An NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia.

Abstract

BACKGROUND AND AIMS:

A substantial number of subjects with autosomal dominant hypercholesterolemia (ADH) do not have LDL receptor (LDLR) or apolipoprotein B (APOB) mutations. Some ADH subjects appear to hyperabsorb sterols from the intestine, thus we hypothesized that they could have variants of the Niemann-Pick C1-Like 1 gene (NPC1L1). NPC1L1 encodes a crucial protein involved in intestinal sterol absorption.

METHODS AND RESULTS:

Four NPC1L1 variants (-133A>G, -18C>A, 1679C>G, 28650A>G) were analyzed in 271 (155 women and 116 men) ADH bearers without mutations in LDLR or APOB aged 30-70years and 274 (180 women and 94 men) control subjects aged 25-65years. The AC haplotype determined by the -133A>G and -18C>A variants was underrepresented in ADH subjects compared to controls (p=0.01). In the ADH group, cholesterol absorption/synthesis markers were significantly lower in AC homozygotes that in all others haplotypes. Electrophoretic mobility shift assay (EMSA) results revealed that the -133A-specific oligonucleotide produced a retarded band stronger than the -133G allele. Luciferase activity with NPC1L1 -133G variant was 2.5-fold higher than with the -133A variant.

CONCLUSION:

The -133A>G polymorphism exerts a significant effect on NPC1L1 promoter activity. NPC1L1 promoter variants might explain in part the hypercholesterolemic phenotype of some subjects with nonLDLR/nonAPOB ADH.

• Authors: B Martín, M Solanas-Barca, A-L García-Otín, S Pampín, M Cofán, E Ros, J-C Rodríguez-Rey, M Pocoví, F Civeira
• Journal: Nutrition, metabolism, and cardiovascular diseases : NMCD (Nutr Metab Cardiovasc Dis) Vol. 20 Issue 4 Pg. 236-42 (May 2010) ISSN: 1590-3729 [Electronic] Netherlands
• PMID: 19747803 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Elsevier B.V. All rights reserved.

Chemical References

• Apolipoproteins B
• Cholesterol, Dietary
• Lipids
• Membrane Proteins
• Membrane Transport Proteins
• NPC1L1 protein, human
• Receptors, LDL
• Sterols
• Luciferases

Topics

• Adult
• Aged
• Apolipoproteins B (genetics)
• Cell Line
• Cholesterol, Dietary (pharmacokinetics)
• Electrophoretic Mobility Shift Assay
• Female
• Genes, Dominant
• Genetic Variation
• Haplotypes
• Humans
• Hyperlipoproteinemia Type II (genetics)
• Lipids (blood)
• Luciferases (genetics)
• Male
• Membrane Proteins (genetics)
• Membrane Transport Proteins
• Middle Aged
• Plasmids (genetics)
• Polymorphism, Genetic (genetics)
• Promoter Regions, Genetic (genetics)
• Receptors, LDL (genetics)
• Sterols (blood)
• Transfection