Post-GWAS methodologies for localisation of functional non-coding variants: ANGPTL3

Atherosclerosis
Federico OldoniAndrew J P Smith

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, wi...Continue Reading

References

Jan 15, 2008·Nature Genetics·Cristen J WillerGonçalo R Abecasis
Dec 9, 2008·Journal of Molecular Biology·Andrew J P Smith, Steve E Humphries
Jan 2, 2010·Biochemical and Biophysical Research Communications·Biao LuKenneth R Feingold
Oct 15, 2010·The New England Journal of Medicine·Kiran MusunuruSekar Kathiresan
Mar 20, 2012·Cell·Sekar Kathiresan, Deepak Srivastava
Jun 19, 2012·Nature Reviews. Genetics·Ross C Hardison, James Taylor
Dec 19, 2012·Cell Stem Cell·Qiurong DingChad A Cowan
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang

❮ Previous
Next ❯

Citations

Jun 11, 2016·Nature Reviews. Neurology·Chris GaiteriDavid A Bennett
Jan 29, 2019·Epigenomics·Kenneth C EhrlichMelanie Ehrlich
Jul 18, 2018·Journal of Cardiovascular Development and Disease·Maria Giovanna Lupo, Nicola Ferri
Oct 13, 2020·Nucleic Acids Research·Wanwen ZengRui Jiang
May 29, 2021·Diabetes, Obesity & Metabolism·Ping LingJianping Weng

❮ Previous
Next ❯

Methods Mentioned

BETA
surgical resection
ChIP-seq
PCR
transfection
Assay
genotyping
FAIRE-seq
electrophoretic mobility shift
immunoprecipitation

Software Mentioned

Metabochip
FAIRE
HaploReg
gen
MatInspector

Related Concepts

Related Feeds

ApoE, Lipids & Cholesterol

Serum cholesterol, triglycerides, apolipoprotein B (APOB)-containing lipoproteins (very low-density lipoprotein (VLDL), immediate-density lipoprotein (IDL), and low-density lipoprotein (LDL), lipoprotein A (LPA)) and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are all connected in diseases. Here is the latest research.