Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy

Sonia Shah; Christopher P. Nelson; Tom R. Gaunt; Pim Van Der Harst; Timothy Barnes; Peter S. Braund; Debbie A. Lawlor; Juan Pablo Casas; Sandosh Padmanabhan; Fotios Drenos; Mika Kivimaki; Philippa J. Talmud; Steve E. Humphries; John Whittaker; Richard W. Morris; Peter H. Whincup; Anna Dominiczak; Patricia B. Munroe; Toby Johnson; Alison H. Goodall; Francois Cambien; Patrick Diemert; Christian Hengstenberg; Willem H. Ouwehand; Janine F. Felix; Nicole L. Glazer; Maciej Tomaszewski; Paul R. Burton; Martin D. Tobin; Dirk J. Van Veldhuisen; Rudolf A. De Boer; Gerjan Navis; Wiek H. Van Gilst; Bongani M. Mayosi; John R. Thompson; Meena Kumari; Peter W. MacFarlane; Ian N.M. Day; Aroon D. Hingorani; Nilesh J. Samani

doi:10.1161/CIRCGENETICS.111.960203

Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy

Sonia Shah, Christopher P. Nelson, Tom R. Gaunt, Pim Van Der Harst, Timothy Barnes, Peter S. Braund, Debbie A. Lawlor, Juan Pablo Casas, Sandosh Padmanabhan, Fotios Drenos, Mika Kivimaki, Philippa J. Talmud, Steve E. Humphries, John Whittaker, Richard W. Morris, Peter H. Whincup, Anna Dominiczak, Patricia B. Munroe, Toby Johnson, Alison H. GoodallFrancois Cambien, Patrick Diemert, Christian Hengstenberg, Willem H. Ouwehand, Janine F. Felix, Nicole L. Glazer, Maciej Tomaszewski, Paul R. Burton, Martin D. Tobin, Dirk J. Van Veldhuisen, Rudolf A. De Boer, Gerjan Navis, Wiek H. Van Gilst, Bongani M. Mayosi, John R. Thompson, Meena Kumari, Peter W. MacFarlane, Ian N.M. Day, Aroon D. Hingorani, Nilesh J. Samani^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

25 Citations (Scopus)

Abstract

Background:

Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH.

Methods and Results:

We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22×10 ^-7) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74×10 ^-8), 15q25.2 (NMB, rs2292462, P=3.23×10 ^-9), and 15q26.3 (IGF1R, rs4966014, P=1.26×10 ^-7) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes.

Conclusions:

These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.

Original language	English
Pages (from-to)	626-635
Number of pages	10
Journal	Circulation: Cardiovascular Genetics
Volume	4
Issue number	6
DOIs	https://doi.org/10.1161/CIRCGENETICS.111.960203
Publication status	Published - 30 Sept 2011
Externally published	Yes

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10.1161/CIRCGENETICS.111.960203

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Shah, S., Nelson, C. P., Gaunt, T. R., Van Der Harst, P., Barnes, T., Braund, P. S., Lawlor, D. A., Casas, J. P., Padmanabhan, S., Drenos, F., Kivimaki, M., Talmud, P. J., Humphries, S. E., Whittaker, J., Morris, R. W., Whincup, P. H., Dominiczak, A., Munroe, P. B., Johnson, T., ... Samani, N. J. (2011). Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy. Circulation: Cardiovascular Genetics, 4(6), 626-635. https://doi.org/10.1161/CIRCGENETICS.111.960203

@article{2178fc2539a148368631f93fac7aa877,

title = "Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy",

abstract = "Background:Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH. Methods and Results:We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22×10 -7) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74×10 -8), 15q25.2 (NMB, rs2292462, P=3.23×10 -9), and 15q26.3 (IGF1R, rs4966014, P=1.26×10 -7) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes. Conclusions:These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.",

author = "Sonia Shah and Nelson, {Christopher P.} and Gaunt, {Tom R.} and {Van Der Harst}, Pim and Timothy Barnes and Braund, {Peter S.} and Lawlor, {Debbie A.} and Casas, {Juan Pablo} and Sandosh Padmanabhan and Fotios Drenos and Mika Kivimaki and Talmud, {Philippa J.} and Humphries, {Steve E.} and John Whittaker and Morris, {Richard W.} and Whincup, {Peter H.} and Anna Dominiczak and Munroe, {Patricia B.} and Toby Johnson and Goodall, {Alison H.} and Francois Cambien and Patrick Diemert and Christian Hengstenberg and Ouwehand, {Willem H.} and Felix, {Janine F.} and Glazer, {Nicole L.} and Maciej Tomaszewski and Burton, {Paul R.} and Tobin, {Martin D.} and {Van Veldhuisen}, {Dirk J.} and {De Boer}, {Rudolf A.} and Gerjan Navis and {Van Gilst}, {Wiek H.} and Mayosi, {Bongani M.} and Thompson, {John R.} and Meena Kumari and MacFarlane, {Peter W.} and Day, {Ian N.M.} and Hingorani, {Aroon D.} and Samani, {Nilesh J.}",

year = "2011",

month = sep,

day = "30",

doi = "10.1161/CIRCGENETICS.111.960203",

language = "English",

volume = "4",

pages = "626--635",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

number = "6",

}

Shah, S, Nelson, CP, Gaunt, TR, Van Der Harst, P, Barnes, T, Braund, PS, Lawlor, DA, Casas, JP, Padmanabhan, S, Drenos, F, Kivimaki, M, Talmud, PJ, Humphries, SE, Whittaker, J, Morris, RW, Whincup, PH, Dominiczak, A, Munroe, PB, Johnson, T, Goodall, AH, Cambien, F, Diemert, P, Hengstenberg, C, Ouwehand, WH, Felix, JF, Glazer, NL, Tomaszewski, M, Burton, PR, Tobin, MD, Van Veldhuisen, DJ, De Boer, RA, Navis, G, Van Gilst, WH, Mayosi, BM, Thompson, JR, Kumari, M, MacFarlane, PW, Day, INM, Hingorani, AD & Samani, NJ 2011, 'Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy', Circulation: Cardiovascular Genetics, vol. 4, no. 6, pp. 626-635. https://doi.org/10.1161/CIRCGENETICS.111.960203

TY - JOUR

T1 - Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy

AU - Shah, Sonia

AU - Nelson, Christopher P.

AU - Gaunt, Tom R.

AU - Van Der Harst, Pim

AU - Barnes, Timothy

AU - Braund, Peter S.

AU - Lawlor, Debbie A.

AU - Casas, Juan Pablo

AU - Padmanabhan, Sandosh

AU - Drenos, Fotios

AU - Kivimaki, Mika

AU - Talmud, Philippa J.

AU - Humphries, Steve E.

AU - Whittaker, John

AU - Morris, Richard W.

AU - Whincup, Peter H.

AU - Dominiczak, Anna

AU - Munroe, Patricia B.

AU - Johnson, Toby

AU - Goodall, Alison H.

AU - Cambien, Francois

AU - Diemert, Patrick

AU - Hengstenberg, Christian

AU - Ouwehand, Willem H.

AU - Felix, Janine F.

AU - Glazer, Nicole L.

AU - Tomaszewski, Maciej

AU - Burton, Paul R.

AU - Tobin, Martin D.

AU - Van Veldhuisen, Dirk J.

AU - De Boer, Rudolf A.

AU - Navis, Gerjan

AU - Van Gilst, Wiek H.

AU - Mayosi, Bongani M.

AU - Thompson, John R.

AU - Kumari, Meena

AU - MacFarlane, Peter W.

AU - Day, Ian N.M.

AU - Hingorani, Aroon D.

AU - Samani, Nilesh J.

PY - 2011/9/30

Y1 - 2011/9/30

N2 - Background:Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH. Methods and Results:We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22×10 -7) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74×10 -8), 15q25.2 (NMB, rs2292462, P=3.23×10 -9), and 15q26.3 (IGF1R, rs4966014, P=1.26×10 -7) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes. Conclusions:These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.

AB - Background:Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH. Methods and Results:We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22×10 -7) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74×10 -8), 15q25.2 (NMB, rs2292462, P=3.23×10 -9), and 15q26.3 (IGF1R, rs4966014, P=1.26×10 -7) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes. Conclusions:These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.

UR - http://www.scopus.com/inward/record.url?scp=84863393615&partnerID=8YFLogxK

U2 - 10.1161/CIRCGENETICS.111.960203

DO - 10.1161/CIRCGENETICS.111.960203

M3 - Article

C2 - 21965548

AN - SCOPUS:84863393615

SN - 1942-325X

VL - 4

SP - 626

EP - 635

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 6

ER -

Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy

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