TY - JOUR
T1 - Genetic variation at the slco1b1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly
AU - Akao, Hironobu
AU - Polisecki, Eliana
AU - Kajinami, Kouji
AU - Trompet, Stella
AU - Robertson, Michele
AU - Ford, Ian
AU - Jukema, J. Wouter
AU - de Craen, Anton J.M.
AU - Westendorp, Rudi G.J.
AU - Shepherd, James
AU - Packard, Christopher
AU - Buckley, Brendan M.
AU - Schaefer, Ernst J.
N1 - Funding Information:
This research was supported by grant R01 HL74753 from the National Institutes of Health , and contract 53-1950-5-003 from the Agricultural Research Service of the US Department of Agriculture . Dr. Akao was supported by a Scholarship from the Rotary International. This research was also supported by a grant to Dr. J.W. Jukema from the European Community on the Pharmacogenetics of Statins .
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
KW - Low density lipoprotein cholesterol lowering response
KW - SLCO1B1 gene
KW - Statin
UR - http://www.scopus.com/inward/record.url?scp=84855932024&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2011.09.028
DO - 10.1016/j.atherosclerosis.2011.09.028
M3 - Article
C2 - 22189199
AN - SCOPUS:84855932024
SN - 0021-9150
VL - 220
SP - 413
EP - 417
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -