The association of common SNPs and haplotypes in the CETP and MDR1 genes with lipids response to fluvastatin in familial hypercholesterolemia.
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.
The Laboratory for Molecular Genetics and Pharmacogenetics, Migal-Galilee Technology Center, Kiryat-Shmona, Israel.
Dani
D
Bercovich
Yechiel
Y
Friedlander
Sigal
S
Korem
Asaf
A
Houminer
Amnon
A
Hoffman
Lilach
L
Kleinberg
Chen
C
Shochat
Eran
E
Leitersdorf
Vardiella
V
Meiner
D000328:Adult; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL / Q000097:blood* / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D005260:Female; D000077340:Fluvastatin; D005500:Follow-Up Studies; D019450:Genes, MDR / Q000235:genetics*; D006023:Glycoproteins / Q000097:blood / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016037:Single-Blind Method; D016896:Treatment Outcome
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005229:Fatty Acids, Monounsaturated; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin