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

Robert A Hegele,Matthew R Ban,Justin Guy,Jian Wang

doi:10.1186/1476-511x-4-16

Robert A Hegele, Matthew R Ban + Show 2 more

Open Access

https://doi.org/10.1186/1476-511x-4-16

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Abstract

BackgroundNPC1L1 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.ResultsIn 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.ConclusionThese preliminary pharmacogenetic results suggest that NPC1L1 variation is associated with inter-individual variation in response to ezetimibe treatment.

Highlights

NPC1L1 encodes a putative intestinal sterol transporter which is the likely target for ezetimibe, a new type of lipid-lowering medication
Ezetimibe probably interferes with the normal function of the NPC1L1 gene product, which appears to govern sterol absorption in the small intestine [2,3,4,5]
The mean plasma low-density lipoprotein (LDL) cholesterol reduction seen with ezetimibe is 20 to 25%, and this has been remarkably consistent across patient subgroups defined by age, gender, ethnic background and concomitant use of other lipid regulating agents, such as statin drugs [6,7,8,9]

Summary

Introduction

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 hypothesized that common variants in NPC1L1 would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe. A possible genetic basis for this inter-individual variation was suggested by our previous observation of rare non-synonymous NPC1L1 mutations in a non-responder to ezetimibe [10]. During the course of those studies, we identified several single nucleotide polymorphisms (SNPs) in NPC1L1 [10] These SNPs have enabled assessment of common genetic variation at NPC1L1, which we hypothesized would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe

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