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Disease Markers
Volume 2017, Article ID 1096916, 10 pages
Research Article

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

1Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, UK
2Cardiovascular Medicine Unit, Center for Molecular Medicine and Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
3Center for Biological Sequence Analysis, Technical University of Denmark, Copenhagen, Denmark
4Department of Primary Care & Population Health, UCL Institute of Epidemiology & Health Care, University College London, London, UK
5Population Health Research Institute, St George’s University of London, Cranmer Terrace, London, UK
6MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
7Farr Institute of Health Informatics Research, University College London, London, UK
8School of Social and Community Medicine, University of Bristol, Bristol, UK
9Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
10Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, UK
11Institute for Social and Economic Research, University of Essex, Colchester, UK
12MRC Unit for Lifelong Health and Ageing, London, UK
13MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
14Institute of Cardiovascular Science, University College London, London, UK

Correspondence should be addressed to Steve E. Humphries;

Received 25 August 2016; Accepted 13 December 2016; Published 28 March 2017

Academic Editor: Olav Lapaire

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.


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 (). One variant at the locus, rs28451064, showed allele-specific protein binding and its minor allele showed 12% higher luciferase expression ( = 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 = 3.98 × 10−5; MRPS6 1.15-fold increase = 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.