Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe

• Published in: Clinical genetics Vol. 67; no. 2; pp. 175 - 177
• Main Authors: Wang, J, Williams, CM, Hegele, RA
• Format: Journal Article
• Language: English
• Published: Oxford, UK; Malden, USA Munksgaard International Publishers 01.02.2005; Blackwell; Blackwell Publishing Ltd
• Subjects: Adult; Anticholesteremic Agents - pharmacology; Anticholesteremic Agents - therapeutic use; atherosclerosis; Azetidines - pharmacology; Azetidines - therapeutic use; Biological and medical sciences; Case-Control Studies; Cholesterol; Deoxyribonucleic acid; DNA; Drug Resistance; Ezetimibe; Female; General aspects. Genetic counseling; Genetics; Humans; Hyperlipidemias - drug therapy; Hyperlipidemias - genetics; lipoproteins; Male; Medical genetics; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - pharmacology; metabolism; Middle Aged; mutation; pharmacogenetics; Phenotype; Polymorphism, Genetic; Proteins - genetics; Proteins - pharmacology; Human; atherosclerosis; mutation; Genetics; metabolism; lipoproteins; pharmacogenetics; Heterozygosity; Polymorphism
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2004.00388.x

Ezetimibe reduces plasma low‐density lipoprotein (LDL) cholesterol by blocking sterol absorption in enterocytes. The NPC1L1 gene product was recently identified as the molecular target for ezetimibe, although functional details are incomplete. We used the non‐response phenotype of plasma LDL cholesterol to ezetimibe treatment to ascertain individuals who might have variant NPC1L1. We found that one non‐responder to ezetimibe was a compound heterozygote for two rare non‐synonymous polymorphisms in NPC1L1 that were absent in normal control subjects. We also characterized other NPC1L1 polymorphisms. While there are many explanations for non‐response to medications, our data suggest a possible relationship between NPC1L1 variation and ezetimibe response and further indicate that a non‐response phenotype might ascertain subjects with genomic DNA variants that could help define metabolic pathways.