Atherosclerosis
Volume 210, Issue 1 , Pages 14-27 , May 2010

The potential influence of genetic variants in genes along bile acid and bile metabolic pathway on blood cholesterol levels in the population

  • Yingchang Lu

      Affiliations

    • Division of Human Nutrition, Wageningen University and Research Center, PO Box 8129, 6700 EV Wageningen, The Netherlands
    • National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands
    • Corresponding Author InformationCorresponding author at: Division of Human Nutrition, Wageningen University and Research Center, PO Box 8129, 6700 EV Wageningen, The Netherlands. Tel.: +31 317 485300; fax: +31 317 482782.
  • ,
  • Edith J.M. Feskens

      Affiliations

    • Division of Human Nutrition, Wageningen University and Research Center, PO Box 8129, 6700 EV Wageningen, The Netherlands
  • ,
  • Jolanda M.A. Boer

      Affiliations

    • National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands
  • ,
  • Michael Müller

      Affiliations

    • Division of Human Nutrition, Wageningen University and Research Center, PO Box 8129, 6700 EV Wageningen, The Netherlands
    • Corresponding Author InformationCorresponding author. Tel.: +31 317 482590; fax: +31 317 483342.

Received 7 July 2009 ,Revised 22 October 2009 ,Accepted 26 October 2009.

References 

  1. Kruit JK, Plosch T, Havinga R, et al. Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. Gastroenterology. 2005;128:147–156
  2. van der Velde AE, Vrins CL, van den Oever K, et al. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice. Gastroenterology. 2007;133:967–975
  3. Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annual Review of Cell and Developmental Biology. 2000;16:459–481
  4. Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. The Journal of Clinical Investigation. 2006;116:3090–3100
  5. Lewis GF. Determinants of plasma HDL concentrations and reverse cholesterol transport. Current Opinion in Cardiology. 2006;21:345–352
  6. Pullinger CR, Eng C, Salen G, et al. Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. The Journal of Clinical Investigation. 2002;110:109–117
  7. Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. The Journal of Clinical Investigation. 1974;53:1033–1043
  8. Bjorkhem K, Boberg K, Leitersdorf E. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In:  Scriver CR,  Beaudet AL,  Valle DS,  Sly W editor. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001;p. 2961–2988
  9. Hubacek JA, Berge KE, Cohen JC, Hobbs HH. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Human Mutation. 2001;18:359–360
  10. Oelkers P, Kirby LC, Heubi JE, Dawson PA. Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2). The Journal of Clinical Investigation. 1997;99:1880–1887
  11. Aulchenko YS, Ripatti S, Lindqvist I, et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nature Genetics. 2009;41:47–55
  12. Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nature Genetics. 2009;41:56–65
  13. Sabatti C, Service SK, Hartikainen AL, et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nature Genetics. 2009;41:35–46
  14. Cohen JC. Contribution of cholesterol 7alpha-hydroxylase to the regulation of lipoprotein metabolism. Current Opinion in Lipidology. 1999;10:303–307
  15. Wang J, Freeman DJ, Grundy SM, Levine DM, Guerra R, Cohen JC. Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. The Journal of Clinical Investigation. 1998;101:1283–1291
  16. Abrahamsson A, Krapivner S, Gustafsson U, et al. Common polymorphisms in the CYP7A1 gene do not contribute to variation in rates of bile acid synthesis and plasma LDL cholesterol concentration. Atherosclerosis. 2005;182:37–45
  17. Nakamoto K, Wang S, Jenison RD, et al. Linkage disequilibrium blocks, haplotype structure, and htSNPs of human CYP7A1 gene. BMC Genetics. 2006;7:29
  18. Couture P, Otvos JD, Cupples LA, Wilson PW, Schaefer EJ, Ordovas JM. Association of the A-204C polymorphism in the cholesterol 7alpha-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study. Journal of Lipid Research. 1999;40:1883–1889
  19. Hofman MK, Groenendijk M, Verkuijlen PJ, et al. Modulating effect of the A-278C promoter polymorphism in the cholesterol 7alpha-hydroxylase gene on serum lipid levels in normolipidaemic and hypertriglyceridaemic individuals. European Journal of Human Genetics. 2004;12:935–941
  20. Hofman MK, Princen HM, Zwinderman AH, Jukema JW. Genetic variation in the rate-limiting enzyme in cholesterol catabolism (cholesterol 7alpha-hydroxylase) influences the progression of atherosclerosis and risk of new clinical events. Clinical Science (London). 2005;108:539–545
  21. Hegele RA, Wang J, Harris SB, et al. Variable association between genetic variation in the CYP7 gene promoter and plasma lipoproteins in three Canadian populations. Atherosclerosis. 2001;154:579–587
  22. Han Z, Heath SC, Shmulewitz D, et al. Candidate genes involved in cardiovascular risk factors by a family-based association study on the island of Kosrae, Federated States of Micronesia. American Journal of Medical Genetics. 2002;110:234–242
  23. Klos KL, Sing CF, Boerwinkle E, et al. Consistent effects of genes involved in reverse cholesterol transport on plasma lipid and apolipoprotein levels in CARDIA participants. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1828–1836
  24. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. A promoter polymorphism in cholesterol 7alpha-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin. Atherosclerosis. 2005;180:407–415
  25. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin. Atherosclerosis. 2004;175:287–293
  26. Thompson JF, Hyde CL, Wood LS, et al. Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the treating to new targets (TNT). Cohort Circulation and Cardiovascular Genetics. 2009;2:173–181
  27. Hofman MK, Weggemans RM, Zock PL, Schouten EG, Katan MB, Princen HM. CYP7A1 A-278C polymorphism affects the response of plasma lipids after dietary cholesterol or cafestol interventions in humans. The Journal of Nutrition. 2004;134:2200–2204
  28. Kovar J, Suchanek P, Hubacek JA, Poledne R. The A-204C polymorphism in the cholesterol 7alpha-hydroxylase (CYP7A1) gene determines the cholesterolemia responsiveness to a high-fat diet. Physiological Research/Academia Scientiarum Bohemoslovaca. 2004;53:565–568
  29. Hubacek JA, Pitha J, Skodova Z, et al. Polymorphisms in CYP-7A1, not APOE, influence the change in plasma lipids in response to population dietary change in an 8 year follow-up; results from the Czech MONICA study. Clinical Biochemistry. 2003;36:263–267
  30. Molowa DT, Chen WS, Cimis GM, Tan CP. Transcriptional regulation of the human cholesterol 7 alpha-hydroxylase gene. Biochemistry. 1992;31:2539–2544
  31. Wang DP, Stroup D, Marrapodi M, Crestani M, Galli G, Chiang JY. Transcriptional regulation of the human cholesterol 7 alpha-hydroxylase gene (CYP7A) in HepG2 cells. Journal of Lipid Research. 1996;37:1831–1841
  32. Lenicek M, Komarek V, Zimolova M, et al. CYP7A1 promoter polymorphism −203A>C affects bile salt synthesis rate in patients after ileal resection. Journal of Lipid Research. 2008;49:2664–2667
  33. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annual Review of Biochemistry. 2003;72:137–174
  34. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiological Reviews. 2009;89:147–191
  35. Verrips A, Hoefsloot LH, Steenbergen GC, et al. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain. 2000;123(Pt 5):908–919
  36. Setchell KD, Schwarz M, O’Connell NC, et al. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease. The Journal of Clinical Investigation. 1998;102:1690–1703
  37. Goizet C, Boukhris A, Durr A, et al. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain. 2009;132:1589–1600
  38. Miettinen TA, Klett EL, Gylling H, Isoniemi H, Patel SB. Liver transplantation in a patient with sitosterolemia and cirrhosis. Gastroenterology. 2006;130:542–547
  39. Hazard SE, Patel SB. Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols. Pflugers Archiv. 2007;453:745–752
  40. Pandit B, Ahn GS, Hazard SE, Gordon D, Patel SB. A detailed Hapmap of the Sitosterolemia locus spanning 69kb; differences between Caucasians and African-Americans. BMC Medical Genetics. 2006;7:13
  41. Rudkowska I, Jones PJ. Polymorphisms in ABCG5/G8 transporters linked to hypercholesterolemia and gallstone disease. Nutrition Reviews. 2008;66:343–348
  42. Weggemans RM, Zock PL, Tai ES, Ordovas JM, Molhuizen HO, Katan MB. ATP binding cassette G5 C1950G polymorphism may affect blood cholesterol concentrations in humans. Clinical Genetics. 2002;62:226–229
  43. Viturro E, de Oya M, Lasuncion MA, et al. Cholesterol and saturated fat intake determine the effect of polymorphisms at ABCG5/ABCG8 genes on lipid levels in children. Genetics in Medicine. 2006;8:594–599
  44. Berge KE, von Bergmann K, Lutjohann D, et al. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8. Journal of Lipid Research. 2002;43:486–494
  45. Gylling H, Hallikainen M, Pihlajamaki J, et al. Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity. Journal of Lipid Research. 2004;45:1660–1665
  46. Hubacek JA, Berge KE, Stefkova J, et al. Polymorphisms in ABCG5 and ABCG8 transporters and plasma cholesterol levels. Physiological research/Academia Scientiarum Bohemoslovaca. 2004;53:395–401
  47. Junyent M, Tucker KL, Smith CE, et al. The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study. Journal of Lipid Research. 2009;50:565–573
  48. Santosa S, Demonty I, Lichtenstein AH, Ordovas JM, Jones PJ. Single nucleotide polymorphisms in ABCG5 and ABCG8 are associated with changes in cholesterol metabolism during weight loss. Journal of Lipid Research. 2007;48:2607–2613
  49. Acalovschi M, Ciocan A, Mostean O, et al. Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms? A preliminary study in siblings with gallstones. European Journal of Internal Medicine. 2006;17:490–494
  50. Plat J, Bragt MC, Mensink RP. Common sequence variations in ABCG8 are related to plant sterol metabolism in healthy volunteers. Journal of Lipid Research. 2005;46:68–75
  51. Herron KL, McGrane MM, Waters D, et al. The ABCG5 polymorphism contributes to individual responses to dietary cholesterol and carotenoids in eggs. The Journal of Nutrition. 2006;136:1161–1165
  52. Kajinami K, Brousseau ME, Nartsupha C, Ordovas JM, Schaefer EJ. ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin. Journal of Lipid Research. 2004;45:653–656
  53. Koeijvoets KC, van der Net JB, Dallinga-Thie GM, et al. ABCG8 gene polymorphisms, plasma cholesterol concentrations, and risk of cardiovascular disease in familial hypercholesterolemia. Atherosclerosis. 2008;
  54. Buch S, Schafmayer C, Volzke H, et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nature Genetics. 2007;39:995–999
  55. Chan DC, Watts GF, Barrett PH, Whitfield AJ, van Bockxmeer FM. ATP-binding cassette transporter G8 gene as a determinant of apolipoprotein B-100 kinetics in overweight men. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2188–2191
  56. Miwa K, Inazu A, Kobayashi J, et al. ATP-binding cassette transporter G8 M429 V polymorphism as a novel genetic marker of higher cholesterol absorption in hypercholesterolaemic Japanese subjects. Clinical Science (London). 2005;109:183–188
  57. Chen ZC, Shin SJ, Kuo KK, Lin KD, Yu ML, Hsiao PJ. Significant association of ABCG8:D19H gene polymorphism with hypercholesterolemia and insulin resistance. Journal of Human Genetics. 2008;53:757–763
  58. Carey MC. Homing-in on the origin of biliary steroids. Gut. 1997;41:721–722
  59. Altmann SW, Davis HR, Zhu LJ, et al. Niemann–Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science (New York, N.Y.). 2004;303:1201–1204
  60. Davies JP, Scott C, Oishi K, Liapis A, Ioannou YA. Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia. The Journal of Biological Chemistry. 2005;280:12710–12720
  61. Zuniga S, Molina H, Azocar L, et al. Ezetimibe prevents cholesterol gallstone formation in mice. Liver International. 2008;28:935–947
  62. Temel RE, Tang W, Ma Y, et al. Hepatic Niemann–Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. The Journal of Clinical Investigation. 2007;117:1968–1978
  63. Cohen JC, Pertsemlidis A, Fahmi S, et al. Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:1810–1815
  64. Fahmi S, Yang C, Esmail S, Hobbs HH, Cohen JC. Functional characterization of genetic variants in NPC1L1 supports the sequencing extremes strategy to identify complex trait genes. Human Molecular Genetics. 2008;17:2101–2107
  65. Wang J, Williams CM, Hegele RA. Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clinical Genetics. 2005;67:175–177
  66. Simon JS, Karnoub MC, Devlin DJ, et al. Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment. Genomics. 2005;86:648–656
  67. Hegele RA, Guy J, Ban MR, Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe. Lipids in Health and Disease. 2005;4:16
  68. Pisciotta L, Fasano T, Bellocchio A, et al. Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients. Atherosclerosis. 2007;194:e116–e122
  69. Chan DC, Watts GF, Wang J, Hegele RA, van Bockxmeer FM, Barrett PH. Variation in Niemann–Pick C1-like 1 gene as a determinant of apolipoprotein B-100 kinetics and response to statin therapy in centrally obese men. Clinical Endocrinology. 2008;69:45–51
  70. Chen CW, Hwang JJ, Tsai CT, et al. The g.−762T>C polymorphism of the NPC1L1 gene is common in Chinese and contributes to a higher promoter activity and higher serum cholesterol levels. Journal of Human Genetics. 2009;
  71. Chiang JY, Kimmel R, Stroup D. Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene. 2001;262:257–265
  72. Goodwin B, Watson MA, Kim H, Miao J, Kemper JK, Kliewer SA. Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha. Molecular Endocrinology (Baltimore, MD). 2003;17:386–394
  73. Repa JJ, Mangelsdorf DJ. The liver X receptor gene team: potential new players in atherosclerosis. Nature Medicine. 2002;8:1243–1248
  74. Yu L, York J, von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH. Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8. The Journal of Biological Chemistry. 2003;278:15565–15570
  75. Robitaille J, Houde A, Lemieux S, Gaudet D, Perusse L, Vohl MC. The lipoprotein/lipid profile is modulated by a gene-diet interaction effect between polymorphisms in the liver X receptor-alpha and dietary cholesterol intake in French-Canadians. The British Journal of Nutrition. 2007;97:11–18
  76. Legry V, Cottel D, Ferrieres J, et al. Association between liver X receptor alpha gene polymorphisms and risk of metabolic syndrome in French populations. International Journal of Obesity (2005). 2008;32:421–428
  77. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Molecular and Cellular Biology. 2001;21:1393–1403
  78. Li T, Chiang JY. Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. American Journal of Physiology Gastrointestinal and Liver Physiology. 2005;288:G74–84
  79. Chiang JY. Bile acids: regulation of synthesis. Journal of Lipid Research. 2009;April 3 [Epub ahead of print]
  80. Dawson PA, Lan T, Rao A. Bile acid transporters. Journal of Lipid Research. 2009;June 4 [Epub ahead of print]
  81. Pearson ER, Pruhova S, Tack CJ, et al. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Diabetologia. 2005;48:878–885
  82. Lu P, Rha GB, Melikishvili M, et al. Structural basis of natural promoter recognition by a unique nuclear receptor, HNF4alpha. Diabetes gene product. The Journal of Biological Chemistry. 2008;283:33685–33697
  83. Zhu Q, Yamagata K, Miura A, et al. T130I mutation in HNF-4alpha gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects. Diabetologia. 2003;46:567–573
  84. Lu Y, Dolle ME, Imholz S, et al. Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations. Journal of Lipid Research. 2008;49:2582–2589
  85. Kosters A, Karpen SJ. Bile acid transporters in health and disease. Xenobiotica; the fate of foreign compounds in biological systems. 2008;38:1043–1071
  86. Holt JA, Luo G, Billin AN, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes & Development. 2003;17:1581–1591
  87. Van Mil SW, Milona A, Dixon PH, et al. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology. 2007;133:507–516
  88. Kovacs P, Kress R, Rocha J, et al. Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans. Journal of Hepatology. 2008;48:116–124
  89. Repa JJ, Turley SD, Lobaccaro JA, et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science (New York, N.Y.). 2000;289:1524–1529
  90. Kolsch H, Lutjohann D, Jessen F, et al. RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism. Journal of Cellular and Molecular Medicine. 2008;
  91. Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:3369–3374
  92. Zhou C, King N, Chen KY, Breslow JL. Activation of pregnane X receptor induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apolipoprotein E deficient mice. Journal of Lipid Research. 2009;May 12 [Epub ahead of print]
  93. Oude Elferink RP, Paulusma CC. Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Archiv. 2007;453:601–610
  94. Tachibana-Iimori R, Tabara Y, Kusuhara H, et al. Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metabolism and Pharmacokinetics. 2004;19:375–380
  95. Zhang W, Chen BL, Ozdemir V, et al. SLCO1B1 521TC functional genetic polymorphism and lipid-lowering efficacy of multiple-dose pravastatin in Chinese coronary heart disease patients. British Journal of Clinical Pharmacology. 2007;64:346–352
  96. Couvert P, Giral P, Dejager S, et al. Association between a frequent allele of the gene encoding OATP1B1 and enhanced LDL-lowering response to fluvastatin therapy. Pharmacogenomics. 2008;9:1217–1227
  97. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. The New England Journal of Medicine. 2008;359:789–799
  98. Meyer Zu Schwabedissen HE, Kim RB. Hepatic OATP1B transporters and nuclear receptors PXR and CAR: interplay, regulation of drug disposition genes, and single nucleotide polymorphisms. Molecular Pharmaceutics. 2009;
  99. Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Research. 2002;30:3894–3900
  100. Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Research. 2003;31:3812–3814
  101. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genetics in Medicine. 2002;4:45–61
  102. Sethupathy P, Collins FS. MicroRNA target site polymorphisms and human disease. Trends in Genetics. 2008;24:489–497
  103. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–753
  104. Pearson TA, Denke MA, McBride PE, Battisti WP, Brady WE, Palmisano J. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clinic proceedings. 2005;80:587–595

PII: S0021-9150(09)00909-5

doi: 10.1016/j.atherosclerosis.2009.10.035

Atherosclerosis
Volume 210, Issue 1 , Pages 14-27 , May 2010