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|Title:||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|
Wichmann, H. E.
Ortlepp, J. R.
Sattler, A. M.
Samani, N. J.
|Citation:||Atherosclerosis, 2010, 208 (1), pp. 183-9|
|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.|
|Description:||Full text of this item is not currently available on the LRA. The final published version may be available through the links above.|
|Appears in Collections:||Published Articles, Dept. of Cardiovascular Sciences|
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