Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

descriptionPublicationkeyboard_double_arrow_right Article , Other literature type 06 May 2019Embargo end date: 06 May 2019 Australia, Switzerland, Germany, Netherlands, Switzerland, Spain, United Kingdom, Germany, Australia, United Kingdom, United Kingdom, Spain, United Kingdom, Switzerland, United Kingdom English Publisher:Springer Science and Business Media LLCJournal:Scientific Reports, volume 9 (eissn: 2045-2322,

Copyright policy )Funded by:EC | EUCLIDS

Authors: Borghini, Lisa; Png, Eileen; Binder, Alexander; Wright, Victoria; Pinnock, Ellie; de Groot, Ronald; Hazelzet, Jan; +193 Authors

Borghini, Lisa; Png, Eileen; Binder, Alexander; Wright, Victoria; Pinnock, Ellie; de Groot, Ronald; Hazelzet, Jan; Emonts, Marieke; van der Flier, Michiel; Schlapbach, Luregn J.; Anderson, Suzanne; Secka, Fatou; Salas, Antonio; Fink, Colin; Carrol, Enitan D.; Pollard, Andrew J.; Coin, Lachlan J.; Kuijpers, Taco W.; Martinon-Torres, Federico; Zenz, Werner; Levin, Michael; Hibberd, Martin L.; Davila, Sonia; Gormley, Stuart; Hamilton, Shea; Herberg, Jethro; Hourmat, Bernardo; Hoggart, Clive; Kaforou, Myrsini; Sancho-Shimizu, Vanessa; Abdulla, Amina F; Agapow, Paul Michael; Bartlett, Maeve; Bellos, Evangelos; Eleftherohorinou, Hariklia; Galassini, Rachel; Inwald, David; Mashbat, Meg; Menikou, Stefanie; Mustafa, Sobia; Nadel, Simon; Rahman, Rahmeen; Thakker, Clare; Bokhandi, S.; Power, Sue; Barham, Heather; Pathan, N.; Ridout, Jenna; White, Deborah; Thurston, Sarah; Faust, S.; Patel, S.; McCorkell, Jenni; Davies, Patrick; Cratev, Lindsey; Navarra, Helen; Carter, Stephanie; Ramaiah, R.; Patel, Rekha; Tuffrey, Catherine; Gribbin, Andrew; McCready, Sharon; Peters, Mark; Hardy, Katie; Standing, Fran; O'Neill, Lauren; Abelake, Eugenia; Deep, Akash; Nsirim, Eniola; Willis, Louise; Young, Zoe; Royad, C.; White, Sonia; Fortune, P.M.; Hudnott, Phil; González, Férnando Álvez; Barral-Arca, Ruth; Cebey-López, Miriam; Curras-Tuala, MJ; García, Natalia; Vicente, Luisa García; Gómez-Carballa, Alberto; Rial, José Gómez; Beiroa, Andrea Grela; Grande, Antonio Justicia; Iglesias, Pilar Leboráns; Santos, Alaba Elena Martínez; Martinón-Torres, Nazareth; Sánchez, José María Martinón; Pérez, Belén Mosquera; Pacheco, Pablo Obando; Pardo-Seco, Jacobo; Pischedda, Sara; Calle, Irene Rivero; Rodríguez-Tenreiro, Carmen; Redondo-Collazo, Lorenzo; Fernández, Sonia Serén; Silva, María del Sol Porto; Vega, Ana; Reyes, Susana Beatriz; León, María Cruz León; Mingorance, Álvaro Navarro; Barrios, Xavier Gabaldó; Vergara, Eider Oñate; Torre, Andrés Concha; Vivanco, Ana; Fernández, Reyes; Sánchez, Francisco Giménez; Forte, Miguel Sánchez; Rojo, Pablo; Contreras, J.Ruiz; Palacios, Alba; Navarro, Marisa; Álvarez, Cristina Álvarez; Lozano, María José; Carreras, Eduardo; Brió Sanagustín, Sonia; Neth, Olaf; Padilla, Ma del Carmen Martínez; Tato, Luis Manuel Prieto; Guillén, Sara; Silveira, Laura Fernández; Moreno Pérez, David; van Furth, A.M.Tutu; van der Flier, Michiel; Boeddha, N.P.; Driessen, G.J.A.; Pajkrt, D.; Sanders, E.A.M.; van de Beek, D.; van der Ende, A.; Philipsen, H.L.A.; Adeel, Abdul O.A; Breukels, M.A.; Brinkman, Daniëlle M.C; de Korte, C.C.M.M.; de Vries, E.; de Waal, W.J.; Dekkers, R.; Dings-Lammertink, Anouk; Doedens, Rienus A; Donker, A.E.; Dousma, M.; Faber, Tina E; Gerrits, G.P.J.M.; Gerver, J.A.M.; Heidema, J.; Homan-van der Veen, J.; Jacobs, Monique A.M; Jansen, N.J.G.; Kawczynski, P.; Klucovska, K.; Kneyber, Martin Christiaan Jacques; Koopman-Keemink, Y.; Langenhorst, V.J.; Leusink, J.; Loza, B.F.; Merth, I.T.; Miedema, C.J.; Neeleman, Chris; Noordzij, J.G.; Obihara, C.C.; van Overbeek-van Gils, A.L.T.; Poortman, G.H.; Potgieter, S.T.; Potjewijd, J.; Rosias, P.P.R.; Sprong, T.; ten Tussher, G.W.; Thio, B.J.; Tramper-Stranders, G.A.; van Deuren, M.; van der Meer, H.; van Kuppevelt, A.J.M.; van Wermeskerken, A.M.; Verwijs, W.A.; Wolfs, T.F.W.; Agyeman, Philipp; Aebi, Christoph; Berger, Christoph; Giannoni, Eric; Stocker, Martin; Posfay-Barbe, Klara M.; Heininger, Ulrich; Bernhard-Stirnemann, Sara; Niederer-Loher, A.; Kahlert, Christian; Hasters, Paul; Relly, Christa; Baer, Walter; Paulus, Stéphane; Frederick, Hannah; Jennings, Rebecca; Johnston, Joanne; Kenwright, Rhian; Agbeko, Rachel; Bojang, Kalifa; Sarr, Isatou; Kebbeh, Ngane; Sey, Gibbi;

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

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Abstract

AbstractNon-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

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Australia, Switzerland, Germany, Netherlands, Switzerland, Spain, United Kingdom, Germany, Australia, United Kingdom, United Kingdom, Spain, United Kingdom, Switzerland, United Kingdom

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Keywords

EMC MM-04-54-08-A, neoplasias hipofaríngeas, infecciones meningocócicas, Células epiteliales, Hypopharyngeal Neoplasms / microbiology, Polimorfismo de nucleótido simple, Meningococcal Infections / microbiology, humanos, EMC NIHES-02-65-01, Neisseria meningitidis, Regulatory Sequences, Nucleic Acid, genómica, Cohort Studies, Hypopharyngeal Neoplasms / pathology, BINDING, Tumor Cells, Cultured, Paediatrics - Radboud University Medical Center, estudios de cohortes, Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences, Cultured, Multidisciplinary, Secuencias reguladoras de ácidos nucleicos, High-Throughput Nucleotide Sequencing, Genomics, Enfermedades transmisibles, Tumor Cells, estudios de asociación genética, Multidisciplinary Sciences, GENOME, Phenotype, Science & Technology - Other Topics, fenotipo, Neisseria meningitidis / isolation & purification, CHUS, EMC OR-02-54-06, estudios de casos y controles, 610, 610 Medicine & health, KAPPA-B, Hypopharyngeal Neoplasms / genetics, Polymorphism, Single Nucleotide, Article, Meningococcal Infections / epidemiology, 618, secuenciación de nucleótidos de alto rendimiento, Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences, Infecciones meningocócicas, SEQUENCE VARIATION, Humans, Meningococcal Infections / genetics*, Meningitis, Genetic Predisposition to Disease, Nucleic Acid*, Internal Medicine - Radboud University Medical Center, Polymorphism, Neisseria meningitidis / genetics*, Genetic Association Studies, Genetic association study, 1000 Multidisciplinary, Science & Technology, Hypopharyngeal Neoplasms, Case-Control Studies; Cohort Studies; Genetic Association Studies; Genetic Predisposition to Disease; Genomics; High-Throughput Nucleotide Sequencing; Humans; Hypopharyngeal Neoplasms/genetics; Hypopharyngeal Neoplasms/microbiology; Hypopharyngeal Neoplasms/pathology; Meningococcal Infections/epidemiology; Meningococcal Infections/genetics; Meningococcal Infections/microbiology; Neisseria meningitidis/genetics; Neisseria meningitidis/isolation & purification; Phenotype; Polymorphism, Single Nucleotide; Regulatory Sequences, Nucleic Acid; Tumor Cells, Cultured, Intensive Care - Radboud University Medical Center, predisposición genética a la enfermedad, Single Nucleotide*, EUCLIDS consortium, Gene regulation, Meningococcal Infections, 10036 Medical Clinic, 1000 General, Case-Control Studies, IDIS, Genetic Predisposition to Disease*, Regulatory Sequences, ddc: ddc:618, ddc: ddc:

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