Abstract 9782: Genetic Variation at the SLCO1B1 Gene Locus and Low Density Lipoprotein Cholesterol Lowering Response to Pravastatin in the Elderly

Abstract

Background: Statins have been shown to significantly lower the risk of coronary heart disease morbidity and mortality, and these benefits have been related t lowering of low density lipoprotein (LDL) cholesterol lowering. Statin metabolism is affected by the liver X receptor alpha ( LXRA ) and the solute carrier organic anion transporter ( SLCO1B1 ). The SLCO1B1 rs4149056 variant has been linked to an increased risk of statin induced myositis due to decreased liver uptake of the statin, increased blood levels, and presumably greater statin uptake in muscle tissue. Our goal was to determine whether genetic variation at these gene loci would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. Methods: We examined associations of single nucleotide polymorphisms (SNPs) at the LXRA (rs12221497) and SLCO1B1 (rs4149056 and rs2306283) gene loci with these variables in 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. Results: 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 of the SLCO1B1 gene product. No effects 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. Conclusions: Our data indicate that the presence of the rs4149056 non-synonymous SNP at the SLCO1B1 gene locus, especially in the approximately 3% of the population that are homozygous for this variant, can significantly decrease the pravastatin induced LDL cholesterol lowering response. Therefore the presence of this variant not only predicts statin induced myositis, but also statin induced LDL lowering response.