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

• Published in: Atherosclerosis 2010-01, Vol.208 (1), p.183-189
• Main Authors: Linsel-Nitschke, Patrick, Heeren, Jörg, Aherrahrou, Zouhair, Bruse, Petra, Gieger, Christian, Illig, Thomas, Prokisch, Holger, Heim, Katharina, Doering, Angela, Peters, Annette, Meitinger, Thomas, Wichmann, H.-Erich, Hinney, Anke, Reinehr, Thomas, Roth, Christian, Ortlepp, Jan. R, Soufi, Mouhidien, Sattler, Alexander M, Schaefer, Jürgen, Stark, Klaus, Hengstenberg, Christian, Schaefer, Arne, Schreiber, Stefan, Kronenberg, Florian, Samani, Nilesh J, Schunkert, Heribert, Erdmann, Jeanette
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; Cells, Cultured - metabolism; Cholesterol, LDL - blood; Cholesterol, LDL - metabolism; Chromosomes, Human, Pair 1; Coronary Artery Disease - epidemiology; Coronary Artery Disease - genetics; Coronary disease; Coronary heart disease; Gene Expression Regulation; Genetic Variation; Genetics; Heart; Humans; Lipoproteins; Medical sciences; Risk Factors; RNA, Messenger - biosynthesis
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2009.06.034

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 × 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 × 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.