Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin

Abstract

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.

Methods and 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.

Trial registration: ClinicalTrials.gov NCT00451828.

Figures

Figure 1. LDLR 3UTR SNPs and haplotypes

A. Inclusion of LDLR 3UTR tagSNPs in inferred haplotypes. Schematic representation of LDLR 3UTR is shown with five tagSNPs indicated by arrows. Chromosomal position labeled is based on genome assembly March 2006. Major alleles are designated by 0 (G, 44243; G, 44857; C, 45622; A, 45645; C, 45935) and minor alleles by 1. B. Cladogram of LDLR 3UTR haplotypes. LDLR 3UTR haplotype 5 (L5) is, shown in grey, was represented by the ancestral allele at all five tagSNPs.

Figure 2. Correlation of simvastatin-mediated induction in in vitro LDLR surface expression with in vivo apolipoprotein B reduction and association with LDLR L5 haplotype

(A) Correlation of in vitro LDLR surface protein induction (simvastatin treated – placebo treated, A.U.) and in vivo apolipoprotein B reductions (simvastatin – baseline, % change) in response to simvastatin exposure. LDLR surface protein expression was measured by FACS following 24 hour exposure to (B) sham buffer or (C) 2μM simvastatin in lymphoblast cell lines derived from 109 LDLR L5 noncarrier and84 LDLR L5 carrier African-American CAP participants.(D) Statin-mediated change in LDLR protein expression is presented as LDLR expression following simvastatin exposure minus LDLR expression following sham exposure(P=0.03 adjusted for age, sex, BMI and smoking status).

Figure 3. Combined influence of LDLR L5 and HMGCR H2/H7 haplotypes on in vivo lipid-lowering response and in vitro LDLR protein response to simvastatin exposure

(A) LDLC and (B) apolipoprotein B were measured before and after simvastatin treatment in 324 African-American CAP participants including 78 noncarriers, 39 LDLR L5 only carriers, 119 HMGCR H2/H7 only carriers, and 89 LDLR L5 + HMGCR H2/H7 carriers. (C)LDLR surface protein was measured following 24 hour exposure with 2mM simvastatin or sham buffer in 193 lymphoblast cell lines derived from African-American CAP participants. Associations adjusted for age, sex, BMI and smoking status. P-values for trends are (A) 0.002, (B) <0.0001, and (C) 0.05.

Figure 4. Association of combined haplotypes on (A) LDLC and (B) apoB change in response to simvastatin treatment

0, noncarriers (N=78); 1, LDLR L5 only or HMGCR H2/H7 only carriers (N=158); 2, LDLR L5 + HMGCR H2/H7 carriers (N=89). Associations adjusted for age, sex, BMI, and smoking status.