Rationale: Although mutations in STAP1 have been found in patients with familial hypercholesterolemia (FH), it is not known to which extent and how these variants could cause this phenotype. 

Objective: We set out to address whether plasma LDL-cholesterol concentrations differ between heterozygous carriers of STAP1 mutations and family controls. As STAP1 is predominantly expressed in B cells, we also investigated the B cell populations in the carriers and studied the effects of STAP1 variants on hepatic LDL uptake in in vitro co-culture experiments.

Methods and Results: Plasma lipid concentrations and the B cell populations by fluorescence activated cell sorting (FACS) were measured in carriers of STAP1 variants and family controls. To assess the effect of the STAP1 variants on LDL-cholesterol homeostasis, we co-cultured HepG2 cells with peripheral blood mononuclear cells (PBMCs) isolated from carriers of STAP1 variants. Analysis of 39 carriers of STAP1 variants (either p.Leu69Ser, p.Ile71Thr or p.Glu97Asp) and 71 family controls showed that plasma LDL-cholesterol, HDL-cholesterol, TG and Lp(a) levels were not statistically different. In a subgroup of 10 STAP1 variant carriers and 10 matched controls, no significant differences in B cell populations between carriers and controls were found. STAP1 mRNA expression in PBMCs also did not differ between the carriers and control. No differences were found in LDLR mRNA and LDLR protein expression as well as LDL uptake in HepG2 cells upon co-culture with PBMCs isolated from either control subjects or STAP1 variant carriers. 

Conclusions: In contrast to previous reports, we now show that variants in STAP1 are not associated with elevated LDL-cholesterol levels and do not affect HepG2 LDL-cholesterol homeostasis. These data do not provide support for STAP1 to be a FH gene.

01 - VARIANTS IN SIGNAL TRANSDUCING ADAPTOR FAMILY MEMBER 1 (STAP1) DO NOT AFFECT LDL-CHOLESTEROL