Functional analysis of the coronary heart disease risk locus on chromosome 21q22

Katherine E Beaney, Andrew Smith, Lasse Folkersen, Jutta Palmen, SG Wannamethee, Barbara J Jefferis, Peter H Whincup, Tom Gaunt, Juan-Pablo Casas, Yoav Ben-Shlomo, Jacqueline F Price, Meena Kumari, Andrew Wong, Ken K Ong, Rebecca Hardy, Diana Kuh, Nicholas J Wareham, Mika Kivimäki, Per Eriksson, Steve E Humphries

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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.
Original languageEnglish
Article number1096916
Number of pages10
JournalDisease Markers
Publication statusPublished - 28 Mar 2017

Structured keywords

  • Bristol Population Health Science Institute

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