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Prediction of LDL cholesterol response to statin using transcriptomic and genetic variation.

ABSTRACT: Statins are widely prescribed for lowering LDL-cholesterol (LDLC) levels and risk of cardiovascular disease. There is, however, substantial inter-individual variation in the magnitude of statin-induced LDLC reduction. To date, analysis of individual DNA sequence variants has explained only a small proportion of this variability. The present study was aimed at assessing whether transcriptomic analyses could be used to identify additional genetic contributions to inter-individual differences in statin efficacy.Using expression array data from immortalized lymphoblastoid cell lines derived from 372 participants of the Cholesterol and Pharmacogenetics clinical trial, we identify 100 signature genes differentiating high versus low statin responders. A radial-basis support vector machine prediction model of these signature genes explains 12.3% of the variance in statin-mediated LDLC change. Addition of SNPs either associated with expression levels of the signature genes (eQTLs) or previously reported to be associated with statin response in genome-wide association studies results in a combined model that predicts 15.0% of the variance. Notably, a model of the signature gene associated eQTLs alone explains up to 17.2% of the variance in the tails of a separate subset of the Cholesterol and Pharmacogenetics population. Furthermore, using a support vector machine classification model, we classify the most extreme 15% of high and low responders with high accuracy.These results demonstrate that transcriptomic information can explain a substantial proportion of the variance in LDLC response to statin treatment, and suggest that this may provide a framework for identifying novel pathways that influence cholesterol metabolism.

SUBMITTER: Kim K

PROVIDER: S-EPMC4180544 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Prediction of LDL cholesterol response to statin using transcriptomic and genetic variation.

Kim Kyungpil K Bolotin Eugene E Theusch Elizabeth E Huang Haiyan H Medina Marisa W MW Krauss Ronald M RM

Genome biology 20140930 9

<h4>Background</h4>Statins are widely prescribed for lowering LDL-cholesterol (LDLC) levels and risk of cardiovascular disease. There is, however, substantial inter-individual variation in the magnitude of statin-induced LDLC reduction. To date, analysis of individual DNA sequence variants has explained only a small proportion of this variability. The present study was aimed at assessing whether transcriptomic analyses could be used to identify additional genetic contributions to inter-individua ...[more]

PMID: 25316374

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Project description:BackgroundAggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the "The lower is the better" concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a "threshold" value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship.MethodsFor a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the "threshold" value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C - threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood.ResultsFor primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01-1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C.ConclusionsOur analysis model suggests that a "threshold" value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes.Trial registrationhttp://www.Clinicaltrialsgov . Unique identifier: NCT01042730.

Dataset Information

Prediction of LDL cholesterol response to statin using transcriptomic and genetic variation.

Publications

Prediction of LDL cholesterol response to statin using transcriptomic and genetic variation.

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