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HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology

Nature Reviews Cardiology volume 15, pages 9–19 (2018)Cite this article

Subjects

Key Points

  • High HDL-cholesterol (HDL-C) level in plasma is a robust marker of reduced risk of cardiovascular disease; but the cholesterol content of HDL is not a causative factor of atherosclerotic cardiovascular disease

  • HDLs are heterogeneous subpopulations of discrete particles that differ quantitatively and qualitatively in apolipoprotein and lipid composition

  • Advances in understanding the molecular mechanisms involved in cholesterol efflux and the pathophysiology of monogenic dyslipoproteinaemia have expanded our knowledge of the role of HDL in reverse cholesterol transport and atherogenesis

  • Critical links between common variation in genetic determinants of HDL-C concentration and a more detailed knowledge of HDL pathways, such as biogenesis, remodelling, structure, molecular composition, function, and catabolism, are lacking

  • An integrated systems biology approach that includes the essential elements of metabolomics, transcriptomics, lipidomics, and proteomics is required to understand the complex metabolism of HDL and its potential atheroprotective properties

  • Genetic analysis of patients receiving therapeutic interventions targeting HDL offers the opportunity to gain insights into the complexities of HDL and the potential benefits of such treatments on atherosclerotic cardiovascular disease

Abstract

Plasma levels of HDL cholesterol (HDL-C) predict the risk of cardiovascular disease at the epidemiological level, but a direct causal role for HDL in cardiovascular disease remains controversial. Studies in animal models and humans with rare monogenic disorders link only particular HDL-associated mechanisms with causality, including those mechanisms related to particle functionality rather than cholesterol content. Mendelian randomization studies indicate that most genetic variants that affect a range of pathways that increase plasma HDL-C levels are not usually associated with reduced risk of cardiovascular disease, with some exceptions, such as cholesteryl ester transfer protein variants. Furthermore, only a fraction of HDL-C variation has been explained by known loci from genome-wide association studies (GWAS), suggesting the existence of additional pathways and targets. Systems genetics can enhance our understanding of the spectrum of HDL pathways, particularly those pathways that involve new and non-obvious GWAS loci. Bioinformatic approaches can also define new molecular interactions inferred from both large-scale genotypic data and RNA sequencing data to reveal biologically meaningful gene modules and networks governing HDL metabolism with direct relevance to disease end points. Targeting these newly recognized causal networks might inform the development of novel therapeutic strategies to reduce the risk of cardiovascular disease.

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References

  1. Rosenson, R. S. et al. HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin. Chem. 57, 392–410 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Rosenson, R. S. et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 125, 1905–1919 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rosenson, R. S. et al. Translation of high-density lipoprotein function into clinical practice: current prospects and future challenges. Circulation 128, 1256–1267 (2013).

    Article  PubMed  Google Scholar 

  4. Rosenson, R. S. et al. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat. Rev. Cardiol. 13, 48–60 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Rye, K. A. & Barter, P. J. Regulation of high-density lipoprotein metabolism. Circ. Res. 114, 143–156 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Khetarpal, S. A. et al. Loss of function of GALNT2 lowers high-density lipoproteins in humans, nonhuman primates, and rodents. Cell Metab. 24, 234–245 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Voight, B. F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 380, 572–580 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Zanoni, P. et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351, 1166–1171 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Bjorkegren, J. L., Kovacic, J. C., Dudley, J. T. & Schadt, E. E. Genome-wide significant loci: how important are they? Systems genetics to understand heritability of coronary artery disease and other common complex disorders. J. Am. Coll. Cardiol. 65, 830–845 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Schaefer, E. J., Santos, R. D. & Asztalos, B. F. Marked HDL deficiency and premature coronary heart disease. Curr. Opin. Lipidol. 21, 289–297 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Norum, R. A. et al. Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. N. Engl. J. Med. 306, 1513–1519 (1982).

    Article  CAS  PubMed  Google Scholar 

  12. Ordovas, J. M., Cassidy, D. K., Civeira, F., Bisgaier, C. L. & Schaefer, E. J. Familial apolipoprotein A-I, C-III, and A-IV deficiency and premature atherosclerosis due to deletion of a gene complex on chromosome 11. J. Biol. Chem. 264, 16339–16342 (1989).

    CAS  PubMed  Google Scholar 

  13. von Eckardstein, A. et al. Structural analysis of human apolipoprotein A-I variants. Amino acid substitutions are nonrandomly distributed throughout the apolipoprotein A-I primary structure. J. Biol. Chem. 265, 8610–8617 (1990).

    CAS  PubMed  Google Scholar 

  14. Lee, E. Y., Klementowicz, P. T., Hegele, R. A., Asztalos, B. F. & Schaefer, E. J. HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature. J. Clin. Lipidol. 7, 169–173 (2013).

    Article  PubMed  Google Scholar 

  15. Schmidt, H. H. et al. Carboxyl-terminal domain truncation alters apolipoprotein A-I in vivo catabolism. J. Biol. Chem. 270, 5469–5475 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Baldassarre, D. et al. Increased carotid artery intima-media thickness in subjects with primary hypoalphalipoproteinemia. Arterioscler. Thromb. Vasc. Biol. 22, 317–322 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Frikke-Schmidt, R. et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. J. Am. Med. Assoc. 299, 2524–2532 (2008).

    Article  CAS  Google Scholar 

  18. Roshan, B. et al. Homozygous lecithin:cholesterol acyltransferase (LCAT) deficiency due to a new loss of function mutation and review of the literature. J. Clin. Lipidol. 5, 493–499 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Saeedi, R., Li, M. & Frohlich, J. A review on lecithin:cholesterol acyltransferase deficiency. Clin. Biochem. 48, 472–475 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Savel, J. et al. Very low levels of HDL cholesterol and atherosclerosis, a variable relationship — a review of LCAT deficiency. Vasc. Health Risk Manag. 8, 357–361 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  21. McNeish, J. et al. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc. Natl Acad. Sci. USA 97, 4245–4250 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aiello, R. J. et al. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler. Thromb. Vasc. Biol. 22, 630–637 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Joyce, C. W. et al. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc. Natl Acad. Sci. USA 99, 407–412 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Klein, H. G. et al. Fish eye syndrome: a molecular defect in the lecithin-cholesterol acyltransferase (LCAT) gene associated with normal alpha-LCAT-specific activity. Implications for classification and prognosis. J. Clin. Invest. 92, 479–485 (1993).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Klein, H. G. et al. Two different allelic mutations in the lecithin:cholesterol acyltransferase (LCAT) gene resulting in classic LCAT deficiency: LCAT (tyr83-->stop) and LCAT (tyr156-->asn). J. Lipid Res. 34, 49–58 (1993).

    CAS  PubMed  Google Scholar 

  26. Klein, H. G. et al. Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123-->Ile) and lecithin-cholesterol acyltransferase (Thr347-->Met). J. Clin. Invest. 89, 499–506 (1992).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Schjoldager, K. T. et al. O-Glycosylation modulates proprotein convertase activation of angiopoietin-like protein 3: possible role of polypeptide GalNAc-transferase-2 in regulation of concentrations of plasma lipids. J. Biol. Chem. 285, 36293–36303 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Holleboom, A. G. et al. Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man. Cell Metab. 14, 811–818 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Kathiresan, S. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56–65 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Willer, C. J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161–169 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Brown, M. L. et al. Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins. Nature 342, 448–451 (1989).

    Article  CAS  PubMed  Google Scholar 

  33. Arai, Y. et al. Deficiency of choresteryl ester transfer protein and gene polymorphisms of lipoprotein lipase and hepatic lipase are not associated with longevity. J. Mol. Med. (Berl.) 81, 102–109 (2003).

    Article  CAS  Google Scholar 

  34. Yokoyama, S. Unique features of high-density lipoproteins in the Japanese: in population and in genetic factors. Nutrients 7, 2359–2381 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Nomura, A. et al. Protein truncating variants at the cholesteryl ester transfer protein gene and risk for coronary heart disease. Circ. Res. 121, 81–88 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Moennig, G. et al. Detection of missense mutations in the genes for lipoprotein lipase and hepatic triglyceride lipase in patients with dyslipidemia undergoing coronary angiography. Atherosclerosis 149, 395–401 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Hegele, R. A. et al. Hepatic lipase deficiency. Clinical, biochemical, and molecular genetic characteristics. Arterioscler. Thromb. 13, 720–728 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Acton, S. et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271, 518–520 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Vergeer, M. et al. Genetic variant of the scavenger receptor BI in humans. N. Engl. J. Med. 364, 136–145 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Hegele, R. A. et al. Targeted next-generation sequencing in monogenic dyslipidemias. Curr. Opin. Lipidol. 26, 103–113 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Cohen, J. C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Sadananda, S. N. et al. Targeted next-generation sequencing to diagnose disorders of HDL cholesterol. J. Lipid Res. 56, 1993–2001 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Hegele, R. A. SNP judgments and freedom of association. Arterioscler. Thromb. Vasc. Biol. 22, 1058–1061 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013).

  46. Dron, J. S. & Hegele, R. A. Genetics of lipid and lipoprotein disorders and traits. Curr. Genet. Med. Rep. 4, 130–141 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Smith, G. D. & Ebrahim, S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol. 32, 1–22 (2003).

    Article  PubMed  Google Scholar 

  48. Roberts, R. Genetics of coronary artery disease. Circ. Res. 114, 1890–1903 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. C Reactive Protein Coronary Heart Disease Genetics Collaboration et al. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 342, d548 (2011).

  51. Haase, C. L. et al. 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 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Johannsen, T. H. et al. Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease. J. Clin. Endocrinol. Metab. 94, 1264–1273 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Johannsen, T. H., Frikke-Schmidt, R., Schou, J., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. J. Am. Coll. Cardiol. 60, 2041–2048 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Kathiresan, S. Will cholesteryl ester transfer protein inhibition succeed primarily by lowering low-density lipoprotein cholesterol? Insights from human genetics and clinical trials. J. Am. Coll. Cardiol. 60, 2049–2052 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Barter, P. et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N. Engl. J. Med. 357, 1301–1310 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Lincoff, A. M. et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N. Engl. J. Med. 376, 1933–1942 (2017).

    Article  PubMed  Google Scholar 

  58. Rosenson, R. S. & Koenig, W. Mendelian randomization analyses for selection of therapeutic targets for cardiovascular disease prevention: a note of circumspection. Cardiovasc. Drugs Ther. 30, 65–74 (2016).

    Article  PubMed  Google Scholar 

  59. Brunham, L. R. & Hayden, M. R. Human genetics of HDL: insight into particle metabolism and function. Prog. Lipid Res. 58, 14–25 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Rosenson, R. S., Davidson, M. H., Hirsh, B. J., Kathiresan, S. & Gaudet, D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J. Am. Coll. Cardiol. 64, 2525–2540 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Arca, M., Minicocci, I. & Maranghi, M. The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism. Curr. Opin. Lipidol. 24, 313–320 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Musunuru, K. et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N. Engl. J. Med. 363, 2220–2227 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Albers, J. J., Vuletic, S. & Cheung, M. C. Role of plasma phospholipid transfer protein in lipid and lipoprotein metabolism. Biochim. Biophys. Acta 1821, 345–357 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Thompson, A. et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. J. Am. Med. Assoc. 299, 2777–2788 (2008).

    Article  CAS  Google Scholar 

  65. Cenarro, A. et al. Genetic variation in the hepatic lipase gene is associated with combined hyperlipidemia, plasma lipid concentrations, and lipid-lowering drug response. Am. Heart J. 150, 1154–1162 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Vergeer, M. et al. Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility. Circulation 122, 470–477 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Ji, A., Wroblewski, J. M., Webb, N. R. & van der Westhuyzen, D. R. Impact of phospholipid transfer protein on nascent high-density lipoprotein formation and remodeling. Arterioscler. Thromb. Vasc. Biol. 34, 1910–1916 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Kim, D. S. et al. PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity. J. Lipid Res. 56, 1351–1362 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Kim, D. S. et al. Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project. J. Lipid Res. 55, 1173–1178 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Beekman, M. et al. Heritabilities of apolipoprotein and lipid levels in three countries. Twin Res. 5, 87–97 (2002).

    Article  PubMed  Google Scholar 

  71. Lusis, A. J. & Weiss, J. N. Cardiovascular networks: systems-based approaches to cardiovascular disease. Circulation 121, 157–170 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Franzen, O. et al. Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases. Science 353, 827–830 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Schadt, E. E. & Bjorkegren, J. L. NEW: network-enabled wisdom in biology, medicine, and health care. Sci. Transl Med. 4, 115rv1 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Schadt, E. E. Molecular networks as sensors and drivers of common human diseases. Nature 461, 218–223 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Leduc, M. S. et al. Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ x SM/J intercross. J. Lipid Res. 53, 1163–1175 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Langfelder, P. et al. A systems genetic analysis of high density lipoprotein metabolism and network preservation across mouse models. Biochim. Biophys. Acta 1821, 435–447 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Foroughi Asl, H. et al. Expression quantitative trait Loci acting across multiple tissues are enriched in inherited risk for coronary artery disease. Circ. Cardiovasc. Genet. 8, 305–315 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Talukdar, H. A. et al. Cross-tissue regulatory gene networks in coronary artery disease. Cell Syst. 2, 196–208 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Wang, S., Guo, X., Wang, W. & Wang, S. Genome-wide study identifies the regulatory gene networks and signaling pathways from chondrocyte and peripheral blood monocyte of Kashin-Beck disease. Genes Cells 17, 619–632 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Zhu, J., Jambhekar, A., Sarver, A. & DeRisi, J. A. Bayesian network driven approach to model the transcriptional response to nitric oxide in Saccharomyces cerevisiae. PLoS ONE 1, e94 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Tardif, J. C. et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ. Cardiovasc. Genet. 8, 372–382 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Tardif, J. C. et al. Genotype-dependent effects of dalcetrapib on cholesterol efflux and inflammation: concordance with clinical outcomes. Circ. Cardiovasc. Genet. 9, 340–348 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02525939 (2017).

  86. Aslibekyan, S., Straka, R. J., Irvin, M. R., Claas, S. A. & Arnett, D. K. Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies. Expert Rev. Cardiovasc. Ther. 11, 355–364 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Gao, F. et al. Rare LPL gene variants attenuate triglyceride reduction and HDL cholesterol increase in response to fenofibric acid therapy in individuals with mixed dyslipidemia. Atherosclerosis 234, 249–253 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Boden, W. E. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. HPS-2 THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371, 203–212 (2014).

  90. Barter, P. J. et al. ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Schwartz, G. G. et al. dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Orsoni, A. et al. Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia. J. Lipid Res. 57, 2073–2087 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Singaraja, R. R. et al. Increased ABCA1 activity protects against atherosclerosis. J. Clin. Invest. 110, 35–42 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Basso, F. et al. Enhanced ABCG1 expression increases atherosclerosis in LDLr-KO mice on a western diet. Biochem. Biophys. Res. Commun. 351, 398–404 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Burgess, B. et al. Overexpression of human ABCG1 does not affect atherosclerosis in fat-fed ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 28, 1731–1737 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Tarling, E. J. et al. Impaired development of atherosclerosis in Abcg1−/− Apoe−/− mice: identification of specific oxysterols that both accumulate in Abcg1−/− Apoe−/− tissues and induce apoptosis. Arterioscler. Thromb. Vasc. Biol. 30, 1174–1180 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Plump, A. S., Scott, C. J. & Breslow, J. L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc. Natl Acad. Sci. USA 91, 9607–9611 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rubin, E. M., Krauss, R. M., Spangler, E. A., Verstuyft, J. G. & Clift, S. M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature 353, 265–267 (1991).

    Article  CAS  PubMed  Google Scholar 

  99. Liu, A. C., Lawn, R. M., Verstuyft, J. G. & Rubin, E. M. Human apolipoprotein A-I prevents atherosclerosis associated with apolipoprotein[a] in transgenic mice. J. Lipid Res. 35, 2263–2267 (1994).

    CAS  PubMed  Google Scholar 

  100. Duverger, N. et al. Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. Circulation 94, 713–717 (1996).

    Article  CAS  PubMed  Google Scholar 

  101. Parolini, C. et al. Apolipoprotein A-I and the molecular variant apoA-I(Milano): evaluation of the antiatherogenic effects in knock-in mouse model. Atherosclerosis 183, 222–229 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Wang, L. et al. Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice. J. Am. Coll. Cardiol. 48, 1459–1468 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Lebherz, C., Sanmiguel, J., Wilson, J. M. & Rader, D. J. Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent. Cardiovasc. Diabetol. 6, 15 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Warden, C. H., Hedrick, C. C., Qiao, J. H., Castellani, L. W. & Lusis, A. J. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science 261, 469–472 (1993).

    Article  CAS  PubMed  Google Scholar 

  105. Escola-Gil, J. C. et al. Human apolipoprotein A-II is a pro-atherogenic molecule when it is expressed in transgenic mice at a level similar to that in humans: evidence of a potentially relevant species-specific interaction with diet. J. Lipid Res. 39, 457–462 (1998).

    CAS  PubMed  Google Scholar 

  106. Tailleux, A. et al. Decreased susceptibility to diet-induced atherosclerosis in human apolipoprotein A-II transgenic mice. Arterioscler. Thromb. Vasc. Biol. 20, 2453–2458 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Marotti, K. R. et al. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 364, 73–75 (1993).

    Article  CAS  PubMed  Google Scholar 

  108. Plump, A. S. et al. Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler. Thromb. Vasc. Biol. 19, 1105–1110 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Westerterp, M. et al. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice. Arterioscler. Thromb. Vasc. Biol. 26, 2552–2559 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Hildebrand, R. B. et al. Restoration of high-density lipoprotein levels by cholesteryl ester transfer protein expression in scavenger receptor class B type I (SR-BI) knockout mice does not normalize pathologies associated with SR-BI deficiency. Arterioscler. Thromb. Vasc. Biol. 30, 1439–1445 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. MacLean, P. S. et al. Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice. Arterioscler. Thromb. Vasc. Biol. 23, 1412–1415 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Foger, B. et al. Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J. Biol. Chem. 274, 36912–36920 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Cazita, P. M. et al. Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice. J. Lipid Res. 44, 33–40 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Casquero, A. C. et al. Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice. J. Lipid Res. 47, 1526–1534 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Hayek, T. et al. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J. Clin. Invest. 96, 2071–2074 (1995).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Herrera, V. L. et al. Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nat. Med. 5, 1383–1389 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Sugano, M. et al. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J. Biol. Chem. 273, 5033–5036 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Rittershaus, C. W. et al. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 20, 2106–2112 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Morehouse, L. A. et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J. Lipid Res. 48, 1263–1272 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Okamoto, H. et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 406, 203–207 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Ishida, T. et al. Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice. J. Biol. Chem. 279, 45085–45092 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Ko, K. W., Paul, A., Ma, K., Li, L. & Chan, L. Endothelial lipase modulates HDL but has no effect on atherosclerosis development in apoE−/− and LDLR−/− mice. J. Lipid Res. 46, 2586–2594 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Gonzalez-Navarro, H. et al. The ligand-binding function of hepatic lipase modulates the development of atherosclerosis in transgenic mice. J. Biol. Chem. 279, 45312–45321 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Mezdour, H., Jones, R., Dengremont, C., Castro, G. & Maeda, N. Hepatic lipase deficiency increases plasma cholesterol but reduces susceptibility to atherosclerosis in apolipoprotein E-deficient mice. J. Biol. Chem. 272, 13570–13575 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Nong, Z. et al. Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice. J. Clin. Invest. 112, 367–378 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Jiang, X. C. et al. Apolipoprotein B secretion and atherosclerosis are decreased in mice with phospholipid-transfer protein deficiency. Nat. Med. 7, 847–852 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Yang, X. P. et al. Increased atherosclerotic lesions in apoE mice with plasma phospholipid transfer protein overexpression. Arterioscler. Thromb. Vasc. Biol. 23, 1601–1607 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Valenta, D. T. et al. Atheroprotective potential of macrophage-derived phospholipid transfer protein in low-density lipoprotein receptor-deficient mice is overcome by apolipoprotein AI overexpression. Arterioscler. Thromb. Vasc. Biol. 26, 1572–1578 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Covey, S. D., Krieger, M., Wang, W., Penman, M. & Trigatti, B. L. Scavenger receptor class B type I-mediated protection against atherosclerosis in LDL receptor-negative mice involves its expression in bone marrow-derived cells. Arterioscler. Thromb. Vasc. Biol. 23, 1589–1594 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Huszar, D. et al. Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. Arterioscler. Thromb. Vasc. Biol. 20, 1068–1073 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Arai, T., Wang, N., Bezouevski, M., Welch, C. & Tall, A. R. Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene. J. Biol. Chem. 274, 2366–2371 (1999).

    Article  CAS  PubMed  Google Scholar 

  132. Santos, R. D. et al. Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states. J. Clin. Lipidol. 2, 237–247 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Yamashita, S., Hirano, K., Sakai, N. & Matsuzawa, Y. Molecular biology and pathophysiological aspects of plasma cholesteryl ester transfer protein. Biochim. Biophys. Acta 1529, 257–275 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Wu, Z. et al. 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 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge the contributions of Qinzhong Chen (Icahn School of Medicine at Mount Sinai, USA), who assisted with manuscript preparation.

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Authors and Affiliations

  1. Cardiometabolics Unit, Icahn School of Medicine at Mount Sinai, Hospital Box 1030, One Gustave L. Levy Place, New York, 10029, New York, USA

    Robert S. Rosenson

  2. Medstar Heart and Vascular Institute, Washington Hospital Center, 110 Irving Street NW, 20010, Washington, DC, USA

    H. Bryan Brewer Jr

  3. School of Medical Sciences, Faculty of Medicine, Level 4E, Wallace Wurth Building, University of New South Wales Sydney, 18 High Street, Sydney, 2052, Kensington New South Wales, Australia

    Philip J. Barter & Kerry-Anne Rye

  4. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029, New York, USA

    Johan L. M. Björkegren

  5. Department of Medicine, Integrated Cardio Metabolic Centre, Karolinska Institutet, Karolinska Universitetssjukhuset, 171 77, Huddinge, Sweden

    Johan L. M. Björkegren

  6. National Institute for Health and Medical Research (INSERM) and Endocrinology Metabolism Service, Pitie-Salpetriere University Hospital, 83 Boulevard de l'Hôpital, Paris, 75651, France

    M. John Chapman

  7. Department of Medicine, Lipidology Unit, Community Genomic Medicine Centre and ECOGENE-21, Université de Montréal, 930 Jacques-Cartier, Saguenay, G7H 7K9, Québec, Canada

    Daniel Gaudet

  8. University of Michigan School of Public Health, M4045 SPH II, 1415 Washington Heights, Ann Arbor, 48109–2029, Michigan, USA

    Daniel Seung Kim

  9. Hartis-Pharma Sàrl, 13c Chemin de Bonmont, 1260, Nyon, Switzerland

    Eric Niesor

  10. Nutrition Department, Harvard T. H. Chan School of Public Health, 665 Huntington Avenue, Boston, 02478, Massachusetts, USA

    Frank M. Sacks

  11. Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montréal, H1T 1C8, Québec, Canada

    Jean-Claude Tardif

  12. Department of Medicine and Robarts Research Institute, Western University, 4288A-1151 Richmond Street North, London, N6A 5B7, Ontario, Canada

    Robert A. Hegele

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Contributions

All authors researched data for the article, provided substantial contributions to discussions of its content, wrote the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Robert S. Rosenson.

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Competing interests

R.S.R. has received payment for consulting fees from Akcea, Amgen, CVS Caremark, Eli Lilly, Regeneron, and Sanofi; for speaker fees from Kowa; for grants or research support from Akcea, Amgen, Eli Lilly, Esperion, Regeneron, and The Medicines Company; and for royalties from UpToDate. H.B.B. Jr has received payment for consulting fees from AstraZeneca, Eli Lilly, InfraReDx, Merck, Pfizer, Roche, and Sanofi; for speaker fees or honoraria from AstraZeneca, Eli Lilly, InfraReDx, Merck, Roche, and Sanofi; and owns stock and/or has directorship roles in HDL Therapeutics and InfraReDx. P.J.B. has received payment for honoraria from Amgen, AstraZeneca, Merck, Pfizer, and Sanofi–Regeneron; for research grants from Merck and Pfizer; and is a member of the Advisory Boards of Amgen, Merck, and Pfizer. F.M.S. has received payment for consulting fees from AstraZeneca, MedImmune, Moderna, and Pfizer; for expert testimony from Aegerion and Pfizer; and is the inventor in a US patent on the use of apolipoprotein C-III, and is a Harvard University patent holder. J.-C.T. has received payment for consulting fees from DalCor, Pfizer, Sanofi, and Servier; for grants or research support from Amarin, AstraZeneca, DalCor, EliLilly, Esperion, Merck, Pfizer, Roche, Sanofi, and Servier; owns stock in DalCor; and has a patent on pharmacogenomic markers of response to dalcetrapib. The other authors declare no competing interests.

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Glossary

Reverse cholesterol transport

Process of overall flux of cholesterol from the entire periphery to the liver, and its ultimate faecal excretion.

Probands

Term used in medical genetics that refers to the first person who is identified with a genetic disorder.

Lipoprotein-X

A lamellar particle found in the LDL density range that is formed in cholestasis.

Remnant particles

Remnant particles or remnant-like lipoproteins are formed from the metabolism of chylomicron and VLDL particles, which are the major triglyceride-containing lipoproteins.

Linkage disequilibrium

Nonrandom association of alleles at different loci in a specific population.

Pleiotropy

Genes that affect multiple, apparently unrelated phenotypes.

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Rosenson, R., Brewer, H., Barter, P. et al. HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology. Nat Rev Cardiol 15, 9–19 (2018). https://doi.org/10.1038/nrcardio.2017.115

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