Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin.
OBJECTIVE
Although statins are efficacious for lowering low-density lipoprotein cholesterol, there is wide interindividual variation in response. We tested the extent to which combined effects of common alleles of LDLR and HMGCR can contribute to this variability.


RESULTS
Haplotypes in the LDLR 3'-untranslated region (3-UTR) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics trial (335 blacks and 609 whites). LDLR haplotype 5 (LDLR L5) was associated with smaller simvastatin-induced reductions in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (P=0.0002 to 0.03) in blacks but not whites. The combined presence of LDLR L5 and previously described HMGCR haplotypes in blacks was associated with significantly attenuated apolipoprotein B reduction (-22.4+/-1.5%, N=89) compared with both noncarriers (-30.6+/-1.5%, N=78, P=0.0001) and carriers of either individual haplotype (-28.2+/-1.1%, N=158, P=0.001). We observed similar differences when measuring simvastatin-mediated induction of low-density lipoprotein receptor surface expression using lymphoblast cell lines (P=0.03).


CONCLUSIONS
We have identified a common LDLR 3-UTR haplotype that is associated with attenuated lipid-lowering response to simvastatin treatment. Response was further reduced in individuals with both LDLR and previously described HMGCR haplotypes. Previously identified racial differences in statin efficacy were partially explained by the greater prevalence of these combined haplotypes in blacks.
Mangravite
Lara M
LM
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA.
Medina
Marisa Wong
MW
Cui
Jinrui
J
Pressman
Sheila
S
Smith
Joshua D
JD
Rieder
Mark J
MJ
Guo
Xiuqing
X
Nickerson
Deborah A
DA
Rotter
Jerome I
JI
Krauss
Ronald M
RM
D020413:3' Untranslated Regions; D001741:Black or African American / Q000235:genetics; D002140:California / Q000453:epidemiology; D002460:Cell Line; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics*; D019821:Simvastatin / Q000627:therapeutic use*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
D020413:3' Untranslated Regions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011973:Receptors, LDL; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases