Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

An association study of 43 SNPs in 16 candidate genes with atorvastatin response

The Pharmacogenomics Journal volume 5, pages 352–358 (2005)Cite this article

Abstract

Variation in individual response to statin therapy has been widely studied for a potential genetic component. Multiple genes have been identified as potential modulators of statin response, but few study findings have replicated. To further examine these associations, 2735 individuals on statin therapy, half on atorvastatin and the other half divided among fluvastatin, lovastatin, pravastatin and simvastatin were genotyped for 43 SNPs in 16 genes that have been implicated in statin response. Associations with low-density lipoprotein cholesterol (LDL-C) lowering, total cholesterol lowering, HDL-C elevation and triglyceride lowering were examined. The only significant associations with LDL-C lowering were found with apoE2 in which carriers of the rare allele who took atorvastatin lowered their LDL-C by 3.5% more than those homozygous for the common allele and with rs2032582 (S893A in ABCB1) in which the two groups of homozygotes differed by 3% in LDL-C lowering. These genetic effects were smaller than those observed with the demographic variables of age and gender. The magnitude of all the differences found is sufficiently small that genetic data from these genes should not influence clinical decisions on statin administration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Abbreviations

ACCESS:

Atorvastatin Comparative Cholesterol Efficacy and Safety Study

Af. Am.:

African American

ANCOVA:

analysis of covariance

Cauc.:

Caucasian

Hisp.:

Hispanic

HMGCR:

3-hydroxy-3-methylglutaryl-coenzyme A reductase

LDL-C:

low-density lipoprotein cholesterol

References

  1. Gresser U, Gathof BS . Atorvastatin: Gold standard for prophylaxis of myocardial ischemia and stroke—comparison of the clinical benefit of statins on the basis of randomized controlled endpoint studies. Eur J Med Res 2004; 9: 1–17.

    CAS  PubMed  Google Scholar 

  2. Shear CL, Franklin FA, Stinnett S, Hurley DP, Bradford RH, Chremos AN et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: effect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins. Circulation 1992; 85: 1293–1303.

    Article  CAS  Google Scholar 

  3. Maitland-van der Zee AH, Klungel OH, Stricker BHC, Verschuren WMM, Kastelein JJP, Leufkins HGM et al. Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors. Atherosclerosis 2002; 163: 213–222.

    Article  CAS  Google Scholar 

  4. Kajinami K, Takekoshia N, Brousseau ME, Schaefer EJ . Pharmacogenetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management. Atherosclerosis 2004; 177: 219–234.

    Article  CAS  Google Scholar 

  5. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP, Ridker PM . Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004; 291: 2821–2827.

    Article  CAS  Google Scholar 

  6. Rieder MJ, Taylor SL, Clark AG, Nickerson DA . Sequence variation in the human angiotensin converting enzyme. Nat Genet 1999; 22: 59–62.

    Article  CAS  Google Scholar 

  7. Tanaka C, Kamide K, Takiuchi S, Miwa Y, Yoshii M, Kawano Y et al. An alternative fast and convenient genotyping method for the screening of angiotensin converting enzyme gene polymorphisms. Hypertens Res 2003; 26: 301–306.

    Article  CAS  Google Scholar 

  8. Ballantyne CM, Andrews TC, Hsia JA, Kramer JH, Shear C . Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol 2001; 88: 265–269.

    Article  CAS  Google Scholar 

  9. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ . Polymorphisms in the multidrug resistance-1 (MDR1) gene influence the response to atorvastatin treatment in a gender-specific manner. Am J Cardiol 2004; 93: 1046–1050.

    Article  CAS  Google Scholar 

  10. Ioannidis JPA, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG . Genetic associations in large versus small studies: an empirical assessment. Lancet 2003; 361: 567–571.

    Article  Google Scholar 

  11. Campbell H, Rudan I . Interpretation of genetic association studies in complex disease. Pharmacogenom J 2002; 2: 349–360.

    Article  CAS  Google Scholar 

  12. Daly AK, King BP . Pharmacogenetics of oral anticoagulants. Pharmacogenetics 2003; 13: 247–252.

    Article  CAS  Google Scholar 

  13. Krynetski EY, Evans WE . Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm. Pharmaceut Res 1999; 16: 342–349.

    Article  CAS  Google Scholar 

  14. Sindrup SH, Brosen K . The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics 1995; 5: 335–346.

    Article  CAS  Google Scholar 

  15. Kaplan RC, Bhalodkar NC, Brown Jr EJ, White J, Brown DL . Race, ethnicity, and sociocultural characteristics predict noncompliance with lipid-lowering medications. Prev Med 2004; 39: 1249–1255.

    Article  Google Scholar 

  16. Thompson JF, Lira ME, Durham LK, Clark RW, Bamberger MJ, Milos PM . Polymorphisms in the CETP gene and association with CETP mass and HDL levels. Atherosclerosis 2003; 167: 195–204.

    Article  CAS  Google Scholar 

  17. 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. J Lipid Res 2004; 45: 653–656.

    Article  CAS  Google Scholar 

  18. Marian AJ, Safavi F, Ferlic L, Dunn JK, Gotto AN, Ballantyne CM . Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. J Am Coll Cardiol 2000; 35: 89–95.

    Article  CAS  Google Scholar 

  19. Lahoz C, Pena R, Mostaza JM, Jimenez J, Subirats E, Pinto X et al. Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy. Atherosclerosis 2003; 168: 289–295.

    Article  CAS  Google Scholar 

  20. Ojala JP, Helve E, Ehnholm C, Aalto-Setala K, Kontula KK, Tikkanen MJ . Effect of apolipoprotein E polymorphism and XbaI polymorphism of apolipoprotein B on response to lovastatin treatment in familial and non-familial hypercholesterolaemia. J Intern Med 1991; 230: 397–405.

    Article  CAS  Google Scholar 

  21. 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: 183–193.

    Article  CAS  Google Scholar 

  22. van Venrooij FV, Stolk RP, Banga JD, Sijmonsma TP, van Tol A, Erkelens DW et al. Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in Type 2 diabetes. Diabetes Care 2003; 26: 1216–1223.

    Article  CAS  Google Scholar 

  23. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ . Cyp3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. Am J Cardiol 2004; 93: 104–107.

    Article  CAS  Google Scholar 

  24. Kivisto KT, Niemi M, Schaeffeler E, Pitkala K, Tilvis R, Fromm MF et al. Lipid lowering response to statins is affected by Cyp3A5 polymorphism. Pharmacogenetics 2004; 14: 523–525.

    Article  Google Scholar 

  25. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ . A promoter polymorphism in cholesterol 7a-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin. Atherosclerosis 2005; 180: 407–415.

    Article  CAS  Google Scholar 

  26. Salazar LA, Hirata MH, Quintao ECR, Hirata RDC . Lipid-lowering response of the HMG-CoA reductase inhibitor fluvastatin is influenced by polymorphisms in the low-density lipoprotein receptor gene in Brazilian patients with primary hypercholesterolemia. J Clin Lab Anal 2000; 14: 125–131.

    Article  CAS  Google Scholar 

  27. Lahoz C, Pena R, Mostaza JM, Laguna F, Garcia-Iglesias MF, Taboada M et al. The –514C/T polymorphism of the hepatic lipase gene significantly modulates the HDL-cholesterol response to statin treatment. Atherosclerosis 2005 (in press).

  28. Mwinyi J, Johne A, Bauer S, Roots I, Gerloff T . Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 2004; 75: 415–421.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank John Tsai, Charles Shear and the Lipitor Team for assistance in the clinical trials; Paul Feeney and Michael Swietek for assistance in sample handling; and the patients for donating samples for research.

Author information

Authors and Affiliations

  1. Discovery Pharmacogenomics, Pfizer Global Research and Development, Groton, CT, USA

    J F Thompson, L S Wood, M E Lira, D B Lloyd, P Banerjee & P M Milos

  2. Nonclinical Statistics, Pfizer Global Research and Development, Ann Arbor, MI, USA

    M Man

  3. Clinical Pharmacogenomics, Pfizer Global Research and Development, Ann Arbor

    K J Johnson

  4. MI, USA

    K J Johnson

  5. World Wide Safety Sciences, Pfizer Global Research and Development, Ann Arbor, MI, USA

    S P Myrand & J Paulauskis

  6. Clinical Pharmacokinetics and Pharmacodynamics, Pfizer Global Research and Development, Ann Arbor, MI, USA

    M A Milad

  7. Pfizer Global Pharmaceuticals, New York, NY, USA

    W J Sasiela

Authors
  1. J F Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Man
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K J Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L S Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M E Lira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D B Lloyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P M Milos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S P Myrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Paulauskis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M A Milad
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. W J Sasiela
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J F Thompson.

Additional information

DUALITY OF INTEREST

All authors are employees of Pfizer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thompson, J., Man, M., Johnson, K. et al. An association study of 43 SNPs in 16 candidate genes with atorvastatin response. Pharmacogenomics J 5, 352–358 (2005). https://doi.org/10.1038/sj.tpj.6500328

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500328

Keywords

This article is cited by

Search

Advanced search

Quick links