Dataset Information

Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin.

ABSTRACT: Although statins are efficacious for lowering low-density lipoprotein cholesterol, there is wide interindividual variation in response. We tested the extent to which combined effects of common alleles of LDLR and HMGCR can contribute to this variability.Haplotypes in the LDLR 3'-untranslated region (3-UTR) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics trial (335 blacks and 609 whites). LDLR haplotype 5 (LDLR L5) was associated with smaller simvastatin-induced reductions in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (P=0.0002 to 0.03) in blacks but not whites. The combined presence of LDLR L5 and previously described HMGCR haplotypes in blacks was associated with significantly attenuated apolipoprotein B reduction (-22.4+/-1.5%, N=89) compared with both noncarriers (-30.6+/-1.5%, N=78, P=0.0001) and carriers of either individual haplotype (-28.2+/-1.1%, N=158, P=0.001). We observed similar differences when measuring simvastatin-mediated induction of low-density lipoprotein receptor surface expression using lymphoblast cell lines (P=0.03).We have identified a common LDLR 3-UTR haplotype that is associated with attenuated lipid-lowering response to simvastatin treatment. Response was further reduced in individuals with both LDLR and previously described HMGCR haplotypes. Previously identified racial differences in statin efficacy were partially explained by the greater prevalence of these combined haplotypes in blacks.

SUBMITTER: Mangravite LM

PROVIDER: S-EPMC2909117 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin.

Mangravite Lara M LM Medina Marisa Wong MW Cui Jinrui J Pressman Sheila S Smith Joshua D JD Rieder Mark J MJ Guo Xiuqing X Nickerson Deborah A DA Rotter Jerome I JI Krauss Ronald M RM

Arteriosclerosis, thrombosis, and vascular biology 20100422 7

<h4>Objective</h4>Although statins are efficacious for lowering low-density lipoprotein cholesterol, there is wide interindividual variation in response. We tested the extent to which combined effects of common alleles of LDLR and HMGCR can contribute to this variability.<h4>Methods and results</h4>Haplotypes in the LDLR 3'-untranslated region (3-UTR) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics trial (335 blacks and 60 ...[more]

PMID: 20413733

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Project description:Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy.Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks), Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks), and Treating to New Targets (10 mg/day atorvastatin, 8 weeks). Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8 x 10(-8)). This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0 x 10(-6)). Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol.Using combined GWA analysis from three clinical trials involving nearly 4,000 individuals treated with simvastatin, pravastatin, or atorvastatin, we have identified SNPs that may be associated with variation in the magnitude of statin-mediated reduction in total and LDL-cholesterol, including one in the CLMN gene for which statistical evidence for association exceeds conventional levels of genome-wide significance.PRINCE and TNT are not registered. CAP is registered at Clinicaltrials.gov NCT00451828.

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Project description:UnlabelledStatins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution ("good" and "poor" responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment.Trial registrationClinicalTrials.gov NCT00451828.

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Dataset Information

Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin.

Publications

Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin.

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