| Physiogenomic analysis of statin-treated patients: domain-specific counter effects within the ACACB gene on low-density lipoprotein cholesterol? | |
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MedLine Citation:
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PMID: 20602615 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIM: Administered at maximal dosages, the most common statins--atorvastatin, simvastatin and rosuvastatin--lower low-density lipoprotein cholesterol (LDLC) by an average of 37-57% in patients with primary hypercholesterolemia. We hypothesized novel genetic underpinnings for variation in LDLC levels in the context of statin therapy. MATERIALS & METHODS: Genotyping of 384 SNPs in 202 volunteers from a lipid outpatient clinic was accomplished and LDLC levels obtained from chart records. The SNPs were distributed across 222 genes representing physiological pathways such as general metabolism, cholesterol biochemistry, cardiovascular function, inflammation, neurobiology and cell proliferation. We discovered significant associations with LDLC levels for the rs34274 SNP (p < 0.0002) and for rs2241220 (p < 0.008) in the acetyl-coenzyme A carboxylase beta (ACACB) gene. When corrected for multiple testing, the false-discovery rate associated with rs34274 was 0.076 (significance threshold: 0.10) and for rs2241220 the false-discovery rate was 0.93 (not significant). The acetyl coenzyme A carboxylase beta enzyme synthesizes malonyl coenzyme A, an essential substrate for hepatic fatty acid synthesis and an inhibitor of fatty acid oxidation. RESULTS: The SNPs were in weak linkage disequilibrium (D = 0.302). Minor alleles at these sites demonstrate opposing influences on LDLC; the C>T substitution at rs34724 is a risk marker and the C>T substitution at rs2241220 a protective marker for LDLC levels. These SNPs hypothetically influence enzymatic activity through different mechanisms, rs34274 through the PII promoter and rs2241220 via alteration of the protein's responsiveness to allosteric influence. CONCLUSION: Physiogenomic evidence suggests a novel link between LDLC levels and the regulation of fatty acid metabolism. The findings complement previously discovered novel SNP relationships to myalgia (pain) and myositis (serum creatine kinase activity). By genotyping for myositis, myalgia and LDLC levels, a physiogenomic model may be developed to help clinicians maximize effectiveness and minimize side effects in prescribing statins. |
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Authors:
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Gualberto Ruaño; Paul D Thompson; John P Kane; Clive R Pullinger; Andreas Windemuth; Richard L Seip; Mohan Kocherla; Theodore R Holford; Alan H B Wu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Pharmacogenomics Volume: 11 ISSN: 1744-8042 ISO Abbreviation: Pharmacogenomics Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-06 Completed Date: 2011-01-06 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 100897350 Medline TA: Pharmacogenomics Country: England |
Other Details:
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Languages: eng Pagination: 959-71 Citation Subset: IM |
Affiliation:
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Genomas, Inc, 67 Jefferson Street, Hartford, CT 06106, USA. g.ruano@genomas.net |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetyl-CoA Carboxylase
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genetics Aged Anticholesteremic Agents / therapeutic use* Cholesterol / blood Cholesterol, LDL / blood* Cross-Sectional Studies Female Fluorobenzenes / therapeutic use Genotype Heptanoic Acids / therapeutic use Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage, adverse effects, therapeutic use* Hypercholesterolemia / chemically induced, drug therapy Male Middle Aged Polymorphism, Single Nucleotide* Pyrimidines / therapeutic use Pyrroles / therapeutic use Simvastatin / therapeutic use Sulfonamides / therapeutic use |
| Grant Support | |
ID/Acronym/Agency:
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4R 44GM085201-02/GM/NIGMS NIH HHS; R44 GM085201-03/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anticholesteremic Agents; 0/Cholesterol, LDL; 0/Fluorobenzenes; 0/Heptanoic Acids; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Pyrimidines; 0/Pyrroles; 0/Sulfonamides; 110862-48-1/atorvastatin; 287714-41-4/rosuvastatin; 57-88-5/Cholesterol; 79902-63-9/Simvastatin; EC 6.4.1.2/Acetyl-CoA Carboxylase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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