title: Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly.
abstract: Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleotide polymorphisms (SNPs) at the liver X receptor alpha (LXRA, rs12221497), and the solute carrier organic anion transporter (SLCO1B1, rs4149056 and rs2306283) gene loci with these variables. We studied 5411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No relationships between genetic variation at the LXRA gene locus with statin induced LDL lowering response or other parameters were noted. Both the SLCO1B1 rs4149056 (valine for alanine at 174) and the rs2306283 (asparagine for aspartic acid at 130) SNPs affect the amino acid sequence of the SLCO1B1 gene product. No effect of the rs2306283 SNP on any of the variables was noted. However the presence of the rs4149056 SNP was associated with significantly less LDL cholesterol lowering response to pravastatin (wildtype, 71.5% of the population, -37.0%; heterozygotes, 25.8% of the population, -36.0%; and homozygotes, 2.7% of the population, -31.8%, p=0.003 at 6 months, and p=0.022 at 12 months). Our data indicate that the presence of the rs4149056 non-synonymous SNP at the SLCO1B1 gene locus can significantly decrease the pravastatin induced LDL cholesterol lowering response.
authors.affiliation: Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Akao
authors.forename: Eliana
authors.initials: E
authors.lastname: Polisecki
authors.forename: Kouji
authors.initials: K
authors.lastname: Kajinami
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.forename: Michele
authors.initials: M
authors.lastname: Robertson
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: James
authors.initials: J
authors.lastname: Shepherd
authors.forename: Christopher
authors.initials: C
authors.lastname: Packard
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D016009:Chi-Square Distribution; D008078:Cholesterol, LDL / Q000097:blood*; D005060:Europe; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D015810:Linkage Disequilibrium; D000071518:Liver X Receptors; D027381:Liver-Specific Organic Anion Transporter 1; D016015:Logistic Models; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D057093:Orphan Nuclear Receptors / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000627:therapeutic use*; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; D027381:Liver-Specific Organic Anion Transporter 1; C000605213:NR1H3 protein, human; D027361:Organic Anion Transporters; D057093:Orphan Nuclear Receptors; C503999:SLCO1B1 protein, human; D017035:Pravastatin