Phenotypic Predictors of Response to Simvastatin Therapy Among African-Americans and Caucasians: The Cholesterol and Pharmacogenetics (CAP) Study

Simon, Joel A.; Lin, Feng; Hulley, Stephen B.; Blanche, Patricia J.; Waters, David D.; Shiboski, Stephen; Rotter, Jerome I.; Nickerson, Deborah A.; Yang, Huiying; Saad, Mohammed F.; Krauss, Ronald M.

doi:10.1016/j.amjcard.2005.09.134

Cited by 182 publications

(203 citation statements)

References 10 publications

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“…Of the 609 self-reported Caucasian (white) and 335 self-reported AfricanAmerican (black) participants of the CAP 40-mg simvastatin/day 6-week clinical trial (ClinicalTrials.gov ID: NCT00451828), 7 LCLs from 100 Caucasian and 50 African-American CAP participants were used in our RNA-seq analyses after quality control filtering. Informed written consent was obtained from the IRBs (Institutional Review Boards) of the sites of recruitment, the University of California Los Angeles and the University of California San Francisco.…”

Section: Study Populationmentioning

confidence: 99%

“…TG was measured in fasting plasma samples at two pre-treatment and two on-treatment time points. 7 TG statin response (log(mean on-treatment TG) − log(mean pretreatment TG)) of this subset was representative of the entire CAP population (Supplementary Figure S1). The pravastatin inflammation/CRP evaluation (PRINCE) 24 week clinical trial of 40 mg per day pravastatin has been previously described.…”

Section: Study Populationmentioning

confidence: 99%

“…Though statins have well-documented clinical efficacy, there is a large degree of inter-individual variability in lipid lowering by statins, 7 and many individuals continue to have CVD events despite statin treatment. 8 There is some debate as to whether statins are as effective at primary prevention of CVD events in women as they are in men, [9][10][11] so further investigation of potential sex differences in statin response is warranted.…”

Section: Introductionmentioning

confidence: 99%

“…Toward this objective, we performed transcriptomic analysis on a panel of lymphoblastoid cell lines (LCLs) derived from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial. 7,24 Though LCLs have been transformed by Epstein-Barr virus (EBV) and thus may not perfectly reflect the genetic background of the human donors, we and others have shown that they are a useful model for the study of cholesterol metabolism and statin response in vitro. [24][25][26][27] Using RNA-seq data collected from 100 Caucasian and 50 African-American controland statin-exposed CAP LCLs, we identified genes with in vitro statin-induced expression changes that were correlated with plasma TG response in the cell line donors.…”

Section: Introductionmentioning

confidence: 99%

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Erratum: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner

Theusch¹,

Kim²,

Stevens³

et al. 2016

Pharmacogenomics J

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Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR = 15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho = 0.32, q = 0.11) was driven by men (interaction P = 0.0055). rs73161338 was associated with INSIG1 expression changes (P = 5.4 × 10 − 5 ) and TG response in two statin clinical trials (P = 0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P = 5.6 × 10 −6 ). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner.

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Section: Study Populationmentioning

confidence: 99%

Section: Study Populationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Erratum: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner

Theusch¹,

Kim²,

Stevens³

et al. 2016

Pharmacogenomics J

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“…A study conducted by Krauss et al [17] identified some statin influenced pathways that may contribute to variability in clinical efficacy and adverse effects. Samples were taken from participants of the 'cholesterol and pharmacogenetics study' [18] in which 40 mg of simvastatin was given to 944 patients for 6 weeks. Samples for metabolomics assessment were taken from 48 individuals, half categorized as good responders (the upper 10 % of LDL-C response) and the remaining half as poor responders.…”

Section: Statinsmentioning

confidence: 99%

Metabolomics: A Tool Ahead for Understanding Molecular Mechanisms of Drugs and Diseases

2014

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To refer to metabolomics as a new field is injustice to ancient doctors who used ants to diagnose the patients of diabetes having glycosuria. Measuring the levels of molecules in biological fluids believing them to be the representatives of biochemical pathways of carbohydrates, fats, proteins, nucleic acids or xenobiotic metabolism and deciphering meaningful data from it is what can be called as metabolomics, just as high glucose in urine suggests diabetes mellitus. Genomics, epigenetics, proteomics, transcriptomics finally converge to metabolomics, which are the signatures of mechanisms of bodily processes which is why understanding this science can have many applications. Just as a heap of stones does not make a house, having data of metabolite levels does not make it a science. Analyzing this data would help us in constructing biochemical pathways and their interactions. Analyzing the changes caused by a drug in the metabolite levels would help us in deriving the mechanisms by which the drug acts. Comparing metabolite levels in diseased with non-diseased, good-responders with poor-responders to a particular drug can help in identifying new markers of a disease or response to a drug respectively. Also, metabolite levels of an endogenous substrate can tell us the status of a person's metabolizing enzymes and help in drug dose titration. Generating hypothesis by identifying the new molecular markers and testing their utility in clinics seems to be the most promising approach in future. This review narrates the modes of quantifying and identifying metabolome, its proposed applications in diagnosis, monitoring and understanding the diseases and drug responses. We also intend to identify hindrances in using metabolomics in clinical studies or experiments.

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Interindividual Variation in Low-Density Lipoprotein Cholesterol Level Reduction With Evolocumab

et al. 2019

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IMPORTANCELittle is known about the heterogeneity in low-density lipoprotein cholesterol levels (LDL-C) lowering with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor medications.OBJECTIVE To evaluate the interindividual variability in LDL-C reduction with the PCSK9 inhibitor drug evolocumab. DESIGN, SETTING, AND PARTICIPANTSWe examined the percentage change in LDL-C levels from baseline in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, a placebo-controlled randomized clinical trial of the PCSK9 inhibitor evolocumab in patients with stable atherosclerotic cardiovascular disease who were taking statin medications. Patients in either treatment arm who had high baseline LDL-C variability during screening and either did not receive the study drug, altered their background lipid-lowering therapy regimen, or had no LDL-C level sample in week 4 were excluded from the primary analysis. Analyses in the patients were stratified by treatment arm. Data was collected from 2013 to 2016, and data were analyzed from January 2018 to November 2018. MAIN OUTCOMES AND MEASURES Interindividual variation in percent reduction in LDL-C with evolocumab.RESULTS There were 27 564 individuals in the cohort; after exclusions for baseline variability (n = 3524) or alterations in background lipid therapy and other causes (n = 2272), 21 768 patients remained. At week 4, the median percent reduction in LDL-C levels from baseline was 66% (interquartile range, 54%-76%; median [interquartile range] baseline value, 90 [79-105] mg/dL; postchange value, 31 [21-44] mg/dL) with evolocumab. During the first year, a total of 10 325 of 10902 patients in the evolocumab group (94.7%) had a reduction 50% or greater in LDL-C levels, 10 669 of 10 902 (97.9%) had a reduction 30% or more, and 10 849 of 10 902 (99.5%) had any reduction in LDL-C levels. Fifty-three patients (0.5%) had no apparent reduction in LDL-C levels. In the placebo arm, the median LDL-C reduction was 4% (interquartile range, 6% increase to 13% reduction; baseline median [IQR] value, 90 [79-106] mg/dL; postchange value, 87 [74-103] mg/dL) at 4 weeks. Waterfall plots showed notable variability in the top and bottom 5% of patients for both evolocumab and placebo groups, with large changes in LDL-C levels in the placebo group (increases of Ն25%, 531 patients [4.9%]; decreases of Ն25%, 985 patients [9.1%]). At 4 weeks, the placebo-adjusted reductions in LDL-C levels with evolocumab were 50% or greater in 9839 of 10 866 patients (90.5%) and 30% or greater in 10 846 of 10 866 patients (99.8%). Results were consistent across clinically relevant subgroups.

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Phenotypic Predictors of Response to Simvastatin Therapy Among African-Americans and Caucasians: The Cholesterol and Pharmacogenetics (CAP) Study

Cited by 182 publications

References 10 publications

Erratum: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner

Erratum: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner

Metabolomics: A Tool Ahead for Understanding Molecular Mechanisms of Drugs and Diseases

Interindividual Variation in Low-Density Lipoprotein Cholesterol Level Reduction With Evolocumab

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