Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22

Katherine E. Beaney; Andrew J. P. Smith; Lasse Westergaard Folkersen; Jutta Palmen; S. Goya Wannamethee; Barbara J. Jefferis; Peter Whincup; Tom R. Gaunt; Juan P. Casas; Yoav Ben-Shlomo; Jacqueline F. Price; Meena Kumari; Andrew Wong; Ken Ong; Rebecca Hardy; Diana Kuh; Nicholas Wareham; Mika Kivimaki; Per Eriksson; Steve E. Humphries

doi:10.1155/2017/1096916

Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22

Katherine E. Beaney, Andrew J. P. Smith, Lasse Westergaard Folkersen, Jutta Palmen, S. Goya Wannamethee, Barbara J. Jefferis, Peter Whincup, Tom R. Gaunt, Juan P. Casas, Yoav Ben-Shlomo, Jacqueline F. Price, Meena Kumari, Andrew Wong, Ken Ong, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Mika Kivimaki, Per Eriksson, Steve E. Humphries

Research output: Contribution to journal › Journal article › Research › peer-review

376 Downloads (Pure)

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 x 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 x 10(-5); MRPS6 1.15-fold increase p = 9.60 x 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 language	English
Article number	1096916
Journal	Disease Markers
Volume	2017
Number of pages	11
ISSN	0278-0240
DOIs	https://doi.org/10.1155/2017/1096916
Publication status	Published - 2017

Bibliographical note

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Access to Document

10.1155/2017/1096916

1096916Final published version, 2.43 MB

OpenUrl availability

Full text

Cite this

Beaney, K. E., Smith, A. J. P., Folkersen, L. W., Palmen, J., Wannamethee, S. G., Jefferis, B. J., Whincup, P., Gaunt, T. R., Casas, J. P., Ben-Shlomo, Y., Price, J. F., Kumari, M., Wong, A., Ong, K., Hardy, R., Kuh, D., Wareham, N., Kivimaki, M., Eriksson, P., & Humphries, S. E. (2017). Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22. Disease Markers, 2017, Article 1096916. https://doi.org/10.1155/2017/1096916

@article{232fc958eb404b0d94f6a82f750397ff,

title = "Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22",

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 x 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 x 10(-5); MRPS6 1.15-fold increase p = 9.60 x 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.",

author = "Beaney, {Katherine E.} and Smith, {Andrew J. P.} and Folkersen, {Lasse Westergaard} and Jutta Palmen and Wannamethee, {S. Goya} and Jefferis, {Barbara J.} and Peter Whincup and Gaunt, {Tom R.} and Casas, {Juan P.} and Yoav Ben-Shlomo and Price, {Jacqueline F.} and Meena Kumari and Andrew Wong and Ken Ong and Rebecca Hardy and Diana Kuh and Nicholas Wareham and Mika Kivimaki and Per Eriksson and Humphries, {Steve E.}",

note = "This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.",

year = "2017",

doi = "10.1155/2017/1096916",

language = "English",

volume = "2017",

journal = "Disease Markers",

issn = "0278-0240",

publisher = "Hindawi Publishing Corporation",

}

Beaney, KE, Smith, AJP, Folkersen, LW, 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 2017, 'Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22', Disease Markers, vol. 2017, 1096916. https://doi.org/10.1155/2017/1096916

TY - JOUR

T1 - Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22

AU - Beaney, Katherine E.

AU - Smith, Andrew J. P.

AU - Folkersen, Lasse Westergaard

AU - Palmen, Jutta

AU - Wannamethee, S. Goya

AU - Jefferis, Barbara J.

AU - Whincup, Peter

AU - Gaunt, Tom R.

AU - Casas, Juan P.

AU - Ben-Shlomo, Yoav

AU - Price, Jacqueline F.

AU - Kumari, Meena

AU - Wong, Andrew

AU - Ong, Ken

AU - Hardy, Rebecca

AU - Kuh, Diana

AU - Wareham, Nicholas

AU - Kivimaki, Mika

AU - Eriksson, Per

AU - Humphries, Steve E.

N1 - This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PY - 2017

Y1 - 2017

N2 - 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 x 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 x 10(-5); MRPS6 1.15-fold increase p = 9.60 x 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.

AB - 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 x 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 x 10(-5); MRPS6 1.15-fold increase p = 9.60 x 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.

U2 - 10.1155/2017/1096916

DO - 10.1155/2017/1096916

M3 - Journal article

C2 - 28458444

SN - 0278-0240

VL - 2017

JO - Disease Markers

JF - Disease Markers

M1 - 1096916

ER -

Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22

Abstract

Bibliographical note

Access to Document

OpenUrl availability

Fingerprint

Cite this