 |
 |

Pharmacogenetic Study of Statin Therapy and Cholesterol Reduction
Daniel I. Chasman, PhD;
David Posada, PhD;
Lakshman Subrahmanyan, MS;
Nancy R. Cook, PhD;
Vincent P. Stanton, Jr, MD;
Paul M Ridker, MD, MPH
JAMA. 2004;291:2821-2827.
Context Polymorphisms in genes involved in cholesterol synthesis, absorption, and transport may affect statin efficacy.
Objective To evaluate systematically whether genetic variation influences response to pravastatin therapy.
Design, Setting, and Population The DNA of 1536 individuals treated with pravastatin, 40 mg/d, was analyzed for 148 single-nucleotide polymorphisms (SNPs) within 10 candidate genes related to lipid metabolism. Variation within these genes was then examined for associations with changes in lipid levels observed with pravastatin therapy during a 24-week period.
Main Outcome Measure Changes in lipid levels in response to pravastatin therapy.
Results Two common and tightly linked SNPs (linkage disequilibrium r2 = 0.90; heterozygote prevalence = 6.7% for both) were significantly associated with reduced efficacy of pravastatin therapy. Both of these SNPs were in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the target enzyme that is inhibited by pravastatin. For example, compared with individuals homozygous for the major allele of one of the SNPs, individuals with a single copy of the minor allele had a 22% smaller reduction in total cholesterol (32.8 vs 42.0 mg/dL [0.85 vs 1.09 mmol/L]; P = .001; absolute difference, 9.2 mg/dL [95% confidence interval {CI}, 3.8-14.6 mg/dL]) and a 19% smaller reduction in low-density lipoprotein (LDL) cholesterol (27.7 vs 34.1 mg/dL [0.72 vs 0.88 mmol/L]; P = .005; absolute difference, 6.4 mg/dL [95% CI, 2.2-10.6 mg/dL]). The association for total cholesterol reduction persisted even after adjusting for multiple tests on all 33 SNPs evaluated in the HMG-CoA reductase gene as well as for all 148 SNPs evaluated was similar in magnitude and direction among men and women and was present in the ethnically diverse total cohort as well as in the majority subgroup of white participants. No association for either SNP was observed for the change in high-density lipoprotein (HDL) cholesterol (P>.80) and neither was associated with baseline lipid levels among those actively treated or among those who did not receive the drug. Among the remaining genes, less robust associations were found for squalene synthase and change in total cholesterol, apolipoprotein E and change in LDL cholesterol, and cholesteryl ester transfer protein and change in HDL cholesterol, although none of these met our conservative criteria for purely pharmacogenetic effects.
Conclusion Individuals heterozygous for a genetic variant in the HMG-CoA reductase gene may experience significantly smaller reductions in cholesterol when treated with pravastatin.
Author Affiliations: Center for Cardiovascular Disease Prevention, the Donald W. Reynolds Center for Cardiovascular Research, and the Leducq Center for Molecular and Genetic Epidemiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (Drs Chasman, Cook, and Ridker); and the former Variagenics Inc, Cambridge, Mass (Drs Chasman, Posada, and Stanton and Mr Subrahmanyan). Dr Posada is now with the Department of Biochemistry, Genetics, and Immunology, University of Vigo, Vigo, Spain.
RELATED LETTER
Genetic Polymorphisms and Statin Therapy
Issam Zineh
JAMA. 2004;292(11):1302-1303.
EXTRACT
| FULL TEXT
RELATED ARTICLE
Using Pharmacogenetics to Improve Drug Safety and Efficacy
Susanne B. Haga and Wylie Burke
JAMA. 2004;291(23):2869-2871.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
 |
Alternative Splicing of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Is Associated With Plasma Low-Density Lipoprotein Cholesterol Response to Simvastatin
Medina et al.
Circulation 2008;118:355-362.
ABSTRACT
| FULL TEXT
Editorial: Unifying the genetics, co-morbidities and management of COPD
Wood and Stockley
Therapeutic Advances in Respiratory Disease 2008;2:113-117.
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
Krauss et al.
Circulation 2008;117:1537-1544.
ABSTRACT
| FULL TEXT
Translational Bioinformatics: At the Interface of Genomics and Quantitative Genetics
Beavis et al.
Crop Sci. 2007;47:S-32-S-43.
ABSTRACT
| FULL TEXT
Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients
Singer et al.
J. Lipid Res. 2007;48:2072-2078.
ABSTRACT
| FULL TEXT
Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease: A Scientific Statement From the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group
Arnett et al.
Circulation 2007;115:2878-2901.
ABSTRACT
| FULL TEXT
Cardiovascular Pharmacogenomics
Momary
Journal of Pharmacy Practice 2007;20:265-276.
ABSTRACT
High-density genotyping and functional SNP localization in the CETP gene
Thompson et al.
J. Lipid Res. 2007;48:434-443.
ABSTRACT
| FULL TEXT
Integrating Molecular Biology into the Veterinary Curriculum
Ryan and Sweeney
jvme 2007;34:658-673.
ABSTRACT
| FULL TEXT
Pharmacogenomics: Challenges and Opportunities.
Roden et al.
ANN INTERN MED 2006;145:749-757.
ABSTRACT
| FULL TEXT
Randomised by (your) god: robust inference from an observational study design
Smith
J. Epidemiol. Community Health 2006;60:382-388.
FULL TEXT
Cardiovascular Genomics
Sabatine et al.
Circulation 2006;113:e450-e455.
FULL TEXT
Implications of Pharmacogenomics for Drug Development and Clinical Practice
Ginsburg et al.
Arch Intern Med 2005;165:2331-2336.
ABSTRACT
| FULL TEXT
Prospects for Personalized Cardiovascular Medicine: The Impact of Genomics
Ginsburg et al.
J Am Coll Cardiol 2005;46:1615-1627.
ABSTRACT
| FULL TEXT
The Year in Non--ST-Segment Elevation Acute Coronary Syndromes
Giugliano and Braunwald
J Am Coll Cardiol 2005;46:906-919.
FULL TEXT
Underappreciated Statin-Induced Myopathic Weakness Causes Disability
Dobkin
Neurorehabil Neural Repair 2005;19:259-263.
ABSTRACT
Genetic Polymorphisms and the Risk of Stroke After Cardiac Surgery
Grocott et al.
Stroke 2005;36:1854-1858.
ABSTRACT
| FULL TEXT
Relative Contributions of Genes, Environment, and Interactions to Blood Lipid Concentrations in a General Adult Population
Costanza et al.
Am J Epidemiol 2005;161:714-724.
ABSTRACT
| FULL TEXT
The "Duty to Warn" a Patient's Family Members About Hereditary Disease Risks
Offit et al.
JAMA 2004;292:1469-1473.
ABSTRACT
| FULL TEXT
Genetic Polymorphisms and Statin Therapy
Zineh
JAMA 2004;292:1302-1303.
FULL TEXT
Genetic Variation in Response to Statin Therapy
Journal Watch Cardiology 2004;2004:1-1.
FULL TEXT
Cardiovascular News
SoRelle
Circulation 2004;109:e9052-e9053.
FULL TEXT
Using Pharmacogenetics to Improve Drug Safety and Efficacy
Haga and Burke
JAMA 2004;291:2869-2871.
FULL TEXT
|