hypercholesterolemia. N Engl J Med 358, 1431–1443.CrossRefGoogle Scholar
  50. Keenan, T., Zhao, W., Rasheed, A., Ho, W.K., Malik, R., Felix, J.F., Young, R., Shah, N., Samuel, M., Sheikh, N., et al. (2016). Causal assessment of serum urate levels in cardiometabolic diseases through a Mendelian randomization study. J Am Coll Cardiol 67, 407–416.CrossRefGoogle Scholar
  51. Kobylecki, C.J., Afzal, S., Davey Smith, G., and Nordestgaard, B.G. (2015). Genetically high plasma vitamin C, intake of fruit and vegetables, and risk of ischemic heart disease and all-cause mortality: a Mendelian randomization study. Am J Clin Nutrit 101, 1135–1143.CrossRefGoogle Scholar
  52. Lawlor, D.A., Nordestgaard, B.G., Benn, M., Zuccolo, L., Tybjaerg-Hansen, A., and Davey Smith, G. (2013). Exploring causal associations between alcohol and coronary heart disease risk factors: findings from a Mendelian randomization study in the Copenhagen General Population Study. Eur Heart J 34, 2519–2528.CrossRefGoogle Scholar
  53. Lieb, W., Jansen, H., Loley, C., Pencina, M.J., Nelson, C.P., Newton-Cheh, C., Kathiresan, S., Reilly, M.P., Assimes, T.L., Boerwinkle, E., et al. (2013). Genetic predisposition to higher blood pressure increases coronary artery disease risk. Hypertension 61, 995–1001.CrossRefGoogle Scholar
  54. Linsel-Nitschke, P., Götz, A., Erdmann, J., Braenne, I., Braund, P., Hengstenberg, C., Stark, K., Fischer, M., Schreiber, S., El Mokhtari, N. E., et al. (2008). Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease—a Mendelian randomisation study. PLoS ONE 3, e2986.CrossRefGoogle Scholar
  55. Lloyd-Jones, D.M., Morris, P.B., Ballantyne, C.M., Birtcher, K.K., Daly, D. D. Jr., DePalma, S.M., Minissian, M.B., Orringer, C.E., and Smith, S.C. Jr. (2016). ACC Expert Consensus Decision Pathway on the role of non-statin therapies for LDL-Cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 68, 92–125.CrossRefGoogle Scholar
  56. Madamanchi, N.R., Tchivilev, I., and Runge, M.S. (2006). Genetic markers of oxidative stress and coronary atherosclerosis. Curr Atheroscler Rep 8, 177–183.CrossRefGoogle Scholar
  57. Manousaki, D., Mokry, L.E., Ross, S., Goltzman, D., and Richards, J.B. (2016). Mendelian randomization studies do not support a role for vitamin D in coronary artery disease. Circ Cardiovasc Genet 9, 349356.CrossRefGoogle Scholar
  58. Merino, J., Leong, A., Posner, D.C., Porneala, B., Masana, L., Dupuis, J., and Florez, J.C. (2017). Genetically driven hyperglycemia increases risk ofcoronary artery disease separately from type 2 diabetes. Dia Care 40, 687–693.CrossRefGoogle Scholar
  59. Mokry, L.E., Ahmad, O., Forgetta, V., Thanassoulis, G., and Richards, J.B. (2015). Mendelian randomisation applied to drug development in cardiovascular disease: a review. J Med Genet 52, 71–79.CrossRefGoogle Scholar
  60. Myocardial Infarction Genetics Consortium Investigators. (2014). Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med 371, 2072–2082.CrossRefGoogle Scholar
  61. Nelson, C.P., Hamby, S.E., Saleheen, D., Hopewell, J.C., Zeng, L., Assimes, T.L., Kanoni, S., Willenborg, C., Burgess, S., Amouyel, P., et al. (2015). Genetically determined height and coronary artery disease. N Engl J Med 372, 1608–1618.CrossRefGoogle Scholar
  62. Nicholls, S.J., Cavender, M.A., Kastelein, J.J.P., Schwartz, G., Waters, D. D., Rosenson, R.S., Bash, D., and Hislop, C. (2012). Inhibition of secretory phospholipase A2 in patients with acute coronary syndromes: rationale and design of the vascular inflammation suppression to treat acute coronary syndrome for 16 weeks (VISTA-16) trial. Cardiovasc Drugs Ther 26, 71–75.CrossRefGoogle Scholar
  63. Nüesch, E., Dale, C., Palmer, T.M., White, J., Keating, B.J., van Iperen, E. P., Goel, A., Padmanabhan, S., Asselbergs, F.W., Asselbergs, F.W., etal. (2016). Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis. Int J Epidemiology 45, 19271937.CrossRefGoogle Scholar
  64. Palmer, T.M., Nordestgaard, B.G., Benn, M., Tybjaerg-Hansen, A., Davey Smith, G., Lawlor, D.A., and Timpson, N.J. (2013). Association of plasma uric acid with ischaemic heart disease and blood pressure: Mendelian randomisation analysis of two large cohorts. BMJ 347, f4262.CrossRefGoogle Scholar
  65. Polfus, L.M., Gibbs, R.A., and Boerwinkle, E. (2015). Coronary heart disease and genetic variants with low phospholipase A2 activity. N Engl J Med 372, 295–296.CrossRefGoogle Scholar
  66. Polisecki, E., Peter, I., Simon, J.S., Hegele, R.A., Robertson, M., Ford, I., Shepherd, J., Packard, C., Jukema, J.W., de Craen, A.J.M., et al. (2010). Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly. J Lipid Res 51, 1201–1207.CrossRefGoogle Scholar
  67. Relton, C.L., and Davey Smith, G. (2015). Mendelian randomization: applications and limitations in epigenetic studies. Epigenomics 7, 12391243.CrossRefGoogle Scholar
  68. Ridker, P.M., Everett, B.M., Thuren, T., MacFadyen, J.G., Chang, W.H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S.D., et al. (2017). Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377, 1119–1131.CrossRefGoogle Scholar
  69. Ringstedt, T., Kraemer, R., Hahn, R., Wang, S., Ibanez, C.F., Rafii, S., and Hempstead, B.L. (2000). Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization. Development 127, 4531–4540.Google Scholar
  70. Ross, S., Gerstein, H.C., Eikelboom, J., Anand, S.S., Yusuf, S., and Paré, G. (2015). Mendelian randomization analysis supports the causal role of dysglycaemia and diabetes in the risk of coronary artery disease. Eur Heart J 36, 1454–1462.CrossRefGoogle Scholar
  71. Sabatine, M.S., Giugliano, R.P., Wiviott, S.D., Raal, F.J., Blom, D.J., Robinson, J., Ballantyne, C.M., Somaratne, R., Legg, J., Wasserman, S. M., et al. (2015). Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 372, 1500–1509.CrossRefGoogle Scholar
  72. Sabatine, M.S., Giugliano, R.P., Keech, A.C., Honarpour, N., Wiviott, S.D., Murphy, S.A., Kuder, J.F., Wang, H., Liu, T., Wasserman, S.M., et al. (2017). Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 376, 1713–1722.CrossRefGoogle Scholar
  73. Shah, S., Casas, J.P., Drenos, F., Whittaker, J., Deanfield, J., Swerdlow, D. I., Holmes, M.V., Kivimaki, M., Langenberg, C., Wareham, N., et al. (2013). Causal relevance of blood lipid fractions in the development of carotid atherosclerosis. Circ Cardiovasc Genet 6, 63–72.CrossRefGoogle Scholar
  74. Stender, S., Frikke-Schmidt, R., Nordestgaard, B.G., Grande, P., and Tybjaerg-Hansen, A. (2013). Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis. J Intern Med 273, 59–68.CrossRefGoogle Scholar
  75. Svensson-Färbom, P., Almgren, P., Hedblad, B., Engström, G., Persson, M., Christensson, A., and Melander, O. (2015). Cystatin C is not causally related to coronary artery disease. PLoS ONE 10, e0129269.CrossRefGoogle Scholar
  76. Tang, W.H.W., Hartiala, J., Fan, Y., Wu, Y., Stewart, A.F.R., Erdmann, J., Kathiresan, S., Kathiresan, S., Roberts, R., McPherson, R., et al. (2012). Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk. Arterioscler Thromb Vasc Biol 32, 2803–2812.CrossRefGoogle Scholar
  77. Thomsen, M., Varbo, A., Tybjaerg-Hansen, A., and Nordestgaard, B.G. (2014). Low nonfasting triglycerides and reduced all-cause mortality: a Mendelian randomization study. Clin Chem 60, 737–746.CrossRefGoogle Scholar
  78. Trenkwalder, T., Kessler, T., Schunkert, H., and Erdmann, J. (2015). Genetics of coronary artery disease: Short people at risk? Expert Rev Cardiovascular Ther 13, 1169–1172.CrossRefGoogle Scholar
  79. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration. (2010). Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 375, 1634–1639.CrossRefGoogle Scholar
  80. van der Laan, S.W., Fall, T., Soumaré, A., Teumer, A., Sedaghat, S., Baumert, J., Zabaneh, D., van Setten, J., Isgum, I., Galesloot, T.E., et al. (2016). Cystatin C and cardiovascular disease. J Am Coll Cardiol 68, 934–945.CrossRefGoogle Scholar
  81. Vandenbroucke, J.P. (2004). When are observational studies as credible as randomised trials? Lancet 363, 1728–1731.CrossRefGoogle Scholar
  82. van Meurs, J.B.J., Pare, G., Schwartz, S.M., Hazra, A., Tanaka, T., Vermeulen, S.H., Cotlarciuc, I., Yuan, X., Mälarstig, A., Bandinelli, S., et al. (2013). Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. Am J Clin Nutrit 98, 668–676.CrossRefGoogle Scholar
  83. Varbo, A., Benn, M., Tybjœrg-Hansen, A., Jørgensen, A.B., Frikke-Schmidt, R., and Nordestgaard, B.G. (2013). Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 61, 427–436.CrossRefGoogle Scholar
  84. Varbo, A., Benn, M., Tybjœrg-Hansen, A., and Nordestgaard, B.G. (2013). Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 128, 1298–1309.CrossRefGoogle Scholar
  85. Voight, B.F., Peloso, G.M., Orho-Melander, M., Frikke-Schmidt, R., Barbalic, M., Jensen, M.K., Hindy, G., Hólm, H., Ding, E.L., Johnson, T., et al. (2012). Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet 380, 572–580.CrossRefGoogle Scholar
  86. White, J., Sofat, R., Hemani, G., Shah, T., Engmann, J., Dale, C., Shah, S., Kruger, F.A., Giambartolomei, C., Swerdlow, D.I., et al. (2016). Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol 4, 327–336.CrossRefGoogle Scholar
  87. Wu, Z., Lou, Y., Qiu, X., Liu, Y., Lu, L., Chen, Q., and Jin, W. (2014). Association of cholesteryl ester transfer protein (CETP) gene polymorphism, high density lipoprotein cholesterol and risk of coronary artery disease: a meta-analysis using a Mendelian randomization approach. BMC Med Genet 15, 118.CrossRefGoogle Scholar
  88. Würtz, P., Kangas, A.J., Soininen, P., Lehtimäki, T., Kähönen, M., Viikari, J.S., Raitakari, O.T., Järvelin, M.R., Davey Smith, G., and Ala-Korpela, M. (2013). Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease. J Am College Cardiology 62, 1906–1908.CrossRefGoogle Scholar
  89. Yaghootkar, H., Lamina, C., Scott, R.A., Dastani, Z., Hivert, M.F., Warren, L.L., Stancáková, A., Buxbaum, S.G., Lyytikäinen, L.P., Henneman, P., et al. (2013). Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes. Diabetes 62, 3589–3598.CrossRefGoogle Scholar
  90. Yang, Q., Bailey, L., Clarke, R., Flanders, W.D., Liu, T., Yesupriya, A., Khoury, M.J., and Friedman, J.M. (2012). Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults. Am J Clin Nutrit 95, 1245–1253.CrossRefGoogle Scholar
  91. Yau, C., and Campbell, K. (2019). Bayesian statistical learning for big data biology. Biophys Rev 11, 95–102.CrossRefGoogle Scholar
  92. Zacho, J., Tybjaerg-Hansen, A., Jensen, J.S., Grande, P., Sillesen, H., and Nordestgaard, B.G. (2008). Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 359, 1897–1908.CrossRefGoogle Scholar
  93. Zhao, J.V., and Schooling, C.M. (2016). Endogenous androgen exposures and ischemic heart disease, a separate sample Mendelian randomization study. Int J Cardiol 222, 940–945.CrossRefGoogle Scholar
  94. Zhao, J.V., and Schooling, C.M. (2017). Homocysteine-reducing B vitamins and ischemic heart disease: a separate-sample Mendelian randomization analysis. Eur J Clin Nutr 71, 267–273.CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.The Key Laboratory of Cardiovascular Remodeling and Function Research, Ministry of Education of China, Ministry of Health of China and Chinese Academy of Medical Sciences, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong UniversityJinanChina
  2. 2.Department of Medical Genetics, School of Medicine, Key Laboratory of Experimental Teratology, Ministry of EducationShandong UniversityJinanChina

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