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- Title
Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22.
- Authors
Beaney, Katherine E.; Smith, Andrew J. P.; Folkersen, Lasse; Palmen, Jutta; Wannamethee, S. Goya; Jefferis, Barbara J.; Whincup, Peter; Gaunt, Tom R.; Casas, Juan P.; Ben-Shlomo, Yoav; Price, Jacqueline F.; Kumari, Meena; Wong, Andrew; Ong, Ken; Hardy, Rebecca; Kuh, Diana; Wareham, Nicholas; Kivimaki, Mika; Eriksson, Per; Humphries, Steve E.
- 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.
- Subjects
CORONARY heart disease risk factors; CORONARY disease; LOCUS (Genetics); HUMAN genetic variation; ELECTROPHORETIC displays; GENETICS
- Publication
Disease Markers, 2017, p1
- ISSN
0278-0240
- Publication type
Article
- DOI
10.1155/2017/1096916