Published Online
on December 9, 2008

A more recent version of this article appeared on December 1, 2008

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Original Article

Pharmacogenetic predictors of statin mediated LDLc reduction and dose response

Deepak Voora¹; Svati H. Shah¹; Carol R. Reed²; Jun Zhai¹; David R. Crosslin¹; Chad J. Messer³; Benjamin A. Salisbury² and Geoffrey S. Ginsburg^1,4

¹ Duke University, Durham, NC;
² PGxHealth, LLC, New Haven, CT;
³ Formerly of Genaissance Pharmaceuticals, New Haven, CT

⁴ E-mail: geoffrey.ginsburg{at}duke.edu

Background—There is interindividual variation in LDLc lowering by statins and limited study into the genetic associations of the dose dependant LCLc lowering by statins.

Methods and Results—509 patients with hyperlipidemia were randomly assigned atorvastatin 10mg, simvastatin 20mg, or pravastatin 10mg (low dose phase) followed by 80mg, 80mg, and 40mg (high dose phase), respectively. 31 genes in statin, cholesterol, and lipoprotein metabolism were sequenced and 489 SNPs with minor allele frequencies > 2% were tested for associations with percentage LDLc lowering at low doses using multivariable adjusted general linear regression. Significant associations from the analysis at low dose were then repeated at high dose statins. At low doses, only one SNP met our experiment wide significance level, ABCA1 rs12003906. 26 subjects carried the minor allele of rs12003906 which was associated with an attenuated LDLc reduction (LDLc reduction in carriers vs. noncarriers -24.1±2.6% vs. -32.2±1.5%, p = 0.0001). In addition, we replicated the association with the APOE 3 allele and a reduced LDLc reduction. At high doses, carriers of the minor allele of ABCA1 rs12003906 and the APOE 3 allele improved their LDLc reduction, but continued to have a diminished LDLc reduction compared to noncarriers (-30.5±4.0% vs. -42.0±2.4%, p = 0.005) and (-38.5±1.9% vs. -45.3±2.8%, p =0.009), respectively.

Conclusions—An intronic SNP in ABCA1 and the APOE 3 allele are associated with reduced LDLc lowering by statins and identify individuals who may be resistant to maximal LDLc lowering by statins.

Key Words: cholesterol • genetics • hypercholesterolemia • pharmacogenetics

Author contributions: Deepak Voora and Svati H. Shah contributed equally to this work.

Related Article

Pharmacogenetic Predictors of Statin-Mediated Low-Density Lipoprotein Cholesterol Reduction and Dose Response

Deepak Voora, Svati H. Shah, Carol R. Reed, Jun Zhai, David R. Crosslin, Chad Messer, Benjamin A. Salisbury, and Geoffrey S. Ginsburg
Circ Cardiovasc Genet 2008 1: 100-106. [Abstract] [Full Text] [PDF]

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