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

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Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. / Smith, Gustav; Felix, Janine F.; Morrison, Alanna C.; Kalogeropoulos, Andreas; Trompet, Stella; Wilk, Jemma B.; Gidlöf, Olof; Wang, Xinchen; Morley, Michael; Mendelson, Michael; Joehanes, Roby; Ligthart, Symen; Shan, Xiaoyin; Bis, Joshua C.; Wang, Ying A.; Sjögren, Marketa; Ngwa, Julius; Brandimarto, Jeffrey; Stott, David J.; Aguilar, David; Rice, Kenneth M.; Sesso, Howard D.; Demissie, Serkalem; Buckley, Brendan M.; Taylor, Kent D.; Ford, Ian; Yao, Chen; Liu, Chunyu; Sotoodehnia, Nona; van der Harst, Pim; Stricker, Bruno H Ch; Kritchevsky, Stephen B.; Liu, Yongmei; Gaziano, J. Michael; Hofman, Albert; Moravec, Christine S.; Uitterlinden, André G.; Kellis, Manolis; van Meurs, Joyce B.; Margulies, Kenneth B.; Dehghan, Abbas; Levy, Daniel; Olde, Björn; Psaty, Bruce M.; Cupples, L. Adrienne; Jukema, J. Wouter; Djousse, Luc; Franco, Oscar H.; Boerwinkle, Eric; Boyer, Laurie A.; Newton-Cheh, Christopher; Butler, Javed; Vasan, Ramachandran S.; Cappola, Thomas P.; Smith, Nicholas L.

In: PLoS Genetics, Vol. 12, No. 5, e1006034, 01.05.2016.

Research output: Contribution to journalArticle

Harvard

Smith, G, Felix, JF, Morrison, AC, Kalogeropoulos, A, Trompet, S, Wilk, JB, Gidlöf, O, Wang, X, Morley, M, Mendelson, M, Joehanes, R, Ligthart, S, Shan, X, Bis, JC, Wang, YA, Sjögren, 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, Newton-Cheh, C, Butler, J, Vasan, RS, Cappola, TP & Smith, NL 2016, 'Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure', PLoS Genetics, vol. 12, no. 5, e1006034. https://doi.org/10.1371/journal.pgen.1006034

APA

Smith, G., Felix, J. F., Morrison, A. C., Kalogeropoulos, A., Trompet, S., Wilk, J. B., ... Smith, N. L. (2016). Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. PLoS Genetics, 12(5), [e1006034]. https://doi.org/10.1371/journal.pgen.1006034

CBE

Smith G, Felix JF, Morrison AC, Kalogeropoulos A, Trompet S, Wilk JB, Gidlöf O, Wang X, Morley M, Mendelson M, Joehanes R, Ligthart S, Shan X, Bis JC, Wang YA, Sjögren 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, Newton-Cheh C, Butler J, Vasan RS, Cappola TP, Smith NL. 2016. Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. PLoS Genetics. 12(5). https://doi.org/10.1371/journal.pgen.1006034

MLA

Vancouver

Author

Smith, Gustav ; Felix, Janine F. ; Morrison, Alanna C. ; Kalogeropoulos, Andreas ; Trompet, Stella ; Wilk, Jemma B. ; Gidlöf, Olof ; Wang, Xinchen ; Morley, Michael ; Mendelson, Michael ; Joehanes, Roby ; Ligthart, Symen ; Shan, Xiaoyin ; Bis, Joshua C. ; Wang, Ying A. ; Sjögren, Marketa ; Ngwa, Julius ; Brandimarto, Jeffrey ; Stott, David J. ; Aguilar, David ; Rice, Kenneth M. ; Sesso, Howard D. ; Demissie, Serkalem ; Buckley, Brendan M. ; Taylor, Kent D. ; Ford, Ian ; Yao, Chen ; Liu, Chunyu ; Sotoodehnia, Nona ; van der Harst, Pim ; Stricker, Bruno H Ch ; Kritchevsky, Stephen B. ; Liu, Yongmei ; Gaziano, J. Michael ; Hofman, Albert ; Moravec, Christine S. ; Uitterlinden, André G. ; Kellis, Manolis ; van Meurs, Joyce B. ; Margulies, Kenneth B. ; Dehghan, Abbas ; Levy, Daniel ; Olde, Björn ; Psaty, Bruce M. ; Cupples, L. Adrienne ; Jukema, J. Wouter ; Djousse, Luc ; Franco, Oscar H. ; Boerwinkle, Eric ; Boyer, Laurie A. ; Newton-Cheh, Christopher ; Butler, Javed ; Vasan, Ramachandran S. ; Cappola, Thomas P. ; Smith, Nicholas L. / Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. In: PLoS Genetics. 2016 ; Vol. 12, No. 5.

RIS

TY - JOUR

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

AU - Smith, Gustav

AU - Felix, Janine F.

AU - Morrison, Alanna C.

AU - Kalogeropoulos, Andreas

AU - Trompet, Stella

AU - Wilk, Jemma B.

AU - Gidlöf, 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 - Sjögren, 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, André G.

AU - Kellis, Manolis

AU - van Meurs, Joyce B.

AU - Margulies, Kenneth B.

AU - Dehghan, Abbas

AU - Levy, Daniel

AU - Olde, Björn

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 - Newton-Cheh, Christopher

AU - Butler, Javed

AU - Vasan, Ramachandran S.

AU - Cappola, Thomas P.

AU - Smith, Nicholas L.

PY - 2016/5/1

Y1 - 2016/5/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84974530805&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1006034

DO - 10.1371/journal.pgen.1006034

M3 - Article

VL - 12

JO - PLoS Genetics

T2 - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7404

IS - 5

M1 - e1006034

ER -