An NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia

作者：Martin B; Solanas Barca M; Garcia Otin A L; Pampin S; Cofan M; Ros E; Rodriguez Rey J C; Pocovi M; Civeira F^*

来源：Nutrition Metabolism and Cardiovascular Diseases, 2010, 20(4): 236-242.

DOI：10.1016/j.numecd.2009.03.023

• Familial hypercholesterolemia
• Polymorphisms
• Cholesterol intestinal absorption

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 30-70 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.

• 出版日期2010-5