Role of pharmacogenomics in Statin Responsiveness; A review

Document Type : Review Article

Authors

Abstract

Statins have been used for decades as a successful cholesterol-lowering class of medicines. Statins are widely prescribed for the primary and secondary prevention of coronary artery disease. They reduce cardiovascular risk and improve health outcomes in people with cardiovascular disease. Although statins are considered as a safe medicine and well tolerated by patients, prediction of individual patient’s response to statin therapy remains unclear. Variation to statin therapy has been attributed to both environmental and genetic factors. In this review, a number of candidates gene that affect statin pharmacokinetics and pharmacodynamics are discussed. Moreover, the association of demographic factors with statin response in related studies is described. We reviewed the literature concerning pharmacogenetic studies on statin response. 50 English-language clinical trials, prospective or retrospective human investigations, case series, case reports, published between 1998 to2015, were evaluated.  Based on these data, there are some candidate genes that have been established as affecting genes on statin efficacy and suggest that drug therapy based on individuals' genetic makeup may result in a clinically important reduction in variation of statin response.Keywords: statins, pharmacogenetic, cardiovascular, pharmacodynamics

Keywords

References

  1. Mikhailidis DP, Athyros VG. Dyslipidaemia in 2013: New statin guidelines and promising novel therapeutics. Nature Reviews Cardiology. 2014;11(2):72-4.
  2. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. Jama. 1999;282(24):2340-6.
  3. Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. The New England journal of medicine. 2008;359(8):789-99.
  4. Simon JA, Lin F, Hulley SB, Blanche PJ, Waters D, Shiboski S, et al. Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. The American journal of cardiology. 2006;97(6):843-50.
  5. Sing CF, Stengård JH, Kardia SL. Genes, environment, and cardiovascular disease. Arteriosclerosis, thrombosis, and vascular biology. 2003;23(7):1190-6.
  6. Smiderle L, Lima LO, Hutz MH, Sand CRVd, Van der Sand LC, Ferreira MEW, et al. Evaluation of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin therapy in a southern Brazilian cohort. Arquivos brasileiros de cardiologia. 2014;103(1):33-40.
  7. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton Jr VP, Ridker PM. Pharmacogenetic study of statin therapy and cholesterol reduction. Jama. 2004;291(23):2821-7.
  8. Gelissen IC, McLachlan AJ. The pharmacogenomics of statins. Pharmacological Research. 2014;88:99-106.
  9. Sorich MJ, Wiese MD, O’Shea RL, Pekarsky B. Review of the cost effectiveness of pharmacogenetic-guided treatment of hypercholesterolaemia. Pharmacoeconomics. 2013;31(5):377-91.
  10. Namazi S, Azarpira N, Hendijani F, Khorshid MB, Vessal G, Mehdipour AR. The impact of genetic polymorphisms and patient characteristics on warfarin dose requirements: a cross-sectional study in Iran. Clinical therapeutics. 2010;32(6):1050-60.
  11. Namazi S, Daneshian A, Mohammadianpanah M, Jafari P, Ardeshir-Rouhani-Fard S, Nasirabadi S. The impact of renin–angiotensin system, angiotensin І converting enzyme (insertion/deletion), and angiotensin ІІ type 1 receptor (A1166C) polymorphisms on breast cancer survival in Iran. Gene. 2013;532(1):108-14.
  12. Namazi S, Kojuri J, Khalili A, Azarpira N. The impact of genetic polymorphisms of P2Y12, CYP3A5 and CYP2C19 on clopidogrel response variability in Iranian patients. Biochemical pharmacology. 2012;83(7):903-8.
  13. Namazi S, Monabati A, Ardeshir-Rouhani-Fard S, Azarpira N. Lack of association of genetic polymorphisms of angiotensin converting enzyme 1 and angiotensin II type 1 receptor with breast cancer risk in Iranian population. Tumor Biology. 2013;34(5):2899-907.
  14. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacology & therapeutics. 1999;84(3):413-28.
  15. Hu M, Mak VW, Xiao Y, Tomlinson B. Associations between the genotypes and phenotype of CYP3A and the lipid response to simvastatin in Chinese patients with hypercholesterolemia. Pharmacogenomics. 2013;14(1):25-34.
  16. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. The American journal of cardiology. 2004;93(1):104-7.
  17. Maggo MSD, Kennedy MA, Clark DW. Clinical implications of pharmacogenetic variation on the effects of statins. Drug Safety. 2011;34(1):1-19.
  18. Scripture CD, Pieper JA. Clinical pharmacokinetics of fluvastatin. Clinical pharmacokinetics. 2001;40(4):263-81.
  19. Kirchheiner J, Kudlicz D, Meisel C, Bauer S, Meineke I, Roots I, et al. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol‐lowering activity of (−)‐3s, 5r‐fluvastatin and (+)‐3r, 5s‐fluvastatin in healthy volunteers. Clinical Pharmacology & Therapeutics. 2003;74(2):186-94.
  20. Buzkova H, Pechandova K, Danzig V, Vařeka T, Perlik F, Žak A, et al. Lipid-lowering effect of fluvastatin in relation to cytochrome P450 2C9 variant alleles frequently distributed in the Czech population. Medical science monitor: international medical journal of experimental and clinical research. 2012;18(8):CR512.
  21. Callaghan R, Crowley E, Potter S, Kerr ID. P‐glycoprotein: So Many Ways to Turn It On. The Journal of Clinical Pharmacology. 2008;48(3):365-78.
  22. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenetics and genomics. 2011;21(3):152.
  23. Keskitalo JE, Kurkinen KJ, Neuvonen M, Backman JT, Neuvonen PJ, Niemi M. No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin. British journal of clinical pharmacology. 2009;68(2):207-13.
  24. Keskitalo JE, Kurkinen KJ, Neuvonen PJ, Niemi M. ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clinical Pharmacology & Therapeutics. 2008;84(4):457-61.
  25. Alzoubi KH, Khabour OF, Al-azzam SI, Mayyas F, Mhaidat NM. The role of Multidrug Resistance-1 (MDR1) variants in response to atorvastatin among Jordanians. Cytotechnology. 2015;67(2):267-74.
  26. Hoenig MR, Walker PJ, Gurnsey C, Beadle K, Johnson L. The C3435T polymorphism in ABCB1 influences atorvastatin efficacy and muscle symptoms in a high-risk vascular cohort. Journal of clinical lipidology. 2011;5(2):91-6.
  27. Mega JL, Morrow DA, Brown A, Cannon CP, Sabatine MS. Identification of genetic variants associated with response to statin therapy. Arteriosclerosis, thrombosis, and vascular biology. 2009;29(9):1310-5.
  28. Thompson J, Man M, Johnson K, Wood L, Lira M, Lloyd D, et al. An association study of 43 SNPs in 16 candidate genes with atorvastatin response. The pharmacogenomics journal. 2005;5(6):352-8.
  29. Niemi M, Pasanen MK, Neuvonen PJ. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clinical Pharmacology & Therapeutics. 2006;80(4):356-66.
  30. Hedman M, Antikainen M, Holmberg C, Neuvonen M, Eichelbaum M, Kivistö KT, et al. Pharmacokinetics and response to pravastatin in paediatric patients with familial hypercholesterolaemia and in paediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes. British journal of clinical pharmacology. 2006;61(6):706-15.
  31. Donnelly L, Doney A, Tavendale R, Lang C, Pearson E, Colhoun H, et al. Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study. Clinical Pharmacology & Therapeutics. 2011;89(2):210-6.
  32. Dai R, Feng J, Wang Y, Yang Y, Deng C, Tang X, et al. Association between SLCO1B1 521 T> C and 388 A> G Polymorphisms and Statins Effectiveness: A Meta-Analysis. Journal of atherosclerosis and thrombosis. 2015(0).
  33. Pedro-Botet J, Schaefer EJ, Bakker-Arkema RG, Black DM, Stein EM, Corella D, et al. Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner. Atherosclerosis. 2001;158(1):183-93.
  34. Barber MJ, Mangravite LM, Hyde CL, Chasman DI, Smith JD, McCarty CA, et al. Genome-wide association of lipid-lowering response to statins in combined study populations. PloS one. 2010;5(3):e9763.
  35. Deshmukh HA, Colhoun HM, Johnson T, McKeigue PM, Betteridge DJ, Durrington PN, et al. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp (a). Journal of lipid research. 2012;53(5):1000-11.
  36. Thompson JF, Hyde CL, Wood LS, Paciga SA, Hinds DA, Cox DR, et al. Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. Circulation: Cardiovascular Genetics. 2009;2(2):173-81.
  37. HAGBERG JM, WILUND KR, FERRELL RE. APO E gene and gene-environment effects on plasma lipoprotein-lipid levels. Physiological Genomics. 2000;4(2):101-8.
  38. Mahley RW, Rall Jr SC. Apolipoprotein E: far more than a lipid transport protein. Annual review of genomics and human genetics. 2000;1(1):507-37.
  39. Postmus I, Trompet S, Deshmukh HA, Barnes MR, Li X, Warren HR, et al. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nature communications. 2014;5.
  40. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160-4.
  41. Chung JY, Cho SK, Oh ES, Lee DH, Lim LA, Jang SB, et al. Effect of HMGCR Variant Alleles on Low‐Density Lipoprotein Cholesterol—Lowering Response to Atorvastatin in Healthy Korean Subjects. The Journal of Clinical Pharmacology. 2012;52(3):339-46.
  42. Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Guo X, et al. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation.
  43. ;117(12):1537-44.
  44. Hu M, Mak V, Chu T, Waye M, Tomlinson B. Pharmacogenetics of HMG-CoA reductase inhibitors: optimizing the prevention of coronary heart disease. Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics). 2009;7(1):1-26.
  45. Singer JB, Holdaas H, Jardine AG, Fellstrøm B, Os I, Bermann G, et al. Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients. Journal of lipid research. 2007;48(9):2072-8.
  46. Mangravite LM, Medina MW, Cui J, Pressman S, Smith JD, Rieder MJ, et al. Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin. Arteriosclerosis, thrombosis, and vascular biology. 2010;30(7):1485-92.
  47. Toplak H, De Campo A, Renner W. BMI and lipid lowering-is there a relation. Journal of Clinical and Basic Cardiology. 2000;3(2):115-7.
  48. Couture P, Brun LD, Szots F, Lelièvre M, Gaudet D, Despres J-P, et al. Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia. Arteriosclerosis, thrombosis, and vascular biology. 1998;18(6):1007-12.
  49. Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. Journal of the American College of Cardiology. 2012;59(6):572-82.
  50. Lahoz C, Peña R, Mostaza JM, Laguna F, Garcia-Iglesias MF, Taboada M, et al. Baseline levels of low-density lipoprotein cholesterol and lipoprotein (a) and the AvaII polymorphism of the low-density lipoprotein receptor gene influence the response of low-density lipoprotein cholesterol to pravastatin treatment. Metabolism. 2005;54(6):741-7.
  51. Knauer MJ, Diamandis EP, Hulot J-S, Kim RB, So D. Clopidogrel and CYP2C19: Pharmacogenetic Testing Ready for Clinical Prime Time? Clinical chemistry. 2015.
Trends in Pharmaceutical Sciences
Volume 1, Issue 4 - Serial Number 4
6
December 2015
Pages 183-190

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