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Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

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Title: Identification of regulatory variants associated with genetic susceptibility to meningococcal disease
Authors: Borghini, L
Png, E
Binder, A
Wright, VJ
Pinnock, E
De Groot, R
Hazelzet, J
Emonts, M
Van der Flier, M
Schlapbach, LJ
Anderson, S
Secka, F
Salas, A
Fink, C
Carrol, ED
Pollard, AJ
Coin, LJ
Kuijpers, TW
Martinon-Torres, F
Zenz, W
Levin, M
Hibberd, ML
Davila, S
Gormley, S
Hamilton, S
Herberg, J
Hourmat, B
Hoggart, C
Kaforou, M
Sancho-Shimizu, V
Abdulla, A
Agapow, P
Bartlett, M
Bellos, E
Eleftherohorinou, H
Galassini, R
Inwald, D
Mashbat, M
Menikou, S
Mustafa, S
Nadel, S
Rahman, R
Thakker, C
Bokhandi, S
Power, S
Barham, H
Pathan, N
Ridout, J
White, D
Thurston, S
Faust, S
Patel, S
McCorkell, J
Davies, P
Cratev, L
Navarra, H
Carter, S
Ramaiah, R
Patel, R
Tuffrey, C
Gribbin, A
McCready, S
Peters, M
Hardy, K
Standing, F
O'Neill, L
Abelake, E
Deep, A
Nsirim, E
Willis, L
Young, Z
Royad, C
White, S
Fortune, PM
Hudnott, P
Alvez Gonzalez, F
Barral-Arca, R
Cebey-Lopez, M
Jose Curras-Tuala, M
Garcia, N
Garcia Vicente, L
Gomez-Carballa, A
Gomez Rial, J
Grela Beiroa, A
Justicia Grande, A
Leborans Iglesias, P
Martinez Santos, AE
Martinon-Torres, N
Martinon Sanchez, JM
Mosquera Perez, B
Obando Pacheco, P
Pardo-Seco, J
Pischedda, S
Rivero Calle, I
Rodriguez-Tenreiro, C
Redondo-Collazo, L
Seren Fernandez, S
Porto Silva, MDS
Vega, A
Beatriz Reyes, S
Leon Leon, MC
Navarro Mingorance, A
Gabaldo Barrios, X
Onate Vergara, E
Concha Torre, A
Vivanco, A
Fernandez, R
Gimenez Sanchez, F
Sanchez Forte, M
Rojo, P
Ruiz Contreras, J
Palacios, A
Navarro, M
Alvarez Alvarez, C
Jose Lozano, M
Carreras, E
Brio Sanagustin, S
Neth, O
Martinez Padilla, MDC
Prieto Tato, LM
Guillen, S
Fernandez Silveira, L
Moreno, D
Van Furth, AMT
Van der Flier, M
Boeddha, NP
Driessen, GJA
Pajkrt, D
Sanders, EAM
Van de Beek, D
Van der Ende, A
Philipsen, HLA
Adeel, AOA
Breukels, MA
Brinkman, DMC
De Korte, CCMM
De Vries, E
De Waal, WJ
Dekkers, R
Dings-Lammertink, A
Doedens, RA
Donker, AE
Dousma, M
Faber, TE
Gerrits, GPJM
Gerver, JAM
Heidema, J
Homan-van der Veen, J
Jacobs, MAM
Jansen, NJG
Kawczynski, P
Klucovska, K
Kneyber, MCJ
Koopman-Keemink, Y
Langenhorst, VJ
Leusink, J
Loza, BF
Merth, IT
Miedema, CJ
Neeleman, C
Noordzij, JG
Obihara, CC
Van Overbeek-van Gils, ALT
Poortman, GH
Potgieter, ST
Potjewijd, J
Rosias, PPR
Sprong, T
Ten Tussher, GW
Thio, BJ
Tramper-Stranders, GA
Van Deuren, M
Van der Meer, H
Van Kuppevelt, AJM
Van Wermeskerken, AM
Verwijs, WA
Wolfs, TFW
Agyeman, P
Aebi, C
Berger, C
Giannoni, E
Stocker, M
Posfay-Barbe, KM
Heininger, U
Bernhard-Stirnemann, S
Niederer-Loher, A
Kahlert, C
Hasters, P
Relly, C
Baer, W
Paulus, S
Frederick, H
Jennings, R
Johnston, J
Kenwright, R
Agbeko, R
Bojang, K
Sarr, I
Kebbeh, N
Sey, G
Saidykhan, M
Cole, F
Thomas, G
Antonio, M
Walcher, W
Geishofer, G
Klobassa, D
Martin, M
Pfurtscheller, K
Reiter, K
Roedl, S
Zobel, G
Zoehrer, B
Toepke, B
Fucik, P
Gabriel, M
Penzien, JM
Diab, G
Miething, R
Deeg, KH
Hammer, J
Varnholt, V
Schmidt, A
Bindl, L
Sillaber, U
Huemer, C
Meier, P
Simic-Schleicher, G
Markart, M
Pfau, E
Broede, H
Ausserer, B
Kalhoff, H
Arpe, V
Schweitzer-Krantz, S
Kasper, J-M
Loranth, K
Bittrich, HJ
Simma, B
Klinge, J
Fedlmaier, M
Weigand, N
Herting, E
Grube, R
Fusch, C
Gruber, A
Schimmel, U
Knaufer-Schiefer, S
Laessig, W
Hennenberger, A
Von der Wense, A
Tillmann, R
Schwarick, J
Sitzmann, FC
Streif, W
Mueller, H
Kurnik, P
Groneck, P
Weiss, U
Groeblacher-Roth, H
Bensch, J
Moser, R
Schwarz, R
Lenz, K
Hofmann, T
Goepel, W
Schulz, D
Berger, T
Hauser, E
Foerster, KM
Peters, J
Nicolai, TH
Kumlien, B
Beckmann, R
Seitz, C
Hueseman, D
Schuermann, R
Ta, VH
Weikmann, E
Evert, W
Hautz, J
Seidenberg, J
Wocko, L
Luigs, P
Reiter, H-L
Quietzach, J
Koenig, M
Herrmann, J
Mitter, H
Seidler, E
Maak, B
Sperl, W
Zwiauer, K
Meissl, M
Koch, R
Cremer, M
Breuer, HA
Goerke, W
Nossal, R
Pernice, W
Brangenberg, R
Salzer, HR
Koch, H
Schaller, G
Paky, F
Strasser, F
Eitelberger, F
Sontheimer, D
Lischka, A
Kronberger, M
Dilch, A
Scheibenpflug, C
Bruckner, R
Mahler, K
Runge, K
Kunze, W
Schermann, P
Item Type: Journal Article
Abstract: Non-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.
Issue Date: 6-May-2019
Date of Acceptance: 17-Apr-2019
URI: http://hdl.handle.net/10044/1/70371
DOI: https://doi.org/10.1038/s41598-019-43292-6
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 9
Issue: 1
Copyright Statement: © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: European Commission
Funder's Grant Number: 279185
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SEQUENCE VARIATION
KAPPA-B
GENOME
BINDING
EUCLIDS consortium
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SEQUENCE VARIATION
KAPPA-B
GENOME
BINDING
Publication Status: Published
Open Access location: https://www.nature.com/articles/s41598-019-43292-6
Article Number: 6966
Online Publication Date: 2019-05-06
Appears in Collections:Department of Medicine (up to 2019)