Taking One Step Back in Familial Hypercholesterolemia: Does Not Alter Plasma LDL (Low-Density Lipoprotein) Cholesterol in Mice and Humans.

Objective: , encoding for STAP1 (signal transducing adaptor family member 1), has been reported as a candidate gene associated with familial hypercholesterolemia. Unlike established familial hypercholesterolemia genes, expression of is absent in liver but mainly observed in immune cells. In this study, we set out to validate as a familial hypercholesterolemia gene. Approach and Results: A whole-body knockout mouse model () was generated and characterized, without showing changes in plasma lipid levels compared with controls. In follow-up studies, bone marrow from mice was transplanted to mice, which did not show significant changes in plasma lipid levels or atherosclerotic lesions. To functionally assess whether expression in B cells can affect hepatic function, HepG2 cells were cocultured with peripheral blood mononuclear cells isolated from heterozygotes carriers of variants and controls. The peripheral blood mononuclear cells from variant carriers and controls showed similar mRNA and protein levels. Also, LDL (low-density lipoprotein) uptake by HepG2 cells did not differ upon coculturing with peripheral blood mononuclear cells isolated from either variant carriers or controls. In addition, plasma lipid profiles of 39 carriers and 71 family controls showed no differences in plasma LDL cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, and lipoprotein(a) levels. Similarly, B-cell populations did not differ in a group of 10 variant carriers and 10 age- and sex-matched controls. Furthermore, recent data from the UK Biobank do not show association between rare gene variants and LDL cholesterol.

Conclusions: Our combined studies in mouse models and carriers of variants indicate that is not a familial hypercholesterolemia gene.