Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22.
Disease markers 2016 ; 2017: 1096916.
Beaney KE, Smith AJP, Folkersen L, Palmen J, Wannamethee SG, Jefferis BJ, Whincup P, Gaunt TR, Casas JP, Ben-Shlomo Y, Price JF, Kumari M, Wong A, Ong K, Hardy R, Kuh D, Wareham N, Kivimaki M, Eriksson P, Humphries SE, Consortium U
DOI : 10.1155/2017/1096916
PubMed ID : 28458444
PMCID : PMC5387827
. 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. . 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. . A suggestive association between QT interval and the locus was observed (rs9982601 = 0.04). One variant at the locus, rs28451064, showed allele-specific protein binding and its minor allele showed 12% higher luciferase expression ( = 4.82 × 10) compared to the common allele. The minor allele of rs9982601 was associated with higher expression of the closest upstream genes ( 1.30-fold increase = 3.98 × 10; 1.15-fold increase = 9.60 × 10) in aortic intima media in ASAP. Both rs9982601 and rs28451064 showed a suggestive association with expression in relevant tissues in the GTEx data. . A candidate functional variant, rs28451064, was identified. Future work should focus on identifying the pathway(s) involved.