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From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
Kiran Musunuru1, Alanna Strong, Maria Frank-Kamenetsky
1Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Nature
|August 6, 2010
Summary
A common genetic variant near the SORT1 gene influences cholesterol levels and heart attack risk by altering how the liver produces very-low-density lipoprotein particles. This finding reveals a new pathway for managing lipoprotein metabolism and cardiovascular disease risk.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Disease Research
Background:
- Genome-wide association studies (GWASs) identified a locus on chromosome 1p13 linked to low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI).
- The precise functional mechanism connecting this genetic locus to clinical phenotypes remained unclear.
Purpose of the Study:
- To elucidate the functional role of the 1p13 locus polymorphism (rs12740374) in lipoprotein metabolism and cardiovascular risk.
- To investigate how this variant impacts hepatic gene expression and very-low-density lipoprotein (VLDL) secretion.
Main Methods:
- Analysis of human cohorts and hepatocyte studies.
- Investigating the effect of the rs12740374 polymorphism on CCAAT/enhancer binding protein (C/EBP) transcription factor binding.
- Utilizing small interfering RNA (siRNA) knockdown and viral overexpression of the SORT1 gene in mouse liver models.
Main Results:
- The rs12740374 polymorphism creates a C/EBP binding site, altering hepatic SORT1 gene expression.
- Sort1 modulation in mice directly impacts plasma LDL-C and VLDL levels by affecting hepatic VLDL secretion.
- Demonstrated that common noncoding DNA variants from GWASs can directly influence clinical outcomes.
Conclusions:
- Identified a novel regulatory pathway for lipoprotein metabolism involving the SORT1 gene.
- Functional evidence supports the role of the 1p13 locus in modulating MI risk through lipoprotein regulation.
- Established that common noncoding genetic variants can have a direct impact on complex human diseases.
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