Published online before print March 10, 2008, doi: 10.1161/CIRCULATIONAHA.107.708388
(Circulation. 2008;117:1537-1544.)
© 2008 American Heart Association, Inc.
Genetics |
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
From the Children’s Hospital of Oakland Research Institute, Oakland, Calif (R.M.K., L.M.M., M.W.M.); Department of Genome Sciences, University of Washington, Seattle (J.D.S., M.J.R., D.A.N.); Medical Genetics Institute, Cedars-Sinai Medical Center (D. Wang, X.G., K.D.T., H.Y., J.I.R.), and Departments of Medicine and Pediatrics, University of California, Los Angeles, School of Medicine (X.G., K.D.T., H.Y., J.I.R.), Los Angeles; General Internal Medicine Section, Medical Service, Veterans Affairs Medical Center, San Francisco, Calif (J.A.S.); Department of Epidemiology and Biostatistics, University of California, San Francisco, School of Medicine, San Francisco (J.A.S., S.B.H.); San Francisco General Hospital, Department of Medicine, San Francisco, Calif (D. Waters); Department of Preventative Medicine, State University of New York Health Sciences Center, Stony Brook (M.S.); and Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, Calif (P.T.W.).
Reprint requests to Ronald M. Krauss, Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609. E-mail rkrauss{at}chori.org
Received April 17, 2007; accepted January 16, 2008.
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Abstract |
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Background— Use of 3-hydroxyl-3-methylglutaryl-3 coenzyme A reductase (HMGCR) inhibitors, or statins, reduces cardiovascular disease risk by lowering plasma low-density lipoprotein cholesterol (LDL-C) concentrations. However, LDL-C response is variable and influenced by many factors, including racial ancestry, with attenuated response in blacks compared with whites. We hypothesized that single nucleotide polymorphisms in the gene encoding HMGCR, a rate-limiting enzyme in cholesterol synthesis and the direct enzymatic target of statins, contribute to variation in statin response.
Methods and Results— Genomic resequencing of HMGCR in 24 blacks and 23 whites identified 79 single nucleotide polymorphisms. Eleven single nucleotide polymorphisms were selected to tag common linkage disequilibrium clusters. These single nucleotide polymorphisms and the common haplotypes inferred from them were tested for association with plasma LDL-C and LDL-C response to simvastatin treatment (40 mg/d for 6 weeks) in 326 blacks and 596 whites. Black carriers of H7 and/or H2 had significantly lower baseline LDL-C (P=0.0006) and significantly attenuated LDL-C response compared with black participants who did not carry either haplotype as measured by absolute response (–1.23±0.04 mmol/L, n=209, versus –1.45±0.06 mmol/L, n=117; P=0.0008) and percent response (–36.9±1.0% versus –40.6±1.3%; P=0.02), but no haplotype effect was observed in whites. Percent LDL-C response was lowest in carriers of both H2 and H7, all but one of whom were black (–28.2±4.9%, n=12 H2+H7 carriers, versus –41.5±0.5%, n=650 H2/H7 noncarriers; P=0.001). LDL-C responses in H7 and/or H2 noncarriers were indistinguishable between blacks and whites.
Conclusions— HMGCR gene polymorphisms are associated with reduced plasma LDL-C and LDL-C response to simvastatin, and these effects are most evident in blacks.
Key Words: cholesterol • genetics • lipids • lipoproteins • statins
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Introduction |
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Physicians commonly prescribe 3-hydroxyl-3-methylglutaryl coenzyme A (HMGCR) inhibitors, or statins, for primary and secondary prevention of cardiovascular disease and act to lower plasma low-density lipoprotein cholesterol (LDL-C) concentrations.1 Although statin therapy has been proven to reduce the risk of cardiovascular events, nearly a third of treated individuals do not meet lipid-lowering goals.2–4 Multiple parameters have been reported to contribute to variations in LDL-C response to statin treatment, including age, smoking status, body weight, diet, physical activity, racial ancestry, and baseline plasma LDL-C concentrations.5–7 Baseline LDL-C concentrations are under genetic influence.8–10 Genetic factors also are likely contributors to the variation in statin response, as suggested by several recent studies.11–14
Clinical Perspective p 1544
Statins act to reduce plasma LDL-C through competitive enzymatic inhibition of HMGCR, which catalyzes an early rate-limiting step in cholesterol synthesis.15 This inhibition causes a reduction in hepatocellular cholesterol production, triggering sterol regulatory element-binding protein–mediated upregulation of LDL receptor expression and subsequent clearance of plasma LDL-C.16 The central role of HMGCR in hepatic regulation of plasma cholesterol makes it a primary candidate gene for studies of genetic sequence variation associated with both basal and statin-responsive lipid and lipoprotein concentrations.
To further assess the contribution of genetic factors to variations in statin response, we undertook the Cholesterol and Pharmacogenetics (CAP) study.7 In this trial, 326 blacks and 596 whites were treated with simvastatin 40 mg/d for 6 weeks. Baseline LDL-C levels did not differ by racial ancestry, but whites had a 3.7% greater LDL-C reduction in response to simvastatin treatment than blacks.7 We used the CAP population to test for associations of polymorphisms in the gene encoding HMGCR with plasma LDL-C concentrations and LDL-C change in response to simvastatin treatment and examined the contribution of these polymorphisms to racial differences in statin response.
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Methods |
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Study Population
The CAP study, a 6-week simvastatin (40 mg/d) trial designed to examine genetic factors affecting response to therapy in blacks and whites, has been previously described.7 Inclusion criteria included age
30 years, total serum cholesterol concentration within the range of 4.14 to 10.36 mmol/L, serum triglyceride <4.52 mmol/L, fasting glucose <6.99 mmol/L, and no medical conditions or use of drugs known to affect lipoprotein metabolism. Participants were considered black if 3 of their grandparents were reported to be African or African American; they were considered white if 3 of their grandparents were reported to be Caucasian. Potential participants not meeting either criterion were not enrolled. Subjects were recruited from 2 clinical centers: the University of California, Los Angeles, School of Medicine and San Francisco (Calif) General Hospital. Informed consent was obtained and approved by the Institutional Review boards at those institutions and all other participating institutions. Baseline health, demographic, physical examination, and laboratory data were obtained on enrollment. Sixty-three subjects dropped out before completing the final visit, leaving 944 subjects (335 blacks and 609 whites). HMGCR genotypes were obtained from 922 subjects (326 blacks and 596 whites). Blood specimens from each subject were obtained after an overnight fast at the screening visit, after a 2-week placebo run-in (enrollment visit), and after 4 and 6 weeks of simvastatin administration. Compliance was assessed by pill count every 2 weeks and averaged >95%.
Laboratory Measurements
Plasma total cholesterol and triglyceride concentrations were determined by enzymatic procedures on an Express 550 Plus analyzer (Ciba Corning, Oberlin, Ohio) and were consistently under control as monitored by the Centers for Disease Control–National Heart, Lung, and Blood Institute standardization program. High-density lipoprotein cholesterol (HDL-C) was measured after dextran sulfate precipitation of plasma,17 and LDL-C was calculated with the Friedewald formula.18 Apolipoprotein (apo) A-I, apoB, and apoC-III concentrations were measured by immunoturbidimetric assay on the Express 550 Plus analyzer.19 Concentrations of total cholesterol, LDL-C, HDL-C, and triglyceride were obtained at all 4 time points. Values for apoAI, apoB, and apoC-III were obtained at enrollment visit and after 6 weeks of treatment.
Sequence Variation Discovery, Tag Single Nucleotide Polymorphism Identification, and Haplotype Construction
DNA sequence variants were identified by genomic resequencing of the entire HMGCR gene plus 2.5 kb upstream and 1.5 kb downstream in 24 black and 23 white individuals. This method of variant identification is estimated to detect >99% of variant sites with minor allele frequency >5%.20 Overlapping segments were amplified via polymerase chain reaction and sequenced. Sequences were assembled with the Phred, Phrap, and Consed programs, and PolyPhred was used to identify 79 sequence variants (Table I and Figure I of the online Data Supplement). The University of California at Santa Cruz Golden Path human genome assembly was used as a reference sequence to identify gene architecture and to map identified single nucleotide polymorphisms (SNPs). A set of 10 maximally informative tagSNPs were identified to represent common linkage disequilibrium clusters (Data Supplement Table II) with the LDselect algorithm as implemented in the MultiPop-TagSelect program using thresholds of r2>0.64 and minor allele frequency >5%.21,22 This software selected a near-minimal set of tagSNPs that account for all observed patterns of linkage disequilibrium in both black and white Americans. These 10 SNPs were genotyped in 445 CAP subjects with BeadArray technology (Illumina, San Diego, Calif). Genotypes for all SNPs except HMGCR:013752 were confirmed and extended to 922 subjects with Sequenom massARRAY technology (San Diego, Calif). Genotypes for each SNP were identified in 900 to 922 subjects, depending on the fail rate for each genotyping assay (0.0% to 2.3% fail rate). HMGCR:013752 did not pass Sequenom assay design but was genotyped in an additional 401 subjects, for a total of 846 subjects, with BeadArray technology. An 11th SNP reported to be associated with attenuated LDL-C response in the Pravastatin Inflammation/CRP Evaluation (PRINCE) study (PRINCE SNP12, HMGCR:011898, or rs17244841) was genotyped in 848 subjects with BeadArray technology.12 All SNPs were in Hardy-Weinberg equilibrium within each racial group (Data Supplement Table II). Three SNPs did not pass Hardy-Weinberg equilibrium when analyzed in the total population, likely because of differences in allelic frequency between blacks and whites (HMGCR:000177, HMGCR:020144, and HMGCR:024558; supplementary Table II). Linkage disequilibrium among tagSNPs was determined with Haploview (supplementary Table III).23 Haplotypes were reconstructed with the bayesian statistical method as implemented in the PHASE version 2.0 program separately in blacks and in whites.24
Statistical Analyses
For total cholesterol, LDL-C, HDL-C, and triglycerides, values were not significantly different between the screening visit and enrollment visit or between 4 and 6 weeks after treatment. Thus, the averages of these values were used to represent baseline values and treatment values, respectively. Tests of Hardy-Weinberg equilibrium and comparisons of genotypic frequencies between racial groups were analyzed with the 
2 test. Associations between individual SNPs and lipid or lipoprotein parameters were assessed by ANCOVA using the general model. For SNPs with <10 minor allele homozygotes (HMGCR:003510, HMGCR:PRINCE SNP12, and HMGCR:024558), the dominant model was used. Because <10 minor allele homozygotes were identified within the majority of the assigned haplotypes, the dominant model was used to assess associations between all haplotypes and lipid parameters. Because previous analysis of the phenotypic data from the CAP population demonstrated a significant relationship between LDL-C response to simvastatin and age, race, and smoking status, these 3 factors were included as covariates in all analyses.7 In addition, ANCOVA was used to confirm that the significance of results persisted after adjustment for sex, body mass index, and compliance. To minimize the impact of multiple testing, we estimated the false discovery rate q value within each phenotype in relation to SNPs or haplotypes using QVALUE.25 The false discovery rate estimates the proportion of false positives among tests found to be significant.26 Only those associations passing this correction (q<0.05) are described in the Results. Log transformations of plasma triglyceride concentrations were performed to improve the symmetry of the distributions. All statistical analyses were performed with JMP version 6.0.2 software (SAS Institute Inc, Cary, NC).
The authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Ten tagSNPs in the gene encoding HMGCR were analyzed for associations with plasma LDL-C response to simvastatin treatment (Table 1
). Two SNPs, HMGCR:024558 and PRINCE SNP12, were significantly associated with altered LDL-C response. HMGCR SNPs also were analyzed for associations with statin-mediated changes in total cholesterol and apoB. HMGCR:013752 was significantly associated with apoB response (P=0.004; Table 1). Post hoc analysis determined that HMGCR:013752 carriers had significantly greater response than did noncarriers (P<0.05). HMGCR:013752 carriers also had significantly higher baseline apoB (0.958±0.009 g/L, n=558, versus 0.918±0.012 g/L, n=288; P=0.005) and percent apoB response (–30.4±0.6%, n=558, versus –28.3±0.8%, n=288; P=0.02) compared with noncarriers. No significant associations were observed between HMGCR SNPs and change in total cholesterol (Table 1) or change in triglycerides, HDL-C, apoAI, or apoC-III (supplementary Table IV). In addition, no SNPs were significantly associated with posttreatment lipid or lipoprotein concentrations.
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Haplotypes were inferred from SNP genotypes, and for the 10 haplotypes with minor allele frequency >5%, haplotype pairs were assigned to each subject (Table 2). HMGCR haplotypes were significantly associated with LDL-C response (overall value for haplotype association, P=0.002) and total cholesterol response (P=0.005) but not apoB response (P=0.15) or change in other lipid and lipoprotein phenotypes. Because haplotype prevalence differed between racial groups for all haplotypes except H10 (Table 2), analyses also were performed separately in blacks and whites. In blacks, HMGCR haplotypes also were significantly associated with LDL-C and total cholesterol responses (P=0.008 and P=0.004), but no significant associations were observed in whites. Among individual haplotypes, H7, defined by the minor alleles for PRINCE SNP12 and HMGCR:024558, was associated with significantly reduced LDL-C response in the total study group (P=0.007) and in blacks (P=0.0009) but not in whites (Table 3). H7 also was associated with reduced baseline LDL-C concentrations in a similar manner (Table 3). Analysis of percent LDL-C response, a variable used as a means of adjustment for baseline effects, demonstrated a significant association with H7 only in blacks (P=0.02; Table 3). A second haplotype, H2, was associated with a smaller LDL-C response specifically in blacks (P=0.04; Table 3). H2 was not significantly associated with baseline LDL-C concentrations or percent LDL-C response. Similar associations were observed between both haplotypes and total cholesterol response (supplementary Table V). There were no associations of individual haplotypes with changes in the other queried lipid or lipoprotein parameters or with posttreatment lipid or lipoprotein concentrations.
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We next examined the combined contribution of HMGCR H2 and H7 to race-specific variation in LDL-C response (Table 4). In the total CAP population, 260 subjects were inferred to carry either H2 or H7, and 12 subjects were inferred to carry both H2 and H7 (H2+H7). The combined group of 272 H2 and/or H7 (H2/H7) carriers had 
6% lower baseline LDL-C than noncarriers (3.27±0.05 versus 3.48±0.03 mmol/L; P=0.0004). Although there was not a significant race-by-genotype interaction, baseline LDL-C concentrations were significantly lower in black H2/H7 carriers than black noncarriers of either haplotype (P=0.0006) with no detectable haplotype effect on baseline LDL-C in whites.
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Absolute LDL-C change also was significantly reduced in H2/H7 carriers compared with noncarriers (P=0.02; Table 4). This association demonstrated a significant race-by-genotype interaction (P=0.04): LDL-C change in H2/H7 carriers was reduced in relation to noncarriers in blacks (P=0.0008) but not whites (Table 3). Furthermore, black H2/H7 carriers had significantly reduced LDL-C change compared with white H2/H7 carriers (P=0.01), but response was indistinguishable between black and white H2/H7 noncarriers.
To adjust for the influence of baseline LDL-C on response, we again examined percent LDL-C response (Table 4). Although the combination of H2/H7 haplotypes was not significantly associated with percent LDL-C response in the total CAP population, there was a significant race-by-genotype interaction (P=0.02). As with absolute LDL-C response, black H2/H7 carriers had a significant reduction in percent LDL-C response compared with black noncarriers (P=0.02). Because black H2/H7 carriers had lower baseline LDL-C than black H2/H7 noncarriers, the observed attenuation in LDL-C response resulted in a narrowing of the difference in absolute LDL-C concentrations between carriers and noncarriers after treatment (2.03±0.04 mmol/L in carriers versus 2.15±0.07 mmol/L in noncarriers; P=0.15). This combination of haplotypes did not affect percent LDL-C response in whites (Table 4). As with absolute LDL-C response, black H2/H7 carriers had a significantly lower percent LDL-C response than did white H2/H7 carriers (P=0.002), but no difference was detected between races in noncarriers. These data suggest that these haplotypes may be partially responsible for the influence of racial ancestry on percent LDL-C response (P<0.0001; Table 4).7 Similar associations of H7 and H2 were observed with total cholesterol (supplementary Table VI).
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Discussion |
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Statin-mediated reduction in LDL-C is an effective and widely used pharmaceutical approach for reducing cardiovascular disease risk.1,3,4,27 We and others have demonstrated that individual responses to statin therapy are variable and are influenced by many factors, including racial ancestry.7 Specifically, we have observed a 3.9% attenuation in LDL-C–lowering response to simvastatin in blacks compared with whites in the CAP population.7 In this study, we have shown that common SNP haplotypes in the gene encoding HMG-CoA reductase, an early, rate-limiting enzyme in cholesterol synthesis and the direct target of statins, contribute to variations in the magnitude of simvastatin-induced LDL-C reduction and to the racial difference in this response.7
Two common HMGCR haplotypes, H7 and H2, were associated with attenuated LDL-C response specifically in blacks. The association of H7 with reduced statin response has been reported previously by Chasman and colleagues,12 who observed a 19% smaller reduction in LDL-C response to pravastatin treatment. Although this observation is similar to that in the present study, Chasman and colleagues did not observe an association of H7 with baseline LDL-C. Furthermore, the majority of PRINCE participants were white (88.7% of 1536 subjects). A third study failed to detect an effect of this haplotype in a smaller, predominantly white (89.1%) population, most of whom were treated with atorvastatin.13 Among possible reasons for these discrepancies are differences in the magnitude of the pharmacogenetic associations for different statins, differing extents of population admixture, and population differences in the linkage disequilibrium of H7 with the true causal variant. Our results suggest that the strength of the H7 association is dependent on the presence of a second haplotype, H2, which had a much higher prevalence in blacks than whites (32% versus 2%; Table 2). Notably, among subjects who carried neither H2 nor H7 (36.0% of blacks and 89.4% of whites), there was no racial difference in LDL-C change, suggesting a significant contribution of these 2 haplotypes to the attenuation of response observed in blacks.7 Within CAP, percent LDL-C change in response to simvastatin treatment was lowest in the 12 subjects inferred to carry both H2 and H7 (–28.2±4.9%, n=12 H2+H7 carriers, versus –41.5±0.5%, n=650 H2/H7 noncarriers; P=0.001), 11 of whom were black. Indeed, in the absence of these 11 H2+H7 carriers, H7 was no longer associated with reduced percent LDL-C response in blacks.
The mechanism underlying the association of the HMGCR haplotypes with LDL-C concentrations or LDL-C response to statin treatment has not yet been determined. Because statins mediate LDL-C reduction by inhibiting HMGCR activity through competitive enzymatic binding, a dual association of this genetic variation with both baseline LDL-C concentrations and LDL-C response could result from structural modifications to the HMGCR active site that alter binding affinities for both HMG-CoA and statins. Although all of the involved SNPs are intronic, they may promote changes in protein sequence by influencing mRNA splicing. Alternatively, they may be in linkage disequilibrium with causal nonsynonymous SNPs, although further resequencing of HMGCR H2 or H7 carriers has failed to identify any such variation (D.C. Crawford, PhD, Dr Krauss, and Dr Nickerson, unpublished data, 2007).
This is the first report that genetic variation in HMGCR may contribute to variations in plasma cholesterol and LDL-C concentrations. Genetic associations with plasma total and LDL cholesterol concentrations have been found for several other genes, including LDLR, APOE, APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9).28–31 Rare mutations in these genes are associated with heritable forms of hypercholesterolemia, and a number of pharmacogenetic studies suggest that common variation in APOE affects statin-mediated LDL-C response.14,32 Rare nonsense mutations in PCSK9, a protease involved in regulation of LDLR expression, are associated with substantial reductions in both plasma LDL-C concentrations and incidence of coronary events.9,33 In addition, common variants in PCSK9 are associated with smaller reductions (3.5% to 30%) in LDL-C concentrations.34 Alterations in LDL-C associated with HMGCR haplotypes are of a magnitude similar to the observed effects of PCSK9 and may represent another heritable effect on plasma cholesterol concentrations and associated cardiovascular disease risk.
We found that the statin-induced reduction in apoB in carriers of HMGCR:013752 was significantly greater than in noncarriers. Although the magnitude of the difference was too small for clinical relevance, association with apoB response that was independent of LDL-C or triglyceride response suggests that HMGCR:013752 may affect a specific apoB-containing particle subpopulation. In preliminary analysis in a subset of CAP participants, we found that HMGCR:013752 carriers had greater reductions in total mass of intermediate density lipoprotein particles as measured by analytical ultracentrifugation (–114.9±3.8 mg/L, n=191 carriers, versus –100.8±5.5 mg/L, n=103 noncarriers; P=0.004) (Dr Krauss, unpublished data, 2007). It may be that HMGCR:013752 affects statin responsiveness by mechanisms that differ from those underlying the relationship of H2/H7 and LDL-C response.
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Conclusions |
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We have identified a variation in the gene encoding HMGCR that is associated with a reduction in both LDL-C concentrations and LDL-C change in response to simvastatin treatment. The overall contribution of HMGCR genotypes to the variation in simvastatin-mediated LDL cholesterol-lowering was small, accounting for <2% of the overall variance in response. However, LDL-C response was 32% lower in carriers than in noncarriers of the combined H2+H7 haplotype, all but one of whom were black. Such reductions in statin response would be estimated to yield a 12% attenuated reduction in cardiovascular disease–related death and a 14% attenuated reduction in incidence of primary coronary events.35 It is not known to what extent these findings may apply to statin drugs other than simvastatin and pravastatin. Moreover, because the HMGCR genotype associations with LDL-C response were demonstrated at a single dose of both simvastatin7 and pravastatin,12 it remains to be tested whether differences in statin response between carriers and noncarriers persist at higher drug doses. These findings indicate the potential for pharmacogenetic studies to add to our understanding of the complex mechanisms controlling plasma LDL-C concentrations and ultimately to identifying composite influences of variation in multiple genes that may contribute substantially to the overall variation in statin efficacy.10,32
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Acknowledgments |
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We thank Patricia Blanche and the Core Lipoprotein Laboratory at the Children’s Hospital of Oakland Research Institute for laboratory measurements and Dr Kenneth Beckman of the Children’s Hospital of Oakland Research Institute Genotyping Facility for additional genotyping.
Sources of Funding
This work was funded by National Institutes of Health grant U01 HL69757. Additional support was provided by the Cedars-Sinai Board of Governors’ Chair in Medical Genetics (Dr Rotter). Genotyping was supported in part by grant M01-RR00425 to the Cedars-Sinai Medical Center General Clinical Research Center Genotyping Core (Dr Taylor). Simvastatin was a gift from Merck Research Laboratories, and additional support was provided by a grant from Pfizer, Inc.
Disclosures
Dr Krauss has served as a consultant to Merck, Merck-Schering Plough, Pfizer, Abbott, Isis Pharmaceuticals, and Bristol-Myers Squibb and has received grant support from Merck, Merck-Schering Plough, Pfizer, and King Pharmaceuticals. Dr Simon has served as a consultant for CA Walnut Commission. Dr Hulley has served as a consultant to Pfizer, Anthera, Atherogenics, and Eli Lily and has received grant support from Merck. The remaining authors report no conflicts.
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Footnotes |
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Clinical trial registration information–URL: http://clinicaltrials.gov. Unique identifier: NCT00451828.
The online Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.708388/DC1.
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Circulation 2008 117: 1499.
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