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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

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

Abstract

Full text of this item is not currently available on the LRA. The final published version may be available through the links above.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.\ud \ud 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.\ud \ud 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).\ud \ud 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.This study was funded by the European Union sponsored project Cardiogenics (LSHM-CT 2006-037593), by the National Genome Network (01GS0418 to Drs. Schunkert, Erdmann, and Hengstenberg; 01GR0466 to Dr. Ziegler) sponsored by the German Federal Ministry of Education and Research (BMBF). The MONICA/KORA Augsburg studies were financed by the Helmhotz Zentrum München (former GSF)-National Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the BMBF and Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. This work was also supported by the “Genomics of Lipid-associated Disorders—GOLD” of the “Austrian Genome Research Programme GEN-AU” (to F.K.)

Topics: Genetics, Coronary disease, Atherosclerosis, Lipoproteins
Publisher: Elsevier
Year: 2010
DOI identifier: 10.1016/j.atherosclerosis.2009.06.034
OAI identifier: oai:lra.le.ac.uk:2381/7911
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