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

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    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 languageEnglish
    Article number1096916
    JournalDisease Markers
    Volume2017
    Number of pages11
    ISSN0278-0240
    DOIs
    Publication statusPublished - 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.

    Cite this

    Beaney, K. E., Smith, A. J. P., Folkersen, L. W., Palmen, J., Wannamethee, S. G., Jefferis, B. J., ... Humphries, S. E. (2017). Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22. Disease Markers, 2017, [1096916]. https://doi.org/10.1155/2017/1096916
    Beaney, Katherine E. ; Smith, Andrew J. P. ; Folkersen, Lasse Westergaard ; 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. / Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22. In: Disease Markers. 2017 ; Vol. 2017.
    @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",

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    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

    Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22. / Beaney, Katherine E.; Smith, Andrew J. P.; Folkersen, Lasse Westergaard; 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.

    In: Disease Markers, Vol. 2017, 1096916, 2017.

    Research output: Contribution to journalJournal articleResearchpeer-review

    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

    VL - 2017

    JO - Disease Markers

    JF - Disease Markers

    SN - 0278-0240

    M1 - 1096916

    ER -

    Beaney KE, Smith AJP, Folkersen LW, Palmen J, Wannamethee SG, Jefferis BJ et al. Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22. Disease Markers. 2017;2017. 1096916. https://doi.org/10.1155/2017/1096916