Linsel-Nitschke, Patrick and Heeren, Joerg and Aherrahrou, Zouhair and Bruse, Petra and Gieger, Christian and Illig, Thomas and Prokisch, Holger and Heim, Katharina and Doering, Angela and Peters, Annette and Meitinger, Thomas and Wichmann, H. -Erich and Hinney, Anke and Reinehr, Thomas and Roth, Christian and Ortlepp, Jan. R. and Soufi, Mouhidien and Sattler, Alexander M. and Schaefer, Juergen and Stark, Klaus and Hengstenberg, Christian and Schaefer, Arne and Schreiber, Stefan and Kronenberg, Florian and Samani, Nilesh J. and Schunkert, Heribert and Erdmann, Jeanette (2010) 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 (1). pp. 183-189. ISSN 0021-9150,
Full text not available from this repository. (Request a copy)Abstract
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 0.14 mmol/L (90% confidence interval (CI) 0.09-0.17 mmol/L, p = 2.6 x 10(-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 = 2.18 x 10(-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. (c) 2009 Elsevier Ireland Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GENOME-WIDE ASSOCIATION; VPS10P DOMAIN; CHOLESTEROL; RECEPTOR; BINDS; LOCI; Genetics; Coronary disease; Atherosclerosis; Lipoproteins |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Aug 2020 07:00 |
| Last Modified: | 12 Aug 2020 07:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/25367 |
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