Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy

• Published in: Journal of human genetics Vol. 51; no. 9; pp. 822 - 826
• Main Authors: Takane, Hiroshi, Miyata, Masanori, Burioka, Naoto, Shigemasa, Chiaki, Shimizu, Eiji, Otsubo, Kenji, Ieiri, Ichiro
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2006
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Anticholesteremic Agents - pharmacology; Apolipoprotein E; Apolipoproteins E - genetics; Cholesterol; Cholesterol 7-alpha-Hydroxylase - genetics; Female; Genes; Genetic diversity; Genotypes; Genotyping; Heterozygotes; Humans; Hydroxylase; Hypercholesterolemia - blood; Hypercholesterolemia - drug therapy; Hypercholesterolemia - genetics; Lipid metabolism; Lipids; Lipids - blood; Liver-Specific Organic Anion Transporter 1; Low density lipoprotein; Male; Middle Aged; Organic Anion Transporters - genetics; Pharmacogenetics; Pravastatin; Pravastatin - pharmacology; Statins
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1007/s10038-006-0025-1

Pravastatin is mainly taken up from the circulation into the liver via organic anion-transporting polypeptide 1B1 (SLCO1B1 gene product). We examined the contribution of genetic variants in the SLCO1B1 gene and other candidate genes to the variability of pravastatin efficacy in 33 hypercholesterolemic patients. In the initial phase of pravastatin treatment (8 weeks), heterozygous carriers of the SLCO1B1*15 allele had poor low-density lipoprotein cholesterol (LDL-C) reduction relative to non-carriers (percent reduction: -14.1 vs -28.9%); however, the genotype-dependent difference in the cholesterol-lowering effect disappeared after 1 year of treatment. Cholesterol 7alpha-hydroxylase (CYP7A1) and apolipoprotein E (APOE) are known to contribute to lipid metabolism. Homozygous carriers of the CYP7A1 -204C allele or heterozygotes for both CYP7A1 -204C and APOE epsilon4 alleles showed significantly poorer LDL-C reduction compared to that in other genotypic groups after 1 year of treatment (-24.3 vs -33.1%). These results suggest that the SLCO1B1*15 allele is associated with a slow response to pravastatin therapy, and the combined genotyping of CYP7A1 and APOE genes is a useful index of the lipid-lowering effect of pravastatin.