Association between a frequent allele of the gene encoding OATP1B1 and enhanced LDL-lowering response to fluvastatin therapy.
BACKGROUND
Marked lowering of low-density-lipoprotein cholesterol (LDL-C) levels (< or =50%) with intensive statin therapy is associated with major reduction in cardiovascular risk, but is limited by a potential increase in adverse effects, thereby justifying optimization of LDL-C reduction with minimal risk. The organic anion transporting polypeptide-1B1 encoded by the SLCO1B1 gene is implicated as a major transporter in cellular uptake of statins, and notably fluvastatin. We postulated that genetic variation in SLCO1B1 might affect statin bioavailability, and might therefore influence drug response and potential adverse effects.


METHODS
Elderly hypercholesterolemic subjects (n = 724), whose plasma lipid profile was determined before and 2 months after fluvastatin extended-release treatment (80 mg/day, n = 420), or placebo (n = 304), were genotyped for the most frequent nonsynonymous polymorphisms (SNP) in the SLCO1B1 gene (c.388A>G, c.463C>A and c.521T>C).


RESULTS
Due to linkage disequilibrium, only four alleles (*1b, *5, *14 and *15) of SLCO1B1 were detected in addition to the wild-type allele (*1a). The c.463A genotype, which was systematically associated with the c.388G SNP corresponding to the *14 allele was significantly associated with percentage LDL-C reduction from baseline (p = 0.005) and with mean post-treatment LDL-C values (p = 0.0005). Subjects homozygous for the c.463C genotype (n = 294) exhibited significantly less LDL-C reduction and higher post-treatment LDL-C levels (-31.5%, 138 mg/dl) relative to heterozygous C/A patients (-36.2%, 126 mg/dl; n = 111), and to homozygous A/A subjects (-41%, 115 mg/dl; n = 15).


CONCLUSIONS
These results reveal that OATP1B1 is implicated in the pharmacological action and efficacy of fluvastatin. Indeed, the common *14 allele, which is distinguished by the presence of the c.463C>A polymorphism, was associated with enhanced lipid-lowering efficacy in this study.
Couvert
Philippe
P
INSERM, UMR S551, Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, F-75013, Paris, France.
Giral
Philippe
P
Dejager
Sylvie
S
Gu
Jessie
J
Huby
Thierry
T
Chapman
M John
MJ
Bruckert
Eric
E
Carrié
Alain
A
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D004311:Double-Blind Method; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D000077340:Fluvastatin; D008040:Genetic Linkage / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*
D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D000077340:Fluvastatin