Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children

Anna Rautanen; Matti Pirinen; Tara C. Mills; Kirk A. Rockett; Amy Strange; Anne W. Ndungu; Vivek Naranbhai; James J. Gilchrist; Céline Bellenguez; Colin Freeman; Gavin Band; Suzannah J. Bumpstead; Sarah Edkins; Eleni Giannoulatou; Emma Gray; Serge Dronov; Sarah E. Hunt; Cordelia Langford; Richard D. Pearson; Zhan Su; Damjan Vukcevic; Alex W. Macharia; Sophie Uyoga; Carolyne Ndila; Neema Mturi; Patricia Njuguna; Shebe Mohammed; James A. Berkley; Isaiah Mwangi; Salim Mwarumba; Barnes S. Kitsao; Brett S. Lowe; Susan C. Morpeth; Iqbal Khandwalla; Jenefer M. Blackwell; Elvira Bramon; Matthew A. Brown; Juan P. Casas; Aiden Corvin; Audrey Duncanson; Janusz Jankowski; Hugh S. Markus; Christopher G. Mathew; Colin N.A. Palmer; Robert Plomin; Stephen J. Sawcer; Richard C. Trembath; Ananth C. Viswanathan; Nicholas W. Wood; Panos Deloukas; Leena Peltonen; Thomas N. Williams; J. Anthony G. Scott; Stephen J. Chapman; Peter Donnelly; Adrian V.S. Hill; Chris C.A. Spencer; The Kenyan Bacteraemia Study Group; Wellcome Trust Case Control Consortium 2 (WTCCC2); The Kilifi Bacteraemia Surveillance Group

doi:10.1016/j.ajhg.2016.03.025

Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children

Anna Rautanen, Matti Pirinen, Tara C. Mills, Kirk A. Rockett, Amy Strange, Anne W. Ndungu, Vivek Naranbhai, James J. Gilchrist, Céline Bellenguez, Colin Freeman, Gavin Band, Suzannah J. Bumpstead, Sarah Edkins, Eleni Giannoulatou, Emma Gray, Serge Dronov, Sarah E. Hunt, Cordelia Langford, Richard D. Pearson, Zhan SuDamjan Vukcevic, Alex W. Macharia, Sophie Uyoga, Carolyne Ndila, Neema Mturi, Patricia Njuguna, Shebe Mohammed, James A. Berkley, Isaiah Mwangi, Salim Mwarumba, Barnes S. Kitsao, Brett S. Lowe, Susan C. Morpeth, Iqbal Khandwalla, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Panos Deloukas, Leena Peltonen, Thomas N. Williams, J. Anthony G. Scott, Stephen J. Chapman, Peter Donnelly, Adrian V.S. Hill, Chris C.A. Spencer, The Kenyan Bacteraemia Study Group, Wellcome Trust Case Control Consortium 2 (WTCCC2), The Kilifi Bacteraemia Surveillance Group

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Abstract

Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10^-9; OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.

Original language	English
Pages (from-to)	1092-1100
Number of pages	9
Journal	American Journal of Human Genetics
Volume	98
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2016.03.025
Publication status	Published - 2 Jun 2016
Externally published	Yes

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Rautanen, A., Pirinen, M., Mills, T. C., Rockett, K. A., Strange, A., Ndungu, A. W., Naranbhai, V., Gilchrist, J. J., Bellenguez, C., Freeman, C., Band, G., Bumpstead, S. J., Edkins, S., Giannoulatou, E., Gray, E., Dronov, S., Hunt, S. E., Langford, C., Pearson, R. D., ... The Kilifi Bacteraemia Surveillance Group (2016). Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children. American Journal of Human Genetics, 98(6), 1092-1100. https://doi.org/10.1016/j.ajhg.2016.03.025

@article{02763fc3253149dd96a5701063f6847c,

title = "Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children",

abstract = "Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10-9; OR = 2.47, 95\% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7\% in control subjects and 6.4\% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.",

author = "Anna Rautanen and Matti Pirinen and Mills, \{Tara C.\} and Rockett, \{Kirk A.\} and Amy Strange and Ndungu, \{Anne W.\} and Vivek Naranbhai and Gilchrist, \{James J.\} and C{\'e}line Bellenguez and Colin Freeman and Gavin Band and Bumpstead, \{Suzannah J.\} and Sarah Edkins and Eleni Giannoulatou and Emma Gray and Serge Dronov and Hunt, \{Sarah E.\} and Cordelia Langford and Pearson, \{Richard D.\} and Zhan Su and Damjan Vukcevic and Macharia, \{Alex W.\} and Sophie Uyoga and Carolyne Ndila and Neema Mturi and Patricia Njuguna and Shebe Mohammed and Berkley, \{James A.\} and Isaiah Mwangi and Salim Mwarumba and Kitsao, \{Barnes S.\} and Lowe, \{Brett S.\} and Morpeth, \{Susan C.\} and Iqbal Khandwalla and Blackwell, \{Jenefer M.\} and Elvira Bramon and Brown, \{Matthew A.\} and Casas, \{Juan P.\} and Aiden Corvin and Audrey Duncanson and Janusz Jankowski and Markus, \{Hugh S.\} and Mathew, \{Christopher G.\} and Palmer, \{Colin N.A.\} and Robert Plomin and Sawcer, \{Stephen J.\} and Trembath, \{Richard C.\} and Viswanathan, \{Ananth C.\} and Wood, \{Nicholas W.\} and Panos Deloukas and Leena Peltonen and Williams, \{Thomas N.\} and Scott, \{J. Anthony G.\} and Chapman, \{Stephen J.\} and Peter Donnelly and Hill, \{Adrian V.S.\} and Spencer, \{Chris C.A.\} and \{The Kenyan Bacteraemia Study Group\} and \{Wellcome Trust Case Control Consortium 2 (WTCCC2)\} and \{The Kilifi Bacteraemia Surveillance Group\}",

note = "Funding Information: We thank all the study participants and Kilifi District Hospital clinical team and laboratory staff for their involvement in data and sample collection. The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (grants 084716/Z/08/Z, 085475/B/08/Z, and 085475/Z/08/Z). This work was partially supported by Wellcome Trust Centre for Human Genetics core grant 090532/Z/09/Z and the Wellcome Trust Sanger Institute Core Award (98051). The fieldwork and phenotyping for this study was supported by the Kenya Medical Research Institute (KEMRI) and the Wellcome Trust of Great Britain. A.R. was supported by the Wellcome Trust (084716/Z/08/Z) and by the European Research Council, M.P. is supported by the Academy of Finland (257654), K.A.R. is supported by the WellcomeTrust (090770/2/09/2), T.N.W. and J.A.G.S. were supported by Senior Research Fellowships from the Wellcome Trust (091758 and 098532, respectively), S.J.C. and C.G.M. were supported by the NIHR Biomedical Research Centres in Oxford and Guy{\textquoteright}s \& St Thomas{\textquoteright}, respectively, P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award, A.V.S.H. is supported by a Wellcome Trust Senior Investigator Award (HCUZZ0) and an ERC Advanced Grant (294557), and C.C.A.S. was supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). This paper was published with the permission of the Director of KEMRI. Publisher Copyright: {\textcopyright} 2016 The Authors.",

year = "2016",

month = jun,

day = "2",

doi = "10.1016/j.ajhg.2016.03.025",

language = "English",

volume = "98",

pages = "1092--1100",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

}

Rautanen, A, Pirinen, M, Mills, TC, Rockett, KA, Strange, A, Ndungu, AW, Naranbhai, V, Gilchrist, JJ, Bellenguez, C, Freeman, C, Band, G, Bumpstead, SJ, Edkins, S, Giannoulatou, E, Gray, E, Dronov, S, Hunt, SE, Langford, C, Pearson, RD, Su, Z, Vukcevic, D, Macharia, AW, Uyoga, S, Ndila, C, Mturi, N, Njuguna, P, Mohammed, S, Berkley, JA, Mwangi, I, Mwarumba, S, Kitsao, BS, Lowe, BS, Morpeth, SC, Khandwalla, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Deloukas, P, Peltonen, L, Williams, TN, Scott, JAG, Chapman, SJ, Donnelly, P, Hill, AVS, Spencer, CCA, The Kenyan Bacteraemia Study Group, Wellcome Trust Case Control Consortium 2 (WTCCC2) & The Kilifi Bacteraemia Surveillance Group 2016, 'Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children', American Journal of Human Genetics, vol. 98, no. 6, pp. 1092-1100. https://doi.org/10.1016/j.ajhg.2016.03.025

TY - JOUR

T1 - Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children

AU - Rautanen, Anna

AU - Pirinen, Matti

AU - Mills, Tara C.

AU - Rockett, Kirk A.

AU - Strange, Amy

AU - Ndungu, Anne W.

AU - Naranbhai, Vivek

AU - Gilchrist, James J.

AU - Bellenguez, Céline

AU - Freeman, Colin

AU - Band, Gavin

AU - Bumpstead, Suzannah J.

AU - Edkins, Sarah

AU - Giannoulatou, Eleni

AU - Gray, Emma

AU - Dronov, Serge

AU - Hunt, Sarah E.

AU - Langford, Cordelia

AU - Pearson, Richard D.

AU - Su, Zhan

AU - Vukcevic, Damjan

AU - Macharia, Alex W.

AU - Uyoga, Sophie

AU - Ndila, Carolyne

AU - Mturi, Neema

AU - Njuguna, Patricia

AU - Mohammed, Shebe

AU - Berkley, James A.

AU - Mwangi, Isaiah

AU - Mwarumba, Salim

AU - Kitsao, Barnes S.

AU - Lowe, Brett S.

AU - Morpeth, Susan C.

AU - Khandwalla, Iqbal

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Duncanson, Audrey

AU - Jankowski, Janusz

AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - Palmer, Colin N.A.

AU - Plomin, Robert

AU - Sawcer, Stephen J.

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C.

AU - Wood, Nicholas W.

AU - Deloukas, Panos

AU - Peltonen, Leena

AU - Williams, Thomas N.

AU - Scott, J. Anthony G.

AU - Chapman, Stephen J.

AU - Donnelly, Peter

AU - Hill, Adrian V.S.

AU - Spencer, Chris C.A.

AU - The Kenyan Bacteraemia Study Group

AU - Wellcome Trust Case Control Consortium 2 (WTCCC2)

AU - The Kilifi Bacteraemia Surveillance Group

N1 - Funding Information: We thank all the study participants and Kilifi District Hospital clinical team and laboratory staff for their involvement in data and sample collection. The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (grants 084716/Z/08/Z, 085475/B/08/Z, and 085475/Z/08/Z). This work was partially supported by Wellcome Trust Centre for Human Genetics core grant 090532/Z/09/Z and the Wellcome Trust Sanger Institute Core Award (98051). The fieldwork and phenotyping for this study was supported by the Kenya Medical Research Institute (KEMRI) and the Wellcome Trust of Great Britain. A.R. was supported by the Wellcome Trust (084716/Z/08/Z) and by the European Research Council, M.P. is supported by the Academy of Finland (257654), K.A.R. is supported by the WellcomeTrust (090770/2/09/2), T.N.W. and J.A.G.S. were supported by Senior Research Fellowships from the Wellcome Trust (091758 and 098532, respectively), S.J.C. and C.G.M. were supported by the NIHR Biomedical Research Centres in Oxford and Guy’s & St Thomas’, respectively, P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award, A.V.S.H. is supported by a Wellcome Trust Senior Investigator Award (HCUZZ0) and an ERC Advanced Grant (294557), and C.C.A.S. was supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). This paper was published with the permission of the Director of KEMRI. Publisher Copyright: © 2016 The Authors.

PY - 2016/6/2

Y1 - 2016/6/2

N2 - Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10-9; OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.

AB - Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10-9; OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.

UR - http://www.scopus.com/inward/record.url?scp=84970016366&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.03.025

DO - 10.1016/j.ajhg.2016.03.025

M3 - Article

C2 - 27236921

AN - SCOPUS:84970016366

SN - 0002-9297

VL - 98

SP - 1092

EP - 1100

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children

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