Evaluation of the role of STAP1 in Familial Hypercholesterolemia

Magdalena Danyel,Claus-Eric Ott,Thomas Grenkowitz,Ilja Demuth,Elisabeth Steinhagen-Thiessen,Thomas Bobbert,Christian Fuchsberger,Andrew A Hicks,Bastian Salewsky,Ursula Kassner

doi:10.1038/s41598-019-48402-y

Abstract

Familial hypercholesterolemia (FH) is characterised by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and a substantial risk for cardiovascular disease. The autosomal-dominant FH is mostly caused by mutations in LDLR (low density lipoprotein receptor), APOB (apolipoprotein B), and PCSK9 (proprotein convertase subtilisin/kexin). Recently, STAP1 has been suggested as a fourth causative gene. We analyzed STAP1 in 75 hypercholesterolemic patients from Berlin, Germany, who are negative for mutations in canonical FH genes. In 10 patients with negative family history, we additionally screened for disease causing variants in LDLRAP1 (low density lipoprotein receptor adaptor protein 1), associated with autosomal-recessive hypercholesterolemia. We identified one STAP1 variant predicted to be disease causing. To evaluate association of serum lipid levels and STAP1 carrier status, we analyzed 20 individuals from a population based cohort, the Cooperative Health Research in South Tyrol (CHRIS) study, carrying rare STAP1 variants. Out of the same cohort we randomly selected 100 non-carriers as control. In the Berlin FH cohort STAP1 variants were rare. In the CHRIS cohort, we obtained no statistically significant differences between carriers and non-carriers of STAP1 variants with respect to lipid traits. Until such an association has been verified in more individuals with genetic variants in STAP1, we cannot estimate whether STAP1 generally is a causative gene for FH.

Highlights

Autosomal-dominant hypercholesterolemia (FH, OMIM 143890) is one of the most common genetic disorders, characterised by severely elevated levels of low-density lipoprotein cholesterol (LDL-C)
Population-based cohort we evaluated association of carrier status for rare STAP1 variants with total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG), since LDL-C levels have previously been postulated to be significantly higher in carriers of rare STAP1 variants compared to wild type[21]
We included a total of 75 unrelated patients, who were diagnosed between 2012 and 2017 in the specialized Lipid Clinic at the Interdisciplinary Metabolism Centre, Charité - Universitätsmedizin Berlin, Germany, and who were initially screened negative for mutations in canonical Familial hypercholesterolemia (FH) genes (LDLR, APOB, PCSK9)[18]

Summary

Introduction

Autosomal-dominant hypercholesterolemia (FH, OMIM 143890) is one of the most common genetic disorders, characterised by severely elevated levels of low-density lipoprotein cholesterol (LDL-C). Diagnosis of FH can be confirmed by presence of a heterozygous pathogenic mutation in one of three genes: LDLR (low density lipoprotein receptor, OMIM 606945)[5,6], APOB (apolipoprotein B, OMIM 107730)[7,8] and PCSK9 (proprotein convertase subtilisin/ kexin, OMIM 607786)[9]. Mutations in LDLRAP1 (low density lipoprotein receptor adaptor protein, OMIM 605747) have been associated with familial hypercholesterolemia inherited in an autosomal-recessive manner (ARH, OMIM 603813)[11,12].These patients can be treated by LDL-apheresis[13] and PCSK9 inhibition with evolocumab in addition to statin and ezetimibe treatment[14,15]. Population-based cohort we evaluated association of carrier status for rare STAP1 variants with total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG), since LDL-C levels have previously been postulated to be significantly higher in carriers of rare STAP1 variants compared to wild type[21]

Methods

Results

Conclusion