Combined Influence of LDLR and HMGCR Sequence Variation on Lipid-Lowering Response to Simvastatin

• Published in: Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 30; no. 7; pp. 1485 - 1492
• Main Authors: Mangravite, Lara M., Medina, Marisa Wong, Cui, Jinrui, Pressman, Sheila, Smith, Joshua D., Rieder, Mark J., Guo, Xiuqing, Nickerson, Deborah A., Rotter, Jerome I., Krauss, Ronald M.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Ovid Technologies (Wolters Kluwer Health) 01.07.2010; American Heart Association, Inc; Lippincott Williams & Wilkins
• Subjects: 3' Untranslated Regions; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Black or African American; Black or African American - genetics; Blood and lymphatic vessels; California; California - epidemiology; Cardiology. Vascular system; Cell Line; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dyslipidemias; Dyslipidemias - blood; Dyslipidemias - drug therapy; Dyslipidemias - ethnology; Dyslipidemias - genetics; General and cellular metabolism. Vitamins; Haplotypes; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl CoA Reductases - genetics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Lipids; Lipids - blood; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Medical sciences; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Receptors, LDL; Receptors, LDL - genetics; Simvastatin; Simvastatin - therapeutic use; Treatment Outcome; White People; White People - genetics; California; Enzyme; Simvastatin; Enzyme inhibitor; Lipids; Cardiovascular disease; Statin derivative; Lipoprotein; Hypocholesterolemic agent; Cholesterol; Vascular disease; pharmacogenomics; HMG-CoA reductase inhibitor; Atherosclerosis; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; cholesterol-lowering drugs; lipoproteins; Antilipemic agent
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/atvbaha.110.203273

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). CONCLUSION—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.