An NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia

• Published in: Nutrition, metabolism, and cardiovascular diseases Vol. 20; no. 4; pp. 236 - 242
• Main Authors: Martín, B., Solanas-Barca, M., García-Otín, Á.-L., Pampín, S., Cofán, M., Ros, E., Rodríguez-Rey, J.-C., Pocoví, M., Civeira, F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2010
• Subjects: Adult; Aged; Apolipoproteins B - genetics; Cardiovascular; Cell Line; Cholesterol intestinal absorption; Cholesterol, Dietary - pharmacokinetics; Electrophoretic Mobility Shift Assay; Familial hypercholesterolemia; Female; Genes, Dominant; Genetic Variation; Haplotypes; Humans; Hyperlipoproteinemia Type II - genetics; Lipids - blood; Luciferases - genetics; Male; Membrane Proteins - genetics; Middle Aged; Plasmids - genetics; Polymorphism, Genetic - genetics; Polymorphisms; Promoter Regions, Genetic - genetics; Receptors, LDL - genetics; Sterols - blood; Transfection; Apo; FH; ADH; FDB; IR; Polymorphisms; bp; CVD; HDL; SNP; Cholesterol intestinal absorption; NPC1L1; LDL; EMSA; DNA; Familial hypercholesterolemia; APOB; LDLR; PCR; apolipoprotein; single nucleotide polymorphism; LDL receptor gene; high-density lipoprotein; base pair; interquartile range; electrophoretic mobility shift assay; deoxyribonucleic acid; polymerase chain reaction; autosomal dominant hypercholesterolemia; cardiovascular disease; low-density lipoprotein; apolipoprotein B gene; familial defective apolipoprotein B; Niemann-Pick C1-Like 1
• ISSN: 0939-4753; 1590-3729; 1590-3729
• DOI: 10.1016/j.numecd.2009.03.023

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. 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 30–70 years and 274 (180 women and 94 men) control subjects aged 25–65 years. 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. 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.