NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe

• Published in: Lipids in health and disease Vol. 4; no. 1; p. 16
• Main Authors: Hegele, Robert A, Guy, Justin, Ban, Matthew R, Wang, Jian
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 12.08.2005; BioMed Central; BMC
• Subjects: Adult; Aged; Azetidines - therapeutic use; Cholesterol, LDL - blood; Ezetimibe; Female; Gene Frequency; Genetic Variation; Haplotypes - genetics; Humans; Hypercholesterolemia - drug therapy; Hypercholesterolemia - genetics; Male; Membrane Proteins - genetics; Middle Aged; Polymorphism, Single Nucleotide; Proteins - genetics
• ISSN: 1476-511X; 1476-511X
• DOI: 10.1186/1476-511X-4-16

NPC1L1 encodes a putative intestinal sterol transporter which is the likely target for ezetimibe, a new type of lipid-lowering medication. We previously reported rare non-synonymous mutations in NPC1L1 in an individual who had no plasma lipoprotein response to ezetimibe. We next hypothesized that common variants in NPC1L1 would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe. In 101 dyslipidemic subjects, we found that NPC1L1 haplotype was significantly associated with inter-individual variation in the response of plasma LDL cholesterol to treatment with ezetimibe for 12 weeks. Specifically, about one subject in eight lacked the common NPC1L1 haplotype 1735C-25342A-27677T and these subjects had a significantly greater reduction in plasma LDL cholesterol with ezetimibe than subjects with at least one copy of this haplotype (-35.9+4.0 versus -23.6+1.6 percent reduction, P = 0.0054). This was paralleled by a similar non-significant trend of between-haplotype difference in reduction of total cholesterol. These preliminary pharmacogenetic results suggest that NPC1L1 variation is associated with inter-individual variation in response to ezetimibe treatment.