|Jukema, J. Wouter|
|De Craen, Anton J. M.|
|Westendorp, Rudi G. J.|
|Buckleyi, Brendan M.|
|Schaefer, Ernst J.|
Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/14/2011
Publication Date: 2/1/2012
Citation: Akao, H., Polisecki, E., Kajinami, K., Trompet, S., Robertson, M., Ford, I., Jukema, J., De Craen, A., Westendorp, R., Shepherd, J., Packard, C., Buckleyi, B., Schaefer, E. 2012. Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly. Atherosclerosis. 220(2):413-417. Interpretive Summary: In addition to lifestyle change the use of cholesterol lowering medications, especially statins which inhibit cholesterol production in the body, have been shown to significantly reduce the risk of heart disease. It is known that the response to statins, in this case pravastatin, can be very different in terms of lowering total blood cholesterol and low density lipoprotein (LDL) cholesterol (the bad cholesterol particle). Our goal was to look at variation in two genes known to be involved in the breakdown of statins by the liver, and to see if any of these genetic markers predicted lowering of LDL cholesterol and heart disease risk reduction in an elderly population of 5,411 people. We found one marker at the solute carrier organic anion transporter 1B1 gene locus which predicted lowering of LDL cholesterol by pravastatin. This finding has not been previously reported. Our data indicate that assessing for this genetic variant not only is a predictor of muscle problems induced by statins as shown by others, but also is a useful clinical marker of LDL cholesterol lowering response. This research is of interest to people who are interested in the prevention and treatment of heart disease, the leading cause of death and disability in our society.
Technical 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.