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

Abstract Background NPC1L1encodes 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 inNPC1L1in an individual who had no plasma lipoprotein response to ezetimibe. We next hypothesized that common variants inNPC1L1would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe. Results In 101 dyslipidemic subjects, we found thatNPC1L1haplotype 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 commonNPC1L1haplotype 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. Conclusion These preliminary pharmacogenetic results suggest thatNPC1L1variation is associated with inter-individual variation in response to ezetimibe treatment.