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Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22.

Beaney, KE; Smith, AJP; Folkersen, L; Palmen, J; Wannamethee, SG; Jefferis, BJ; Whincup, P; Gaunt, TR; Casas, JP; Ben-Shlomo, Y; et al. Beaney, KE; Smith, AJP; Folkersen, L; Palmen, J; Wannamethee, SG; Jefferis, BJ; Whincup, P; Gaunt, TR; Casas, JP; Ben-Shlomo, Y; Price, JF; Kumari, M; Wong, A; Ong, K; Hardy, R; Kuh, D; Wareham, N; Kivimaki, M; Eriksson, P; Humphries, SE; Consortium, U (2017) Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22. Dis Markers, 2017. p. 1096916. ISSN 1875-8630 https://doi.org/10.1155/2017/1096916
SGUL Authors: Whincup, Peter Hynes

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Abstract

Background. The coronary heart disease (CHD) risk locus on 21q22 (lead SNP rs9982601) lies within a "gene desert." The aim of this study was to assess if this locus is associated with CHD risk factors and to identify the functional variant(s) and gene(s) involved. Methods. A phenome scan was performed with UCLEB Consortium data. Allele-specific protein binding was studied using electrophoretic mobility shift assays. Dual-reporter luciferase assays were used to assess the impact of genetic variation on expression. Expression quantitative trait analysis was performed with Advanced Study of Aortic Pathology (ASAP) and Genotype-Tissue Expression (GTEx) consortium data. Results. A suggestive association between QT interval and the locus was observed (rs9982601  p = 0.04). One variant at the locus, rs28451064, showed allele-specific protein binding and its minor allele showed 12% higher luciferase expression (p = 4.82 × 10(-3)) compared to the common allele. The minor allele of rs9982601 was associated with higher expression of the closest upstream genes (SLC5A3 1.30-fold increase p = 3.98 × 10(-5); MRPS6 1.15-fold increase p = 9.60 × 10(-4)) in aortic intima media in ASAP. Both rs9982601 and rs28451064 showed a suggestive association with MRPS6 expression in relevant tissues in the GTEx data. Conclusions. A candidate functional variant, rs28451064, was identified. Future work should focus on identifying the pathway(s) involved.

Item Type: Article
Additional Information: Copyright © 2017 Katherine E. Beaney et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Oncology & Carcinogenesis, 1116 Medical Physiology
SGUL Research Institute / Research Centre: Academic Structure > Population Health Research Institute (INPH)
Journal or Publication Title: Dis Markers
ISSN: 1875-8630
Language: eng
Dates:
DateEvent
28 March 2017Published
13 December 2016Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
RG/10/12/28456British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/13/16/30528British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
K013351Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
ID85374Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
RG/07/008/23674British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
HL036310National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
5RO1AG13196National Institute on Aginghttp://dx.doi.org/10.13039/100000049
HS06516Agency for Health Care Policy ResearchUNSPECIFIED
AG1764406S1National Institute on Aginghttp://dx.doi.org/10.13039/100000049
MC_UU_12019/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PG/13/66/30442British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/98002British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
CZB/4/672Chief Scientist Officehttp://dx.doi.org/10.13039/501100000589
G0500877Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
CZQ/1/38Chief Scientist Officehttp://dx.doi.org/10.13039/501100000589
10/0003985Diabetes UKhttp://dx.doi.org/10.13039/501100000361
MC_UU_12013/1-9Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BHF PG08/008British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
1270920Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
FS/13/6/29977British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 28458444
Web of Science ID: WOS:000399215100001
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/108816
Publisher's version: https://doi.org/10.1155/2017/1096916

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