Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment.
BACKGROUND
Use of 3-hydroxyl-3-methylglutaryl-3 coenzyme A reductase (HMGCR) inhibitors, or statins, reduces cardiovascular disease risk by lowering plasma low-density lipoprotein cholesterol (LDL-C) concentrations. However, LDL-C response is variable and influenced by many factors, including racial ancestry, with attenuated response in blacks compared with whites. We hypothesized that single nucleotide polymorphisms in the gene encoding HMGCR, a rate-limiting enzyme in cholesterol synthesis and the direct enzymatic target of statins, contribute to variation in statin response.


RESULTS
Genomic resequencing of HMGCR in 24 blacks and 23 whites identified 79 single nucleotide polymorphisms. Eleven single nucleotide polymorphisms were selected to tag common linkage disequilibrium clusters. These single nucleotide polymorphisms and the common haplotypes inferred from them were tested for association with plasma LDL-C and LDL-C response to simvastatin treatment (40 mg/d for 6 weeks) in 326 blacks and 596 whites. Black carriers of H7 and/or H2 had significantly lower baseline LDL-C (P=0.0006) and significantly attenuated LDL-C response compared with black participants who did not carry either haplotype as measured by absolute response (-1.23+/-0.04 mmol/L, n=209, versus -1.45+/-0.06 mmol/L, n=117; P=0.0008) and percent response (-36.9+/-1.0% versus -40.6+/-1.3%; P=0.02), but no haplotype effect was observed in whites. Percent LDL-C response was lowest in carriers of both H2 and H7, all but one of whom were black (-28.2+/-4.9%, n=12 H2+H7 carriers, versus -41.5+/-0.5%, n=650 H2/H7 noncarriers; P=0.001). LDL-C responses in H7 and/or H2 noncarriers were indistinguishable between blacks and whites.


CONCLUSIONS
HMGCR gene polymorphisms are associated with reduced plasma LDL-C and LDL-C response to simvastatin, and these effects are most evident in blacks.
Krauss
Ronald M
RM
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA. rkrauss@chori.org
Mangravite
Lara M
LM
Smith
Joshua D
JD
Medina
Marisa W
MW
Wang
Dai
D
Guo
Xiuqing
X
Rieder
Mark J
MJ
Simon
Joel A
JA
Hulley
Steven B
SB
Waters
David
D
Saad
Mohammed
M
Williams
Paul T
PT
Taylor
Kent D
KD
Yang
Huiying
H
Nickerson
Deborah A
DA
Rotter
Jerome I
JI
D044383:Black People; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects*; D004252:DNA Mutational Analysis; D006239:Haplotypes; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics*; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology; D044465:White People
D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases