Triglyceride-rich lipoproteins and coronary artery disease risk: New insights from human genetics

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 35, Issue 2, 2015, Pages e3-e9

  Khetarpal, Sumeet A ^a   Rader, Daniel J ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

apolipoprotein AV human; apolipoprotein C III; coronary artery disease; exome; myocardial infarction; triglycerides

Indexed keywords

APOLIPOPROTEIN C3; LIPOPROTEIN; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; TRIACYLGLYCEROL; VERY LOW DENSITY LIPOPROTEIN; ANTILIPEMIC AGENT; APOA5 PROTEIN, HUMAN; APOLIPOPROTEIN A; BIOLOGICAL MARKER; LIPOPROTEIN LIPASE; LPL PROTEIN, HUMAN;

APOA5 GENE; APOC3 GENE; CORONARY ARTERY DISEASE; GENE; GENE LOCUS; GENE MUTATION; GENE SEQUENCE; GENETIC ASSOCIATION; GENETIC VARIABILITY; HUMAN; LPL GENE; PRIORITY JOURNAL; REVIEW; RISK FACTOR; RISK REDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; ANIMAL; BLOOD; DRUG DESIGN; GENETIC PREDISPOSITION; GENETICS; MOLECULARLY TARGETED THERAPY; MUTATION; PHENOTYPE; UPREGULATION;

ANIMALS; APOLIPOPROTEIN C-III; APOLIPOPROTEINS A; BIOLOGICAL MARKERS; CORONARY ARTERY DISEASE; DRUG DESIGN; GENETIC PREDISPOSITION TO DISEASE; HUMANS; HYPOLIPIDEMIC AGENTS; LIPOPROTEIN LIPASE; LIPOPROTEINS; MOLECULAR TARGETED THERAPY; MUTATION; PHENOTYPE; RISK FACTORS; TRIGLYCERIDES; UP-REGULATION;

EID: 84921963597     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.114.305172     Document Type: Review

References (74)

1. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. doi: 10.1056/NEJMoa040583.
2. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435. doi: 10.1056/NEJMoa050461.
3. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-2445. doi: 10.1001/ jama.294.19.2437.
4. Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep. 2012;14:1-10. doi: 10.1007/s11883-011-0219-7.
5. Staniak HL, Salgado Filho W, Miname MH, Benseñor IM, Lotufo PA, Sharovsky R, Rochitte CE, Bittencourt MS, Santos RD. Association between postprandial triglycerides and coronary artery disease detected by coronary computed tomography angiography. Atherosclerosis. 2014;233:381-386. doi: 10.1016/j.atherosclerosis.2013.12.036.
6. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299-308. doi: 10.1001/ jama.298.3.299.
7. Langsted A, Freiberg JJ, Tybjaerg-Hansen A, Schnohr P, Jensen GB, Nordestgaard BG. Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med. 2011;270:65-75 doi: 10.1111/j.1365-2796.2010.02333.x.
8. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298:309-316. doi: 10.1001/jama.298.3.309.
9. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213-219.
10. Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E; PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724-730. doi: 10.1016/j. jacc.2007.10.038.
11. Kohli P, Cannon CP. Triglycerides: how much credit do they deserve? Med Clin North Am. 2012;96:39-55. doi: 10.1016/j.mcna.2011.11.006.
12. Janssens AC, van Duijn CM. Genome-based prediction of common diseases: advances and prospects. Hum Mol Genet. 2008;17(R2):R166-R173. doi: 10.1093/hmg/ddn250.
13. Kathiresan S, Srivastava D. Genetics of human cardiovascular disease. Cell. 2012;148:1242-1257. doi: 10.1016/j.cell.2012.03.001.
14. Shin SY, Petersen AK, Wahl S, et al. Interrogating causal pathways linking genetic variants, small molecule metabolites, and circulating lipids. Genome Med. 2014;6:25. doi: 10.1186/gm542.
15. Jansen H, Samani NJ, Schunkert H. Mendelian randomization studies in coronary artery disease. Eur Heart J. 2014;35:1917-1924. doi: 10.1093/ eurheartj/ehu208.
16. Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, Kahn J, Afonso L, Williams KA Sr, Flack JM. 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. doi: 10.1016/j. jacc.2012.09.017.
17. Holmes MV, Dale CE, Zuccolo L, et al; InterAct Consortium. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ. 2014;349:g4164.
18. 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. doi: 10.1016/S0140-6736(12)60312-2.
19. Rip J, Nierman MC, Ross CJ, Jukema JW, Hayden MR, Kastelein JJ, Stroes ES, Kuivenhoven JA. Lipoprotein lipase S447X: a naturally occurring gain-of-function mutation. Arterioscler Thromb Vasc Biol. 2006;26:1236-1245. doi: 10.1161/01.ATV.0000219283.10832.43.
20. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Response: lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease: a note on Mendelian randomization studies. J Am Coll Cardiol. 2013;62:1908-1909. doi: 10.1016/j.jacc.2013.08.1615.
21. Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. Circulation. 1999;99:2901-2907.
22. Humphries SE, Nicaud V, Margalef J, Tiret L, Talmud PJ. Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS). Arterioscler Thromb Vasc Biol. 1998;18:526-534.
23. Henderson HE, Kastelein JJ, Zwinderman AH, Gagné E, Jukema JW, Reymer PW, Groenemeyer BE, Lie KI, Bruschke AV, Hayden MR, Jansen H. Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins. J Lipid Res. 1999;40:735-743.
24. Gagné SE, Larson MG, Pimstone SN, Schaefer EJ, Kastelein JJ, Wilson PW, Ordovas JM, Hayden MR. A common truncation variant of lipoprotein lipase (Ser447X) confers protection against coronary heart disease: the Framingham Offspring Study. Clin Genet. 1999;55:450-454.
25. Groenemeijer BE, Hallman MD, Reymer PW, Gagné E, Kuivenhoven JA, Bruin T, Jansen H, Lie KI, Bruschke AV, Boerwinkle E, Hayden MR, Kastelein JJ. Genetic variant showing a positive interaction with beta-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients. The Ser447-stop substitution in the lipoprotein lipase gene. REGRESS Study Group. Circulation. 1997;95:2628-2635.
26. Reymer PW, Gagné E, Groenemeyer BE, Zhang H, Forsyth I, Jansen H, Seidell JC, Kromhout D, Lie KE, Kastelein J. A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis. Nat Genet. 1995;10:28-34. doi: 10.1038/ ng0595-28.
27. Lettre G, Palmer CD, Young T, et al. Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe project. PLoS Genet. 2011;7:e1001300. doi: 10.1371/ journal.pgen.1001300.
28. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707-713.
29. Waterworth DM, Ricketts SL, Song K, et al; Wellcome Trust Case Control Consortium. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol. 2010;30:2264-2276. doi: 10.1161/ATVBAHA.109.201020.
30. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345-1352. doi: 10.1038/ng.2795.
31. Ooi EM, Barrett PH, Chan DC, Watts GF. Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. Clin Sci (Lond). 2008;114:611-624. doi: 10.1042/CS20070308.
32. Sundaram M, Yao Z. Intrahepatic role of exchangeable apolipoproteins in lipoprotein assembly and secretion. Arterioscler Thromb Vasc Biol. 2012;32:1073-1078. doi: 10.1161/ATVBAHA.111.241455.
33. Eisenberg S, Patsch JR, Sparrow JT, Gotto AM, Olivecrona T. Very low density lipoprotein. Removal of apolipoproteins C-II and C-III-1 during lipolysis in vitro. J Biol Chem. 1979;254:12603-12608.
34. Aalto-Setälä K, Fisher EA, Chen X, Chajek-Shaul T, Hayek T, Zechner R, Walsh A, Ramakrishnan R, Ginsberg HN, Breslow JL. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Invest. 1992;90:1889-1900. doi: 10.1172/JCI116066.
35. Aalto-Setälä K, Weinstock PH, Bisgaier CL, Wu L, Smith JD, Breslow JL. Further characterization of the metabolic properties of triglyceriderich lipoproteins from human and mouse apoC-III transgenic mice. J Lipid Res. 1996;37:1802-1811.
36. Gerritsen G, Rensen PC, Kypreos KE, Zannis VI, Havekes LM, Willems van Dijk K. ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression. J Lipid Res. 2005;46:1466-1473. doi: 10.1194/jlr. M400479-JLR200.
37. Jong MC, Rensen PC, Dahlmans VE, van der Boom H, van Berkel TJ, Havekes LM. Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice. J Lipid Res. 2001;42:1578-1585.
38. Qin W, Sundaram M, Wang Y, et al. Missense mutation in apoc3 within the c-terminal lipid binding domain of human apoc-iii results in impaired assembly and secretion of triacylglycerol-rich very low density lipoproteins: evidence that apoc-iii plays a major role in the formation of lipid precursors within the microsomal lumen. J Biol Chem. 2011;286:27769-27780.
39. Sharma V, Forte TM, Ryan RO. Influence of apolipoprotein A-V on the metabolic fate of triacylglycerol. Curr Opin Lipidol. 2013;24:153-159. doi: 10.1097/MOL.0b013e32835c8c1a.
40. Pennacchio LA, Olivier M, Hubacek JA, Cohen JC, Cox DR, Fruchart JC, Krauss RM, Rubin EM. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001;294:169-173. doi: 10.1126/science.1064852.
41. The TG and HDL Working Group of the Exome Sequencing Project, NHLBI. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22-31.
42. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32-41. doi: 10.1056/NEJMoa1308027.
43. Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB, Post W, McLenithan JC, Bielak LF, Peyser PA, Mitchell BD, Miller M, O'Connell JR, Shuldiner AR. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322:1702-1705. doi: 10.1126/science.1161524.
44. Cohen JC, Stender S, Hobbs HH. Apoc3, coronary disease, and complexities of Mendelian randomization. Cell Metab. 2014;20:387-389.
45. Mendivil CO, Rimm EB, Furtado J, Chiuve SE, Sacks FM. Lowdensity lipoproteins containing apolipoprotein C-III and the risk of coronary heart disease. Circulation. 2011;124:2065-2072. doi: 10.1161/ CIRCULATIONAHA.111.056986.
46. Shin MJ, Krauss RM. Apolipoprotein CIII bound to apoB-containing lipoproteins is associated with small, dense LDL independent of plasma triglyceride levels in healthy men. Atherosclerosis. 2010;211:337-341. doi: 10.1016/j.atherosclerosis.2010.02.025.
47. Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. J Lipid Res. 2011;52:189-206. doi: 10.1194/jlr.R009720.
48. Johansen CT, Wang J, Lanktree MB, et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet. 2010;42:684-687. doi: 10.1038/ng.628.
49. Tang Y, Sun P, Guo D, Ferro A, Ji Y, Chen Q, Fan L. A genetic variant c.553G T in the apolipoprotein A5 gene is associated with an increased risk of coronary artery disease and altered triglyceride levels in a Chinese population. Atherosclerosis. 2006;185:433-437. doi: 10.1016/j. atherosclerosis.2005.06.026.
50. Soufi M, Sattler AM, Kurt B, Schaefer JR. Mutation screening of the APOA5 gene in subjects with coronary artery disease. J Investig Med. 2012;60:1015-1019. doi: 10.231/JIM.0b013e3182686918.
51. Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare ldlr and apoa5 alleles conferring risk for myocardial infarction [published online ahead of print December 10, 2014]. Nature. doi: 10.1038/nature13917. http:// www.nature.com/nature/journal/vaop/ncurrent/full/nature13917.html.
52. Li B, Leal SM. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet. 2008;83:311-321. doi: 10.1016/j.ajhg.2008.06.024.
53. Purcell SM, Moran JL, Fromer M, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185-190. doi: 10.1038/ nature12975.
54. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973;52:1544-1568. doi: 10.1172/JCI107332.
55. Hazzard WR, Goldstein JL, Schrott MG, Motulsky AG, Bierman EL. Hyperlipidemia in coronary heart disease. 3 Evaluation of lipoprotein phenotypes of 156 genetically defined survivors of myocardial infarction. J Clin Invest. 1973;52:1569-1577. doi: 10.1172/JCI107333.
56. Graham MJ, Lee RG, Bell TA 3rd, Fu W, Mullick AE, Alexander VJ, Singleton W, Viney N, Geary R, Su J, Baker BF, Burkey J, Crooke ST, Crooke RM. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112:1479-1490. doi: 10.1161/CIRCRESAHA.111.300367.
57. Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, Geary RS, Baker BF, Graham MJ, Crooke RM, Witztum JL. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200-2206. doi: 10.1056/NEJMoa1400284.
58. Liu H, Labeur C, Xu CF, Ferrell R, Lins L, Brasseur R, Rosseneu M, Weiss KM, Humphries SE, Talmud PJ. Characterization of the lipid-binding properties and lipoprotein lipase inhibition of a novel apolipoprotein C-III variant Ala23Thr. J Lipid Res. 2000;41:1760-1771.
59. Beckstead JA, Wong K, Gupta V, Wan CP, Cook VR, Weinberg RB, Weers PM, Ryan RO. The C terminus of apolipoprotein A-V modulates lipidbinding activity. J Biol Chem. 2007;282:15484-15489. doi: 10.1074/jbc. M611797200.
60. Sharma V, Witkowski A, Witkowska HE, Dykstra A, Simonsen JB, Nelbach L, Beckstead JA, Pullinger CR, Kane JP, Malloy MJ, Watson G, Forte TM, Ryan RO. Aberrant hetero-disulfide bond formation by the hypertriglyceridemia-associated p.Gly185Cys APOA5 variant (rs2075291). Arterioscler Thromb Vasc Biol. 2014;34:2254-2260. doi: 10.1161/ATVBAHA.114.304027.
61. Kersten S. Physiological regulation of lipoprotein lipase. Biochim Biophys Acta. 2014;1841:919-933. doi: 10.1016/j.bbalip.2014.03.013.
62. Lee EC, Desai U, Gololobov G, et al. Identification of a new functional domain in angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) involved in binding and inhibition of lipoprotein lipase (LPL). J Biol Chem. 2009;284:13735-13745. doi: 10.1074/jbc.M807899200.
63. Yau MH, Wang Y, Lam KS, Zhang J, Wu D, Xu A. A highly conserved motif within the NH2-terminal coiled-coil domain of angiopoietin-like protein 4 confers its inhibitory effects on lipoprotein lipase by disrupting the enzyme dimerization. J Biol Chem. 2009;284:11942-11952. doi: 10.1074/jbc.M809802200.
64. Larsson M, Vorrsjö E, Talmud P, Lookene A, Olivecrona G. Apolipoproteins C-I and C-III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets. J Biol Chem. 2013;288:33997-34008. doi: 10.1074/jbc.M113.495366.
65. Yin W, Romeo S, Chang S, Grishin NV, Hobbs HH, Cohen JC. Genetic variation in ANGPTL4 provides insights into protein processing and function. J Biol Chem. 2009;284:13213-13222. doi: 10.1074/jbc.M900553200.
66. Miida T, Hirayama S. Impacts of angiopoietin-like proteins on lipoprotein metabolism and cardiovascular events. Curr Opin Lipidol. 2010;21:70-75. doi: 10.1097/MOL.0b013e328333269e.
67. Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH, Cohen JC. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest. 2009;119:70-79. doi: 10.1172/JCI37118.
68. Willer CJ, Schmidt EM, et al; Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nature Genet. 2013;45:1274-1283.
69. Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363:2220-2227. doi: 10.1056/NEJMoa1002926.
70. Romeo S, Pennacchio LA, Fu Y, Boerwinkle E, Tybjaerg-Hansen A, Hobbs HH, Cohen JC. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet. 2007;39:513-516. doi: 10.1038/ng1984.
71. Talmud PJ, Smart M, Presswood E, Cooper JA, Nicaud V, Drenos F, Palmen J, Marmot MG, Boekholdt SM, Wareham NJ, Khaw KT, Kumari M, Humphries SE; EARSII Consortium; HIFMECH Consortium. ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk. Arterioscler Thromb Vasc Biol. 2008;28:2319-2325. doi: 10.1161/ATVBAHA.108.176917.
72. Hatsuda S, Shoji T, Shinohara K, Kimoto E, Mori K, Fukumoto S, Koyama H, Emoto M, Nishizawa Y. Association between plasma angiopoietin-like protein 3 and arterial wall thickness in healthy subjects. J Vasc Res. 2007;44:61-66. doi: 10.1159/000098153.
73. Korstanje R, Eriksson P, Samnegård A, Olsson PG, Forsman-Semb K, Sen S, Churchill GA, Rollins J, Harris S, Hamsten A, Paigen B. Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans. Atherosclerosis. 2004;177:443-450. doi: 10.1016/j.atherosclerosis.2004.08.006.
74. Folsom AR, Peacock JM, Demerath E, Boerwinkle E. Variation in ANGPTL4 and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Metabolism. 2008;57:1591-1596. doi: 10.1016/j. metabol.2008.06.016.