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.

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.

• Authors: Patrick Linsel-Nitschke, Jörg Heeren, Zouhair Aherrahrou, Petra Bruse, Christian Gieger, Thomas Illig, Holger Prokisch, Katharina Heim, Angela Doering, Annette Peters, Thomas Meitinger, H-Erich Wichmann, Anke Hinney, Thomas Reinehr, Christian Roth, Jan R Ortlepp, Mouhidien Soufi, Alexander M Sattler, Jürgen Schaefer, Klaus Stark, Christian Hengstenberg, Arne Schaefer, Stefan Schreiber, Florian Kronenberg, Nilesh J Samani, Heribert Schunkert, Jeanette Erdmann
• Journal: Atherosclerosis (Atherosclerosis) Vol. 208 Issue 1 Pg. 183-9 (Jan 2010) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 19660754 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Cholesterol, LDL
• RNA, Messenger
• sortilin

Topics

• Adaptor Proteins, Vesicular Transport (genetics)
• Cells, Cultured (metabolism)
• Cholesterol, LDL (blood, metabolism)
• Chromosomes, Human, Pair 1
• Coronary Artery Disease (epidemiology, genetics)
• Gene Expression Regulation
• Genetic Variation
• Humans
• RNA, Messenger (biosynthesis)
• Risk Factors