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Pharmacogenetic Study of Statin Therapy
and Cholesterol Reduction
Daniel I. Chasman, PhD
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 prava-
statin, 40 mg/d, was analyzed for 148 single-nucleotide polymorphisms (SNPs) within 10 candidate genes related to lipid metabolism. Variation within these genes was thenexamined for associations with changes in lipid levels observed with pravastatin therapy THERAPYWITH3-HYDROXY-3- duringa24-weekperiod.
Main Outcome Measure Changes in lipid levels in response to pravastatin therapy.
Results Two common and tightly linked SNPs (linkage disequilibrium r2=0.90; hetero-
zygote 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 a19% 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 the use of genetic screening to guide se- was present in the ethnically diverse total cohort as well as in the majority subgroup of lection of lipid-lowering therapy, clini- white participants. No association for either SNP was observed for the change in high- density lipoprotein (HDL) cholesterol (PϾ.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 cho- lesteryl ester transfer protein and change in HDL cholesterol, although none of these met (APOE), apolipoprotein B (APOB), cho- our conservative criteria for purely pharmacogenetic effects.
lesteryl ester transfer protein (CETP ), Conclusion Individuals heterozygous for a genetic variant in the HMG-CoA reduc-
tase gene may experience significantly smaller reductions in cholesterol when treated polymorphisms (SNPs) across 10 can-didate genes known to affect choles- to correlate variation within these genes with the change in total, LDL, and high-density lipoprotein (HDL) cholesterol Author Affiliations: Center for Cardiovascular Dis-
Stanton and Mr Subrahmanyan). Dr Posada is now with ease Prevention, the Donald W. Reynolds Center for Car- the Department of Biochemistry, Genetics, and Immu- diovascular Research, and the Leducq Center for Mo- nology, University of Vigo, Vigo, Spain.
lecular and Genetic Epidemiology, Brigham and Women’s Corresponding Author: Paul M Ridker, MD, MPH,
Hospital, Harvard Medical School, Boston, Mass (Drs Center for Cardiovascular Disease Prevention, Brigham Chasman, Cook, and Ridker); and the former Varia- and Women’s Hospital, 900 Commonwealth Ave E, See also p 2869.
genics Inc, Cambridge, Mass (Drs Chasman, Posada, and Boston, MA 02215 (pridker@partners.org).
2004 American Medical Association. All rights reserved.
(Reprinted) JAMA, June 16, 2004—Vol 291, No. 23 2821
Table 1. Candidate Genes for Genetic Analysis of Lipid Reduction
Encoded Protein
Functional Role
ATP-binding cassette, subfamily G, member 5 Cholesterol transport across the plasma membrane ATP-binding cassette, subfamily G, member 8 Cholesterol transport across the plasma membrane Major binding protein for LDL cholesterol Major binding protein for VLDL/IDL cholesterol Transfer of cholesteryl esters among lipoprotein particles Cytochrome P450, subfamily IIIA, polypeptide 4 Cytochrome P450, subfamily IIIA, polypeptide 5 Farnesyldiphosphate farnesyltransferase 1, squalene synthase 3-Hydroxy-3-methylglutaryl coenzyme A reductase Abbreviations: ATP, adenosine triphosphate; IDL, intermediate density lipoprotein; LDL, low-density lipoprotein; OMIM, Online Mendelian Inheritance in Man13; SNP, single-nucleotide polymorphism; VLDL, very low-density lipoprotein.
osine triphosphate–binding cassette pro- study protocol by providing baseline, 12- teins, APOE, APOB, CETP, LDLR, and tion and genotyping as outlined herein.
to result in profound effects on lipid lev- these criteria and form the basis for these els.10 On the basis of prior evidence for their central role in controlling lipid lev- identified as white, with 100 (6.5%) self- Study Population
SNP Selection and Genotyping
prior observations that null mutations in all of them, except FDFT1 and the CYP3A full listing of the 148 SNPs genotyped in genes, grossly alter lipid levels and cause the study is available from the authors.
coded by the FDFT1 gene is a target for cholesterol reduction therapy; CYP3A genes were included because of their role sites representing 49 states and the Dis- trict of Columbia, with no single site en- pravastatin.12 Within the 10 selected can- participants were free of statin use in the didate genes (TABLE 1), we identified the
no contraindication to statin therapy. For quencing in panels of 32 to 96 cell lines Statistical Analysis and Correction
of P Values for Multiple Alleles
viewing the literature. By further explor- 2822 JAMA, June 16, 2004—Vol 291, No. 23 (Reprinted)
2004 American Medical Association. All rights reserved.
and response to pravastatin, we first cal- self-identified white subpopulation, rep- Polymorphism in the HMG-CoA
edged the risk of being too conservative, Reductase Gene
for each SNP. Statistical tests were per- solely on the change in lipid levels with in lipid response to pravastatin and that fulfilled our additional qualitative cri- teria for association. Both of these SNPs get for statin therapy, and the extent of their linkage disequilibrium (r2= 0.90; PϽ.001) ensured that the results for the tistic for no association of genotype with the difference in lipid levels with 10000 f o r t h e 2 S N P s w e r e i n H a r d y - lipid values.15 P values determined from shown in TABLE 2 for the case of SNP
gard to sex, traditional risk factors, or pothesis. Accordingly, in addition to the uncorrected P values estimated from the permutations, we corrected each P value statistical analysis or in the tables.
tic analysis except CYP3A4, which was terol associated with pravastatin use was the major allele was −42.0 mg/dL (−1.09 determine corrected P values.15 This permutation approach to correcting P 3.8-14.6 mg/dL]; P = .001). For SNP 29 treated patients was 64.0 (12.5) years.
Beyond requiring corrected PϽ.05 for tential for false-positive findings by im- baseline levels of total cholesterol, LDL [95% CI, 3.8-14.7 mg/dL]; PϽ.001).
2004 American Medical Association. All rights reserved.
(Reprinted) JAMA, June 16, 2004—Vol 291, No. 23 2823
nificant after correction for all 33 SNPs gene (both corrected P values Ͻ.02) (TABLE 3). These effects were largely
(P = .008 and P = .02, respectively).
tion after taking pravastatin (both P val- 6.4 mg/dL [95% CI, 2.2-10.7 mg/dL]).
stratification; the P value for SNP 29 In contrast, there was no significant dif- els at baseline or the change in lipid lev- ses. First, in the total cohort, the dif- logical effect of study participation.
rection for all 148 SNPs evaluated across all 10 genes (fully corrected P = .04 for SNP 12 and P=.049 for SNP 29). To ad- siduals in the change in either total cho- FIGURE, haplotype 7 at the tip of one
branch in the HMG-CoA reductasecladogram is defined uniquely by the Table 2. Baseline Characteristics of Treated Patients*
minor alleles of SNPs 12 and 29 and wasthe sole haplotype significantly associ- HMG-CoA Reductase
SNP 12 Genotype†
P
Characteristics
All Treated
Value‡
graphical explanation of their high link- Findings for Other Genes
differential effect of pravastatin on lipid reduction but failed to meet at least 1 of our qualitative criteria for association.
Abbreviations: HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; SNP, single-nucleotide polymorphism.
thase gene (FDFT1) was associated with SI conversions: To convert total, HDL, and LDL cholesterol to mmol/L, multiply by 0.0259.
*Patients with lipid levels measured at baseline and after both 12 and 24 weeks of treatment. Data are presented as and persisted in analyses limited to white †As described in the “Methods” section, genotyping for HMG-CoA reductase SNP 12 was successful in 97.9% of the ‡P values assessed statistical differences in each characteristic for the 2 genotypes of HMG-CoA reductase SNP 12 to be significantly associated with base- observed in the treated cohort of Pravastatin Inflammation/CRP Evaluation. They were computed by a 2-sided t testor by a ␹2 test for the continuously valued or categorically valued characteristics, respectively.
line levels of total cholesterol; thus, af- §Body mass index was calculated as weight in kilograms divided by the square of height in meters.
ter regression against baseline levels, the 2824 JAMA, June 16, 2004—Vol 291, No. 23 (Reprinted)
2004 American Medical Association. All rights reserved.
tered expression, activity, or drug bind- Similarly, while SNP 17 in the APOE eral possible molecular interpretations.
gesting that they may not be directly in- gous for the minor allele (P = .001; corrected P = .047), it too was associ- ation and effects on transcription. It is rected PϽ.001). Moreover, its effect was cant in our analysis limited to white par- ticipants (P=.02; corrected P=.22). The lesteryl ester transfer protein (CETP ) to a third SNP in a 3Ј untranslated exon in HDL cholesterol among men (P=.007; corrected P=.02) but, again, it was also terol level (corrected P=.003) and the (P=.59; corrected P=.99), among whitemen (P=.04; corrected P=.17), or in the Table 3. Association of HMG-CoA Reductase Genotype With Lipid Changes*
sex-combined data (P=.046; corrected Mean Change (% Change)
P=.26). Finally, in the cladistic evolu- in Lipid Level by
Genotype, mg/dL†
Mean Change
P
Corrected
(% Change)‡
P Value
Total Cholesterol
els in response to pravastatin and not as- sociated with baseline lipid levels.
LDL Cholesterol
HDL Cholesterol
Abbreviations: HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; SNP, single-nucleotide polymorphism.
SI conversions: To convert total, HDL, and LDL cholesterol to mmol/L, multiply by 0.0259.
*To exclude possible confounding due to population stratification by ethnicity, the statistical analysis was also applied to the subgroup of participants who were self-identified as white.
†Mean change in total, LDL, and HDL cholesterol levels, respectively, for the average of measurements after 12 and 24 weeks of pravastatin treatment. Genotypes AA and TT are homozygous for the major allele of the HMG-CoA reduc-tase gene SNPs 12 and 29, respectively. Genotypes AT and TG are heterozygous genotypes for SNPs 12 and 29, ‡Difference in mean changes in lipids for individuals in the 2 genetic classes and percentage mean changes from the §P values from permutation test for the analysis of variance F statistic.
P values corrected for all 33 SNPs in the HMG-CoA reductase gene.
2004 American Medical Association. All rights reserved.
(Reprinted) JAMA, June 16, 2004—Vol 291, No. 23 2825
only by less conservative statistical con- effects due to rare alleles was limited.
using our conservative analysis plan.
ever, the dose of pravastatin used is the leles of 3% or greater frequency. For al- highest dose routinely given for thisagent and is the only dose that has beentested in clinical end-point trials. Third, Figure. Evolutionary Analysis of the Association of Mean Total Cholesterol Change With
despite our study’s large sample size and Haplotypes of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase our conservative statistical analysis,these data require independent confir-mation, as would be true for any ge- likely that our study population, whichwas derived from 49 states and the Dis- trict of Columbia, is subject to any ma-jor selection bias. Finally, despite the proportion of the variance that can beexplained by HMG-CoA reductase SNPs the expected influence of clinical de-terminants such as compliance and diet.
considerable pathophysiological inter-est and provide strong clinical evi- concept of “personalized medicine” and (0.23 mmol/L), an effect large enoughto affect health on a population basis.
Future studies must determine whetherthis difference can be offset by dose ad-justment or the choice of an alterna-tive nonstatin lipid-lowering therapy.
Each node in the tree corresponds to a different haplotype (Hap) as labeled, with node area proportional tothe number of observations of the corresponding haplotype among participants meeting the study criteria.
Lines connect haplotypes inferred to have arisen close to each other during the evolutionary history of the 3-hydroxy-3-methylglutaryl coenzyme A reductase locus. Small, unlabeled nodes correspond to haplotypesinferred to have existed during evolution but not found in the study population. Only haplotype 7 (gray), which is uniquely defined by single-nucleotide polymorphisms (SNPs) 12 and 29, was associated with an altered re- 2826 JAMA, June 16, 2004—Vol 291, No. 23 (Reprinted)
2004 American Medical Association. All rights reserved.
Author Contributions: Drs Chasman and Ridker had
Templeton, PhD, for suggesting the haplotype analy- 10. Tsimikas S, Mooser V. Molecular Biology of Li-
full access to all of the data in the study and take re- poproteins and Dislipidemias in Molecular Basis of sponsibility for the integrity of the data and the ac- Cardiovascular Disease. 2nd ed. Antman EM, ed. Phila- REFERENCES
Study concept and design: Stanton, Ridker 11. Albert MA, Danielson E, Rifai N, Ridker PM. Effect
Acquisition of data: Chasman, Stanton, Ridker.
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Critical revision of the manuscript for important in- drug disposition, drug targets, and side effects. N Engl Atherosclerosis: Pharmacologic Therapy in Cardio- tellectual content: Chasman, Posada, Subrahmanyan, vascular Therapeutics. 2nd ed. Antman EM, ed. Phila- 3. Roses AD. Genome-based pharmacogenetics and
Statistical expertise: Chasman, Cook, Ridker.
the pharmaceutical industry. Nat Rev Drug Discov. 13. Online Mendelian Inheritance in Man. Available at:
http://www.ncbi.nlm.nih.gov/omim/omimfaq.html.
Administrative, technical, or material support: Stanton, 4. Ordovas JM, Mooser V. The APOE locus and the
Accessibility verified May 26, 2004.
pharmacogenetics of lipid response. Curr Opin Lipi- 14. Kokoris M, Dix K, Moynihan K, et al. High-
Supervision: Stanton, Ridker.
throughput SNP genotyping with the Masscode sys- Financial Disclosures: Drs Chasman, Posada, and Stan-
5. Brorholt-Petersen JU, Jensen HK, Raungaard B,
tem. Mol Diagn. 2000;5:329-340.
ton and Mr Subrahmanyan were employees of Varia- Gregersen N, Faergeman O. LDL-receptor gene mu- 15. Westfall PH, Young SS. Resampling-based Mul-
genics Inc when this project was initiated. Dr Ridker re- tations and the hypocholesterolemic response to statin tiple Testing. New York, NY: John Wiley & Sons; 1993.
ceived research support from Variagenics Inc for portions therapy. Clin Genet. 2001;59:397-405.
16. Templeton AR, Boerwinkle E, Sing CF. A cladistic
of this work. Variagenics Inc no longer exists.
6. Kuivenhoven JA, Jukema JW, Zwinderman AH, et
analysis of phenotypic associations with haplotypes in- Funding/Support: Components of this work were sup-
al; Regression Growth Evaluation Statin Study Group.
ferred from restriction endonuclease mapping, I: ba- ported by grants from the National Heart, Lung, and The role of a common variant of the cholesteryl ester sic theory and an analysis of alcohol dehydrogenase Blood Institute, the Doris Duke Charitable Founda- transfer protein gene in the progression of coronary activity in Drosophila. Genetics. 1987;117:343-351.
tion (New York, NY), the Fondation Leducq (Paris, atherosclerosis. N Engl J Med. 1998;338:86-93.
17. Stephens M, Smith NJ, Donnelly P. A new statis-
France), the Donald W. Reynolds Foundation (Las Ve- 7. Ordovas JM, Lopez-Miranda J, Perez-Jimenez F, et
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Role of the Sponsors: The study sponsors played no
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role in the design and analysis of these data. The inhibitor therapy. Atherosclerosis. 1995;113:157-166.
puter program to estimate gene genealogies. Mol Ecol. PRINCE clinical trial was an investigator-initiated project 8. Hansen PS, Meinertz H, Gerdes LU, Klausen IC,
supported by Bristol-Myers Squibb. SNP discovery and Faergeman O. Treatment of patients with familial de- 19. Pruitt KD, Maglott DR. RefSeq and LocusLink:
genotyping for this project were performed at Varia- fective apolipoprotein B-100 with pravastatin and gem- NCBI gene-centered resources. Nucleic Acids Res. fibrozil: a two-period cross-over study. Clin Investig. Acknowledgment: We thank Mike Mendelsohn, MD,
20. Executive summary of the third report of the Na-
for his involvement in conceptualization of this project, 9. Watanabe J, Kobayashi K, Umeda F, et al. Apoli-
tional Cholesterol Education Program (NCEP) Expert Martin Zillmann, PhD, for his efforts in overseeing the poprotein E polymorphism affects the response to Panel on Detection, Evaluation, and Treatment of High genotyping assays, Carsten Wiuf, PhD, for his con- pravastatin on plasma apolipoproteins in diabetic pa- Blood Cholesterol in Adults (Adult Treatment Panel tribution to the initial phase of the analysis, and Alan tients. Diabetes Res Clin Pract. 1993;20:21-27.
III). JAMA. 2001;285:2486-2497.
Humanity needs practical men, who get the most outof their work, and, without forgetting the general good,safeguard their own interests. But humanity also needsdreamers, for whom the disinterested development ofan enterprise is so captivating that it becomes impos-sible for them to devote their care to their own ma-terial profit.
2004 American Medical Association. All rights reserved.
(Reprinted) JAMA, June 16, 2004—Vol 291, No. 23 2827

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