Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly

• Published in: Atherosclerosis 2012-02, Vol.220 (2), p.413-417
• Main Authors: Akao, Hironobu, Polisecki, Eliana, Kajinami, Kouji, Trompet, Stella, Robertson, Michele, Ford, Ian, Jukema, J. Wouter, de Craen, Anton J.M, Westendorp, Rudi G.J, Shepherd, James, Packard, Christopher, Buckley, Brendan M, Schaefer, Ernst J
• Format: Article
• Language: English
• Subjects: Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; Blood. Blood coagulation. Reticuloendothelial system; Cardiology. Vascular system; Cardiovascular; Cardiovascular Diseases - blood; Cardiovascular Diseases - genetics; Cardiovascular Diseases - prevention & control; Chi-Square Distribution; Cholesterol, LDL - blood; Europe; Female; Heterozygote; Homozygote; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia - blood; Hypercholesterolemia - complications; Hypercholesterolemia - drug therapy; Hypercholesterolemia - genetics; Linkage Disequilibrium; Liver X Receptors; Logistic Models; Low density lipoprotein cholesterol lowering response; Male; Medical sciences; Organic Anion Transporters - genetics; Orphan Nuclear Receptors - genetics; Pharmacology. Drug treatments; Phenotype; Polymorphism, Single Nucleotide; Pravastatin - therapeutic use; Prospective Studies; Risk Assessment; Risk Factors; SLCO1B1 gene; Solute Carrier Organic Anion Transporter Family Member 1b1; Statin; Time Factors; Treatment Outcome
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.09.028

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.