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Simon, J.S. et al.

Simon, Karnoub, Devlin, Arreaza, Qiu, Monks, Severino, Deutsch, Palmisano, Sachs, Bayne, Plump, Schadt,

Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.

Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response.[1]

References

Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment. Simon, J.S., Karnoub, M.C., Devlin, D.J., Arreaza, M.G., Qiu, P., Monks, S.A., Severino, M.E., Deutsch, P., Palmisano, J., Sachs, A.B., Bayne, M.L., Plump, A.S., Schadt, E.E. Genomics (2005) [Pubmed]

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