Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

J. Gustav Smith; Janine F. Felix; Alanna C. Morrison; Andreas Kalogeropoulos; Stella Trompet; Jemma B. Wilk; Olof Gidloef; Xinchen Wang; Michael Morley; Michael Mendelson; Roby Joehanes; Symen Ligthart; Xiaoyin Shan; Joshua C. Bis; Ying A. Wang; Marketa Sjoegren; Julius Ngwa; Jeffrey Brandimarto; David J. Stott; David Aguilar; Kenneth M. Rice; Howard D. Sesso; Serkalem Demissie; Brendan M. Buckley; Kent D. Taylor; Ian Ford; Chen Yao; Chunyu Liu; Nona Sotoodehnia; Pim van der Harst; Bruno H. Ch. Stricker; Stephen B. Kritchevsky; Yongmei Liu; J. Michael Gaziano; Albert Hofman; Christine S. Moravec; Andre G. Uitterlinden; Manolis Kellis; Joyce B. van Meurs; Kenneth B. Margulies; Abbas Dehghan; Daniel Levy; Bjoern Olde; Bruce M. Psaty; L. Adrienne Cupples; J. Wouter Jukema; Luc Djousse; Oscar H. Franco; Eric Boerwinkle; Laurie A. Boyer; CHARGE-SCD Consortium; EchoGen Consortium; QT-IGC Consortium; CHARGE-QRS Consortium

doi:10.1371/journal.pgen.1006034

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

J. Gustav Smith^*, Janine F. Felix, Alanna C. Morrison, Andreas Kalogeropoulos, Stella Trompet, Jemma B. Wilk, Olof Gidloef, Xinchen Wang, Michael Morley, Michael Mendelson, Roby Joehanes, Symen Ligthart, Xiaoyin Shan, Joshua C. Bis, Ying A. Wang, Marketa Sjoegren, Julius Ngwa, Jeffrey Brandimarto, David J. Stott, David AguilarKenneth M. Rice, Howard D. Sesso, Serkalem Demissie, Brendan M. Buckley, Kent D. Taylor, Ian Ford, Chen Yao, Chunyu Liu, Nona Sotoodehnia, Pim van der Harst, Bruno H. Ch. Stricker, Stephen B. Kritchevsky, Yongmei Liu, J. Michael Gaziano, Albert Hofman, Christine S. Moravec, Andre G. Uitterlinden, Manolis Kellis, Joyce B. van Meurs, Kenneth B. Margulies, Abbas Dehghan, Daniel Levy, Bjoern Olde, Bruce M. Psaty, L. Adrienne Cupples, J. Wouter Jukema, Luc Djousse, Oscar H. Franco, Eric Boerwinkle, Laurie A. Boyer, CHARGE-SCD Consortium, EchoGen Consortium, QT-IGC Consortium, CHARGE-QRS Consortium

^*Corresponding author for this work

Cardiovascular Centre (CVC)

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

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Abstract

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10(-9)). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10(-40)) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10(-4)). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

Original language	English
Article number	1006034
Number of pages	19
Journal	PLoS genetics
Volume	12
Issue number	5
DOIs	https://doi.org/10.1371/journal.pgen.1006034
Publication status	Published - May-2016

Keywords

GENOME-WIDE ASSOCIATION
PRESERVED EJECTION FRACTION
EPIDEMIOLOGY CHARGE CONSORTIUM
AGING RESEARCH
HUMAN-POPULATIONS
AFRICAN ANCESTRY
VARIANTS
RISK
METAANALYSIS
SURVIVAL

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Smith, J. G., Felix, J. F., Morrison, A. C., Kalogeropoulos, A., Trompet, S., Wilk, J. B., Gidloef, O., Wang, X., Morley, M., Mendelson, M., Joehanes, R., Ligthart, S., Shan, X., Bis, J. C., Wang, Y. A., Sjoegren, M., Ngwa, J., Brandimarto, J., Stott, D. J., ... CHARGE-QRS Consortium (2016). Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. PLoS genetics, 12(5), Article 1006034. https://doi.org/10.1371/journal.pgen.1006034

@article{6d0a94042af9403e9e1ef77e03ebd405,

title = "Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure",

abstract = "Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10(-9)). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10(-40)) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10(-4)). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.",

keywords = "GENOME-WIDE ASSOCIATION, PRESERVED EJECTION FRACTION, EPIDEMIOLOGY CHARGE CONSORTIUM, AGING RESEARCH, HUMAN-POPULATIONS, AFRICAN ANCESTRY, VARIANTS, RISK, METAANALYSIS, SURVIVAL",

author = "Smith, {J. Gustav} and Felix, {Janine F.} and Morrison, {Alanna C.} and Andreas Kalogeropoulos and Stella Trompet and Wilk, {Jemma B.} and Olof Gidloef and Xinchen Wang and Michael Morley and Michael Mendelson and Roby Joehanes and Symen Ligthart and Xiaoyin Shan and Bis, {Joshua C.} and Wang, {Ying A.} and Marketa Sjoegren and Julius Ngwa and Jeffrey Brandimarto and Stott, {David J.} and David Aguilar and Rice, {Kenneth M.} and Sesso, {Howard D.} and Serkalem Demissie and Buckley, {Brendan M.} and Taylor, {Kent D.} and Ian Ford and Chen Yao and Chunyu Liu and Nona Sotoodehnia and {van der Harst}, Pim and Stricker, {Bruno H. Ch.} and Kritchevsky, {Stephen B.} and Yongmei Liu and Gaziano, {J. Michael} and Albert Hofman and Moravec, {Christine S.} and Uitterlinden, {Andre G.} and Manolis Kellis and {van Meurs}, {Joyce B.} and Margulies, {Kenneth B.} and Abbas Dehghan and Daniel Levy and Bjoern Olde and Psaty, {Bruce M.} and Cupples, {L. Adrienne} and Jukema, {J. Wouter} and Luc Djousse and Franco, {Oscar H.} and Eric Boerwinkle and Boyer, {Laurie A.} and {CHARGE-SCD Consortium} and {EchoGen Consortium} and {QT-IGC Consortium} and {CHARGE-QRS Consortium}",

year = "2016",

month = may,

doi = "10.1371/journal.pgen.1006034",

language = "English",

volume = "12",

journal = "PLoS genetics",

issn = "1553-7404",

publisher = "PUBLIC LIBRARY SCIENCE",

number = "5",

}

Smith, JG, Felix, JF, Morrison, AC, Kalogeropoulos, A, Trompet, S, Wilk, JB, Gidloef, O, Wang, X, Morley, M, Mendelson, M, Joehanes, R, Ligthart, S, Shan, X, Bis, JC, Wang, YA, Sjoegren, M, Ngwa, J, Brandimarto, J, Stott, DJ, Aguilar, D, Rice, KM, Sesso, HD, Demissie, S, Buckley, BM, Taylor, KD, Ford, I, Yao, C, Liu, C, Sotoodehnia, N, van der Harst, P, Stricker, BHC, Kritchevsky, SB, Liu, Y, Gaziano, JM, Hofman, A, Moravec, CS, Uitterlinden, AG, Kellis, M, van Meurs, JB, Margulies, KB, Dehghan, A, Levy, D, Olde, B, Psaty, BM, Cupples, LA, Jukema, JW, Djousse, L, Franco, OH, Boerwinkle, E, Boyer, LA, CHARGE-SCD Consortium, EchoGen Consortium, QT-IGC Consortium & CHARGE-QRS Consortium 2016, 'Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure', PLoS genetics, vol. 12, no. 5, 1006034. https://doi.org/10.1371/journal.pgen.1006034

TY - JOUR

T1 - Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

AU - Smith, J. Gustav

AU - Felix, Janine F.

AU - Morrison, Alanna C.

AU - Kalogeropoulos, Andreas

AU - Trompet, Stella

AU - Wilk, Jemma B.

AU - Gidloef, Olof

AU - Wang, Xinchen

AU - Morley, Michael

AU - Mendelson, Michael

AU - Joehanes, Roby

AU - Ligthart, Symen

AU - Shan, Xiaoyin

AU - Bis, Joshua C.

AU - Wang, Ying A.

AU - Sjoegren, Marketa

AU - Ngwa, Julius

AU - Brandimarto, Jeffrey

AU - Stott, David J.

AU - Aguilar, David

AU - Rice, Kenneth M.

AU - Sesso, Howard D.

AU - Demissie, Serkalem

AU - Buckley, Brendan M.

AU - Taylor, Kent D.

AU - Ford, Ian

AU - Yao, Chen

AU - Liu, Chunyu

AU - Sotoodehnia, Nona

AU - van der Harst, Pim

AU - Stricker, Bruno H. Ch.

AU - Kritchevsky, Stephen B.

AU - Liu, Yongmei

AU - Gaziano, J. Michael

AU - Hofman, Albert

AU - Moravec, Christine S.

AU - Uitterlinden, Andre G.

AU - Kellis, Manolis

AU - van Meurs, Joyce B.

AU - Margulies, Kenneth B.

AU - Dehghan, Abbas

AU - Levy, Daniel

AU - Olde, Bjoern

AU - Psaty, Bruce M.

AU - Cupples, L. Adrienne

AU - Jukema, J. Wouter

AU - Djousse, Luc

AU - Franco, Oscar H.

AU - Boerwinkle, Eric

AU - Boyer, Laurie A.

AU - CHARGE-SCD Consortium

AU - EchoGen Consortium

AU - QT-IGC Consortium

AU - CHARGE-QRS Consortium

PY - 2016/5

Y1 - 2016/5

N2 - Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10(-9)). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10(-40)) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10(-4)). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

AB - Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10(-9)). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10(-40)) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10(-4)). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

KW - GENOME-WIDE ASSOCIATION

KW - PRESERVED EJECTION FRACTION

KW - EPIDEMIOLOGY CHARGE CONSORTIUM

KW - AGING RESEARCH

KW - HUMAN-POPULATIONS

KW - AFRICAN ANCESTRY

KW - VARIANTS

KW - RISK

KW - METAANALYSIS

KW - SURVIVAL

U2 - 10.1371/journal.pgen.1006034

DO - 10.1371/journal.pgen.1006034

M3 - Article

C2 - 27149122

SN - 1553-7404

VL - 12

JO - PLoS genetics

JF - PLoS genetics

IS - 5

M1 - 1006034

ER -

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

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