The association of common SNPs and haplotypes in the CETP and MDR1 genes with lipids response to fluvastatin in familial hypercholesterolemia

Dani Bercovich, Yechiel Friedlander, Sigal Korem, Asaf Houminer, Amnon Hoffman, Lilach Kleinberg, Chen Shochat, Eran Leitersdorf, Vardiella Meiner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Objective: To examine whether genetic polymorphisms in the cholesteryl-ester transfer protein (CETP) and the P-glycoprotein drug transporter (MDR1), are associated with variable lipid response to fluvastatin. Methods: Lipid levels were determined in a compliance-monitored clinical study at baseline and following 20 weeks of treatment with 40 mg dose of fluvastatin in 76 FH patients. CETP and MDR1 SNP genotyping was performed and linear regression was used to examine the associations between common SNPs and haplotypes and lipid response. Results: Treatment with 40 mg of fluvastatin resulted in mean low density lipoprotein cholesterol (LDL-C) reduction of 21.5%; mean triglyceride (TG) reduction of 8.3%; and a mean high-density lipoprotein cholesterol (HDL-C) increase of 13.4%. Five tagging SNPs in both genes were used to reconstruct five and six haplotypes accounting for 71.4% and 90.2% of the observed haplotypes in the CETP and MDR1 genes, respectively. CETP-H13 and MDR1-h4 were associated with an increase in LDL-C response. CETP-H5 was significantly associated with decreased TG and HDL-C response, whereas MDR1-h10 was associated with decreased TG response. A multivariate regression model indicated an independent additive effect of CETP-H5 and MDR1-h10 on the level of TG response. Conclusions: CETP and MDR1 have independent effects on lipid changes following fluvastatin treatment. The results of this study may lead to an improved understanding of the genetic determinants of lipids response to treatment.

Original languageAmerican English
Pages (from-to)97-107
Number of pages11
JournalAtherosclerosis
Volume185
Issue number1
DOIs
StatePublished - Mar 2006

Keywords

  • Cholestrol ester transfer protein
  • Haplotypes
  • Hydroxymethylglutaryl-CoA reductase inhibitors
  • Hypercholesterolemia familial
  • MDR
  • Pharmacogenetics
  • Single nucleotide polymorphism

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