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Dis Markers. 2017;2017:1096916. doi: 10.1155/2017/1096916. Epub 2017 Mar 28.

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

Author information

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

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.

PMID:
28458444
PMCID:
PMC5387827
DOI:
10.1155/2017/1096916
[Indexed for MEDLINE]
Free PMC Article

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