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Abstract
Genome-wide association studies have confirmed the involvement of non-coding angiopoietin-like 3 (ANGPTL3) gene variants with coronary artery disease, levels of low-density lipoprotein cholesterol (LDL-C), triglycerides and ANGPTL3
mRNA transcript. Extensive linkage disequilibrium at the locus,
however, has hindered efforts to identify the potential functional
variants. Using regulatory annotations from ENCODE, combined with
functional in vivo assays such as allele-specific
formaldehyde-assisted isolation of regulatory elements, statistical
approaches including eQTL/lipid colocalisation, and traditional in vitro methodologies including electrophoretic mobility shift assay and luciferase reporter assays, variants affecting the ANGPTL3 regulome were examined. From 253 variants associated with ANGPTL3
mRNA expression, and/or lipid traits, 46 were located within liver
regulatory elements and potentially functional. One variant, rs10889352,
demonstrated allele-specific effects on DNA-protein interactions,
reporter gene expression and chromatin accessibility, in line with
effects on LDL-C levels and expression of ANGPTL3 mRNA. The ANGPTL3 gene lies within DOCK7, although the variant is within non-coding regions outside of ANGPTL3, within DOCK7,
suggesting complex long-range regulatory effects on gene expression.
This study illustrates the power of combining multiple genome-wide
datasets with laboratory data to localise functional non-coding
variation and provides a model for analysis of regulatory variants from
GWAS.
Original language | English |
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Pages (from-to) | 193-201 |
Number of pages | 9 |
Journal | Atherosclerosis |
Volume | 246 |
Early online date | 12 Dec 2015 |
DOIs | |
Publication status | Published - Mar 2016 |
Keywords
- ANGPTL3
- Polymorphism
- Regulation
- Chromatin
- Genome-wide
- Functional polymorphism
- FAIRE
- LDL-C
Fingerprint
Dive into the research topics of 'Post-GWAS methodologies for localisation of functional non-coding variants: ANGPTL3'. Together they form a unique fingerprint.Projects
- 2 Finished
-
MRC UoB UNITE Unit - Programme 5
Lawlor, D. A. (Principal Investigator) & Lawlor, D. A. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
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MRC UoB UNITE Unit - Programme 1
Davey Smith, G. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research