Mice lacking global Stap1 expression do not manifest hypercholesterolemia

Abstract

Background Autosomal dominant familial hypercholesterolemia (ADH; MIM#143890) is one of the most common monogenic disorders characterized by elevated circulatory LDL cholesterol. Initial studies in humans with ADH identified a potential relationship with variants of the gene encoding signal transducing adaptor family member protein 1 (STAP1; MIM#604298). However, subsequent studies have been contradictory. In this study, mice lacking global Stap1 expression (Stap1−/−) were characterized under standard chow and a 42% kcal western diet (WD). Methods Mice were studied for changes in different metabolic parameters before and after a 16-week WD regime. Growth curves, body fats, circulatory lipids, parameters of glucose homeostasis, and liver architecture were studied for comparisons. Results Surprisingly, Stap1−/− mice fed the 16-week WD demonstrated no marked differences in any of the metabolic parameters compared to Stap1+/+ mice. Furthermore, hepatic architecture and cholesterol content in FPLC-isolated lipoprotein fractions also remained comparable to wild-type mice. Conclusion These results strongly suggest that STAP1 does not alter lipid levels, that a western diet did not exacerbate a lipid disorder in Stap1 deficient mice and support the contention that it is not causative for hyperlipidemia in ADH patients. These results support other published studies also questioning the role of this locus in human hypercholesterolemia.

Analysis of 200 000 exome-sequenced UK Biobank subjects illustrates the contribution of rare genetic variants to hyperlipidaemia

“…Other genes for which notably negative results are obtained are APOB (SLP = 0.00) a known cause of familial hypercholesterolaemia, and HMGCR (SLP = -0.07), which codes for the rate-limiting enzyme in cholesterol synthesis which is the target of statins [34]. Also negative was STAP1 (SLP = -1.02), for which there were initial claims of an association with familial hypercholesterolaemia although more recent work has thrown doubt on this [35]. These three genes were also subjected to the variant category analysis and this revealed that disruptive variants in APOB were more frequent in controls (OR = 0.71 (0.60 -0.85), SLP = -3.74) but that there were much large numbers of nonsynonymous variants which overall did not show association with hyperlipidaemia, accounting for the negative result of weighted burden analysis.…”

Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia

“…The STAP1 gene was originally included in both assays due to the report by Fouchier et al (32) documenting its association with FH. This gene-disease association has since been questioned (33)(34)(35) and no potentially pathogenic variants in STAP1 were identified in this study.…”

Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia

“…The STAP1 gene was originally included in both assays due to the report by Fouchier et al (32) documenting its association with FH. This gene-disease association has since been questioned (33)(34)(35) and no potentially pathogenic variants in STAP1 were identified in this study.…”