Pharmacogenetic Study of Statin Therapy and Cholesterol Reduction

Chasman, Daniel I.; Posada, David; Subrahmanyan, Lakshman; Cook, Nancy R.; Stanton, Vincent P.; Ridker, Paul M.

doi:10.1001/jama.291.23.2821

Cited by 410 publications

(193 citation statements)

References 18 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…Gene variants are known to influence lipid homeostasis (Knoblauch et al 2004;Klos et al 2006) and response to hypolipemic treatment (Chasman et al 2004;Thompson et al 2005;Schmitz and Langmann 2006). In addition, continuous cell lines are often used to study cardiovascular pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Genetic profiling of human cell lines used as in vitro model to study cardiovascular pathophysiology and pharmacotoxicology

et al. 2008

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic profiling of human cell lines used as in vitro model to study cardiovascular pathophysiology and pharmacotoxicology

et al. 2008

View full text Add to dashboard Cite

show abstract

“…A number of genetic polymorphisms have been reported to have an impact on response to statins, but few results have been replicated and most published studies have evaluated only one SNP at a time (67Y69). In addition, the magnitude of the genetic effects found has been in most cases small (67Y69, 71,72).…”

Section: Effectiveness Of Pravastatinmentioning

confidence: 99%

Influence of Drug Transporter Polymorphisms on Pravastatin Pharmacokinetics in Humans

2006

View full text Add to dashboard Cite

The role of drug transporters in pravastatin disposition is underlined by the fact that pravastatin does not undergo significant cytochrome P-450 (CYP)-mediated biotransformation. The organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, and multidrug resistance-associated protein 2 [MRP2 (ABCC2)], are thought to be the major transporters involved in the pharmacokinetics of pravastatin in humans. Other transporters that may play a role include OATP2B1, organic anion transporter 3 (OAT3), bile salt export pump (BSEP), and the breast cancer resistance protein (BCRP). OATP1B1 and MRP2 mediate the hepatic uptake and biliary excretion of pravastatin, respectively. The SLCO1B1 and ABCC2 polymorphisms probably contribute to the high interindividual variability in pravastatin disposition. Recent small studies have characterized the impact of the SLCO1B1 polymorphism on pravastatin in humans, and especially the c.521T>C single-nucleotide polymorphism (SNP) seems to be an important determinant of pravastatin pharmacokinetics. Pravastatin plasma concentrations may be up to 100% higher in subjects carrying the c.521C variant, as found in the *5, *15, *16, and *17 haplotypes, reflecting diminished OATP1B1-mediated uptake into the major site of pravastatin elimination, the liver. The SLCO1B1 polymorphism seems to have a similar impact on the pharmacokinetics of single- and multiple-dose pravastatin. Overall, 2-5% of individuals in various populations may be expected to show markedly elevated plasma pravastatin concentrations due to the SLCO1B1 polymorphism. Of note, the impact of the SLCO1B1 polymorphism on statins may be dependent on ethnicity. Although individuals with a diminished hepatic uptake of pravastatin might be expected to show reduced cholesterol-lowering efficacy due to lower intracellular pravastatin concentrations, there is preliminary evidence to suggest that the SLCO1B1 polymorphism is not a major determinant of non-response to pravastatin. The possible consequences of drug transporter polymorphisms, especially the SLCO1B1 and ABCC2 polymorphisms, for the lipid-lowering efficacy and tolerability of pravastatin in various ethnic groups warrant further study.

show abstract

“…Initial candidate analysis focusing on genes proximal to the known pharmcodynamic and pharmacokinetic pathways of statin mechanism identified associations with LDLC lowering in the HMGCR gene, encoding the target of statin therapy, [89][90][91] APOE, LDLR, and genes encoding statin transporters. [92][93][94] Subsequent genome-wide genetic analysis confirmed many of these associations for treatment response with rosuvastatin, 95 simvastatin, 96 and atorvastatin.…”

Section: Statin Therapymentioning

confidence: 99%

Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

Paynter

Ridker

Chasman

2016

Circulation Research

Self Cite

View full text Add to dashboard Cite

T he Presidential Precision Medicine Initiative imagines a future in which medical decisions are increasingly tailored to the clinical profile of each patient.1 Incorporation of genetic information is a key component of the envisioned profile, continuing the goals of integration with patient care set out at the completion of the human genome sequence 15 years ago. As the cost of determining genetic information plummets and point-of-care genetic analysis is increasingly available, it Atherosclerosis Compendium© 2016 American Heart Association, Inc.

show abstract

Pharmacogenetic Study of Statin Therapy and Cholesterol Reduction

Cited by 410 publications

References 18 publications

Genetic profiling of human cell lines used as in vitro model to study cardiovascular pathophysiology and pharmacotoxicology

Genetic profiling of human cell lines used as in vitro model to study cardiovascular pathophysiology and pharmacotoxicology

Influence of Drug Transporter Polymorphisms on Pravastatin Pharmacokinetics in Humans

Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

Contact Info

Product

Resources

About