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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
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…
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In the liver, sortilin acts as a lipoprotein receptor controlling hepatic uptake and release of cholesterol-rich lipoproteins, explaining genome-wide association of SORT1 with plasma cholesterol levels and risk of myocardial infarction.
“In the liver, it acts as a lipoprotein receptor controlling hepatic uptake but also release of cholesterol-rich lipoproteins, explaining genome-wide association of the encoding gene SORT1 with plasma cholesterol levels and the risk of myocardial infarction2,3,7–9”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [9]
GWAS studies identified single-nucleotide polymorphisms mapping to 1p13.3 that are strongly associated with plasma LDL levels and coronary heart disease.
“Recently, GWAS studies have identified single-nucleotide polymorphisms mapping to 1p13.3 that strongly associated with plasma LDL levels and coronary heart disease.14–19”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [16]
Overexpression of SORT1 increases LDL clearance and decreases plasma LDL levels.
“Overexpression of SORT1 increases LDL clearance and decreases plasma LDL levels,16,21,22”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [16]
SORT1 is a hepatic clearance receptor for LDL that also regulates VLDL secretion and plasma triglycerides.
“SORT1 is a recently identified hepatic clearance receptor for LDL, which also regulates VLDL secretion and plasma triglycerides.16,20–22,38”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [16]
Citations
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From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
Musunuru, K., Strong, A., Frank-Kamenetsky, M., Lee, N. E., Ahfeldt, T., Sachs, K. V., Li, X., Li, H., Kuperwasser, N., Ruda, V. M., et al. (2010) · Nature · doi:10.1038/nature09266 · Cited by 1,140
Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism
Strong, A., Ding, Q., Edmondson, A. C., Millar, J. S., Sachs, K. V., Li, X., Kumaravel, A., Wang, M. Y., Ai, D., Guo, L., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63563 · Cited by 222
From genotype to phenotype in human atherosclerosis - recent findings
Holdt, L. M., & Teupser, D. (2013) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3283654e7c · Cited by 62
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Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism
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Utility of genetic determinants of lipids and cardiovascular events in assessing risk
Holmes, M. V., Harrison, S., Talmud, P. J., Hingorani, A. D., & Humphries, S. E. (2011) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2011.6 · Cited by 44
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Metadata
- Authors
- Linsel-Nitschke, P., Heeren, J., Aherrahrou, Z., Bruse, P., Gieger, C., Illig, T., Prokisch, H., Heim, K., Doering, A., Peters, A., Meitinger, T., Wichmann, H.-E., Hinney, A., Reinehr, T., Roth, C., Ortlepp, J. R., Soufi, M., Sattler, A. M., Schaefer, J., Stark, K., Hengstenberg, C., Schaefer, A., Schreiber, S., Kronenberg, F., Samani, N. J., Schunkert, H., & Erdmann, J.
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 208
- Issue
- 1
- Pages
- 183-189
- ISSN
- 0021-9150
- Cited by
- 141
- References
- 2
- Language
- en
- Funders
- Growing Spine Foundation
- European Commission (LSHM-CT 2006-037593)
- Bundesministerium für Bildung und Forschung
- Helmholtz Zentrum München
- Münchner Zentrum für Gesundheitswissenschaften, Ludwig-Maximilians-Universität München
- National Center for Environmental Health
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