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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. Electronic address: anna.rautanen@well.ox.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Rautanen
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Matti
authors.initials: M
authors.lastname: Pirinen
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Mills
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Strange
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Anne W
authors.initials: AW
authors.lastname: Ndungu
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Vivek
authors.initials: V
authors.lastname: Naranbhai
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Gilchrist
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Céline
authors.initials: C
authors.lastname: Bellenguez
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Colin
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authors.lastname: Freeman
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Band
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Suzannah J
authors.initials: SJ
authors.lastname: Bumpstead
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Giannoulatou
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Gray
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Serge
authors.initials: S
authors.lastname: Dronov
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hunt
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Cordelia
authors.initials: C
authors.lastname: Langford
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Pearson
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Su
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Damjan
authors.initials: D
authors.lastname: Vukcevic
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Macharia
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Sophie
authors.initials: S
authors.lastname: Uyoga
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Carolyne
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authors.lastname: Ndila
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
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authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Patricia
authors.initials: P
authors.lastname: Njuguna
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Shebe
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: James A
authors.initials: JA
authors.lastname: Berkley
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Isaiah
authors.initials: I
authors.lastname: Mwangi
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Salim
authors.initials: S
authors.lastname: Mwarumba
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Barnes S
authors.initials: BS
authors.lastname: Kitsao
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Lowe
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya; Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 9DU, UK; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Morpeth
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Khandwalla
authors.affiliation: Cambridge Institute for Medical Research and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK; Telethon Kids Institute, The University of Western Australia, Subiaco, WA 6008, Australia.
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service (NHS) Foundation Trust and Institute of Psychiatry, King's College London, Denmark Hill, London SE5 8AF, UK.
authors.forename: Elvira
authors.initials: E
authors.lastname: Bramon
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia.
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authors.initials: MA
authors.lastname: Brown
authors.affiliation: Farr Institute of Health Informatics, University College London, London NW1 2DA, UK.
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authors.initials: JP
authors.lastname: Casas
authors.affiliation: Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Aiden
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authors.lastname: Corvin
authors.affiliation: Molecular and Physiological Sciences, The Wellcome Trust, London NW1 2BE, UK.
authors.forename: Audrey
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authors.affiliation: Associate Deans Office, John Bull Building, Peninsula School of Medicine and Dentistry, Plymouth PL6 8BU, UK.
authors.forename: Janusz
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authors.lastname: Jankowski
authors.affiliation: Department of Neurology, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK; Sydney Brenner Institute for Molecular Bioscience, University of Witwatersrand, Johannesburg 2193, South Africa.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.affiliation: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Colin N A
authors.initials: CNA
authors.lastname: Palmer
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
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authors.lastname: Plomin
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
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authors.initials: SJ
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authors.affiliation: London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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authors.affiliation: NIHR Biomedical Research Centre at Moorfields Eye Hospital NHSFT and UCL Institute of Ophthalmology, London EC1V 2PD, UK.
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authors.initials: AC
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authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
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authors.initials: NW
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
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authors.lastname: Peltonen
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya; Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 9DU, UK; Department of Medicine, Imperial College, London W21NY, UK; INDEPTH Network, Accra, Ghana.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi 80108, Kenya; Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 9DU, UK; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors.forename: J Anthony G
authors.initials: JAG
authors.lastname: Scott
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford Centre for Respiratory Medicine, Churchill Hospital Site, Oxford University Hospitals, Oxford OX3 7LE, UK.
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authors.initials: SJ
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Statistics, University of Oxford, Oxford OX1 3TG, UK.
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authors.lastname: Donnelly
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Adrian V S
authors.initials: AVS
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Statistics, University of Oxford, Oxford OX1 3TG, UK.
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mesh_terms: D000293:Adolescent; D016470:Bacteremia / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007630:Kenya / Q000453:epidemiology; D011018:Pneumonia, Pneumococcal / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D012307:Risk Factors; D013296:Streptococcus pneumoniae / Q000235:genetics*
chemical_list: D062085:RNA, Long Noncoding