Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22.
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Authors
Smith, Andrew JP
Palmen, Jutta
Wannamethee, S Goya
Casas, Juan P
Price, Jacqueline F
Kuh, Diana
Consortium, Ucleb
Publication Date
2017-01Journal Title
Disease markers
ISSN
0278-0240
Volume
2017
Pages
1096916
Language
English
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Beaney, K. E., Smith, A. J., Folkersen, L., Palmen, J., Wannamethee, S. G., Jefferis, B. J., Whincup, P., et al. (2017). Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22.. Disease markers, 2017 1096916. https://doi.org/10.1155/2017/1096916
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.
Keywords
Chromosomes, Human, Pair 21, Humans, Long QT Syndrome, Coronary Disease, Polymorphism, Single Nucleotide, Genetic Loci, Hep G2 Cells
Sponsorship
MRC (MC_UU_12015/2)
Identifiers
External DOI: https://doi.org/10.1155/2017/1096916
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266508
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International