Taking One Step Back in Familial Hypercholesterolemia

Abstract

Objective: STAP1 , 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 STAP1 is absent in liver but mainly observed in immune cells. In this study, we set out to validate STAP1 as a familial hypercholesterolemia gene. Approach and Results: A whole-body Stap1 knockout mouse model ( Stap1 −/− ) was generated and characterized, without showing changes in plasma lipid levels compared with controls. In follow-up studies, bone marrow from Stap1 −/− mice was transplanted to Ldlr −/− mice, which did not show significant changes in plasma lipid levels or atherosclerotic lesions. To functionally assess whether STAP1 expression in B cells can affect hepatic function, HepG2 cells were cocultured with peripheral blood mononuclear cells isolated from heterozygotes carriers of STAP1 variants and controls. The peripheral blood mononuclear cells from STAP1 variant carriers and controls showed similar LDLR 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 STAP1 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 STAP1 variant carriers and 10 age- and sex-matched controls. Furthermore, recent data from the UK Biobank do not show association between STAP1 rare gene variants and LDL cholesterol. Conclusions: Our combined studies in mouse models and carriers of STAP1 variants indicate that STAP1 is not a familial hypercholesterolemia gene.

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

“…Furthermore STAP1 was suggested to be associated with FH, however, we were not able to confirm this in a recent study on 75 hypercholesterolemic patients from Berlin, Germany, who were negative for mutations in canonical FH genes 14,15 . In a recent study on mouse models and samples from STAP1 carriers the gene was ruled out as a FH causing candidate 16 . In 2010, a meta‐analysis of genome‐wide association studies identified multiple common single nucleotide polymorphisms (SNPs) to be strongly associated with elevated LDL‐C concentrations 17 .…”

“…14,15 In a recent study on mouse models and samples from STAP1 carriers the gene was ruled out as a FH causing candidate. 16 In 2010, a meta-analysis of genomewide association studies identified multiple common single nucleotide polymorphisms (SNPs) to be strongly associated with elevated LDL-C concentrations. 17 Talmud et al hypothesized that the mutation negative FH patients might carry a greater-than-average number of these common LDL-C raising variants and assembled a 12-SNP polygenic score based on the variants with the strongest LDL-C associations.…”

Improving Familial Hypercholesterolemia Index Case Detection: Sequential Active Screening from Centralized Analytical Data

“…Consistent with ACMG criteria, clinically relevant variants were classified as pathogenic (class I), likely pathogenic (class II), and variants of unknown significance (class III). Since STAP1 is very unlikely to be a causative FH gene, variants in this gene were not considered [ 29 ].…”

Next-generation sequencing to confirm clinical familial hypercholesterolemia

“…5 We excluded STAP1 variants from this analysis, as this is no longer considered a FH gene. 16,17 Next, the allele frequency of variants in the minor FH genes in FH mutation-negative patients was numerically compared with the allele frequency reported in the European non-Finnish population in gnomAD V2.1.1. (https:// gnomad.broadinstitute.org/).…”