Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22. (28th March 2017)

• Record Type: Journal Article
• 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.; Consortium, UCLEB
• Other Names: Lapaire Olav Academic Editor.
• Is Part Of: Disease markers. Volume 2017(2017)
• Publication Date: 2017-03-28
• Subjects: Diagnosis -- Periodicals; Biochemical markers -- Periodicals; Pathology -- Periodicals; 616
• DOI: 10.1155/2017/1096916
• Languages: English
• ISSNs: 0278-0240

Abstract

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 (r s 9982601 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.