PuSH - Publication Server of Helmholtz Zentrum München

Linsel-Nitschke, P.* ; Heeren, J.* ; Aherrahrou, Z* ; Bruse, P.* ; Gieger, C. ; Illig, T. ; Prokisch, H. ; Heim, K. ; Döring, A. ; Peters, A. ; Meitinger, T. ; Wichmann, H.-E. ; Hinney, A.* ; Reinehr, T.* ; Roth, C.* ; Ortlepp, J.R.* ; Soufi, M.* ; Sattler, A.M.* ; Schaefer, J.* ; Stark, K.* ; Hengstenberg, C.* ; Schaefer, A.* ; Schreiber, S.* ; Kronenberg, F.* ; Samani, N.J.* ; Schunkert, H.* ; Erdmann, J.*

Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease.

Atherosclerosis 208, 183-189 (2010)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
BACKGROUND: A single nucleotide polymorphism (SNP) rs599839 located at chromosome 1p13.3 has previously been associated with risk of coronary artery disease (CAD) and with serum levels of low-density lipoprotein cholesterol (LDL-C). A functional link explaining the association of SNP rs599839 with LDL-C levels and CAD risk has not yet been elucidated. METHODS: We analyzed the association of rs599839 with LDL-C in 6605 individuals across a wide age spectrum and with CAD in four case-control studies comprising 4287 cases and 7572 controls. Genome-wide expression array data was used to assess the association of SNP rs599839 with gene expression at chromosome 1p13. Finally, we overexpressed sortilin in transfected cells to study LDL-uptake in vitro. RESULTS: Each copy of the G-allele of rs599839 associated with a decrease of serum LDL-C by 0.14mmol/L (90% confidence interval (CI) 0.09-0.17mmol/L, p=2.6x10(-11)). Moreover, each copy of the G-allele associated with a 9% decrease of CAD risk (90% CI 4-14%) in the presently studied four case-control samples and with a 13% decrease (90% CI 10-17%, p=2.18x10(-9)) in a pooled meta-analysis including recent genome-wide association studies on CAD. The same allele was associated with higher mRNA-expression levels of the multiligand receptor sortilin (log transformed mRNA AA vs. GG=8.31 vs. 8.55; p=0.01). Overexpression of SORT1 cDNA resulted in a significant increase in LDL-particle uptake (+23%, p=0.01). CONCLUSIONS: Rs599839 associates with decreased LDL-C and a lower risk of CAD. Effects appear to be mediated by increased sortilin expression and subsequently enhanced LDL-uptake into cells.
Altmetric
Additional Metrics?
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genetics; Coronary disease; Atherosclerosis; Lipoproteins
ISSN (print) / ISBN 0021-9150
e-ISSN 1879-1484
Journal Atherosclerosis
Quellenangaben Volume: 208, Issue: 1, Pages: 183-189 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Non-patent literature Publications
Reviewing status Peer reviewed