Identification of regulatory variants associated with genetic susceptibility to meningococcal disease


Por: 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, Gonzalez, FA, Barral-Arca, R, Cebey-Lopez, M, Curras-Tuala, MJ, Garcia, N, Vicente, LG, Gomez-Carballa, A, Rial, JG, Beiroa, AG, Grande, AJ, Iglesias, PL, Santos, AEM, Martinon-Torres, N, Sanchez, JMM, Perez, BM, Pacheco, PO, Pardo-Seco, J, Pischedda, S, Calle, IR, Rodriguez-Tenreiro, C, Redondo-Collazo, L, Fernandez, SS, Silva, MDP, Vega, A, Reyes, SB, Leon, MCL, Mingorance, AN, Barrios, XG, Vergara, EO, Torre, AC, Vivanco, A, Fernandez, R, Sanchez, FG, Forte, MS, Rojo, P, Contreras, JR, Palacios, A, Navarro, M, Alvarez, CA, Lozano, MJ, Carreras, E, Sanagustin, SB, Neth, O, Padilla, MDM, Tato, LMP, Guillen, S, Silveira, LF, 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, Rodl, S, Zobel, G, Zohrer, B, Topke, 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, JM, 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, Lassig, W, Hennenberger, A, von der Wense, A, Tillmann, R, Schwarick, J, Sitzmann, FC, Streif, W, Muller, H, Kurnik, P, Groneck, P, Weiss, U, Groblacher-Roth, H, Bensch, J, Moser, R, Schwarz, R, Lenz, K, Hofmann, T, Gopel, W, Schulz, D, Berger, T, Hauser, E, Forster, KM, Peters, J, Nicolai, TH, Kumlien, B, Beckmann, R, Seitz, C, Huseman, D, Schurmann, R, Ta, VH, Weikmann, E, Evert, W, Hautz, J, Seidenberg, J, Wocko, L, Luigs, P, Reiter, HL, Quietzach, J, Konig, M, Herrmann, J, Mitter, H, Seidler, E, Maak, B, Sperl, W, Zwiauer, K, Meissl, M, Koch, R, Cremer, M, Breuer, HA, Gorke, 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

Publicada: 6 may 2019
Resumen:
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 nasopharyngea I 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.

Filiaciones:
Borghini, L:
 Genome Inst Singapore, Human Genet, Singapore, Singapore

 Genome Inst Singapore, Infect dis, Singapore, Singapore

Png, E:
 Genome Inst Singapore, Infect dis, Singapore, Singapore

Binder, A:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Wright, VJ:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Pinnock, E:
 Univ Warwick, Micropathol Ltd, Warwick, England

de Groot, R:
 Radboud Univ Nijmegen, Dept Pediat, Med Ctr, Nijmegen, Netherlands

 Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands

Hazelzet, J:
 Univ Med Ctr, Erasmus Med Ctr, Dept Pediat, Sophia Childrens Hosp, Rotterdam, Netherlands

Emonts, M:
 Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

 Newcastle Tyne Hosp Fdn Trust, Great North Childrens Hosp, Paediat Infect Dis & Immunol Dept, Newcastle Upon Tyne, Tyne & Wear, England

Van der Flier, M:
 Radboud Univ Nijmegen, Dept Pediat, Med Ctr, Nijmegen, Netherlands

 Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands

Schlapbach, LJ:
 Univ Queensland, Fac Med, Brisbane, Qld, Australia

 Univ Queensland, Mater Res Inst, Paediat Crit Care Res Grp, Brisbane, Qld, Australia

 Lady Cilento Childrens Hosp, Paediat Intens Care Unit, Brisbane, Qld, Australia

 Univ Bern, Bern Univ Hosp, Dept Pediat, Inselspital, Bern, Switzerland

Anderson, S:
 Med Res Council Unit Gambia, Banjul, Gambia

Secka, F:
 Med Res Council Unit Gambia, Banjul, Gambia

Salas, A:
 Univ Santiago Compostela, Fac Med, Inst Ciencias Forenses, Dept Anat PatolOx & Ciencias Forenses, Galicia, Spain

 Hosp Clin Univ Santiago, Inst Invest Sanitarias IDIS, GenPoB Res Grp, Galicia, Spain

Fink, C:
 Univ Warwick, Micropathol Ltd, Warwick, England

Carrol, ED:
 Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England

Pollard, AJ:
 Univ Oxford, Dept Pediat, Oxford Vaccine Grp, Oxford, England

 NIHR Oxford Biomed Res Ctr, Oxford, England

Coin, LJ:
 Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia

Kuijpers, TW:
 Emma Childrens Hosp Acad, Div Pediat Hematol, Immunol & Infect Dis, Med Ctr, Amsterdam, Netherlands

Martinon-Torres, F:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Zenz, W:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Levin, M:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Hibberd, ML:
 Genome Inst Singapore, Infect dis, Singapore, Singapore

 London Sch Hyg & Trop Med, Infect & Trop Dis, London, England

Davila, S:
 Genome Inst Singapore, Human Genet, Singapore, Singapore

 Singhlth Duke NUS Inst Precis Med PRISM, Singapore, Singapore

 Duke NUS Med Sch, Singapore, Singapore

Gormley, S:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Hamilton, S:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Herberg, J:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Hourmat, B:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Hoggart, C:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Kaforou, M:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Sancho-Shimizu, V:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Abdulla, A:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Agapow, P:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Bartlett, M:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Bellos, E:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Eleftherohorinou, H:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Galassini, R:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Inwald, D:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Mashbat, M:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Menikou, S:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Mustafa, S:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Nadel, S:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Rahman, R:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Thakker, C:
 Imperial Coll London, Dept Med, Div Infect Dis, Sect Paediat, London, England

Bokhandi, S:
 Poole Hosp NHS Fdn Trust, Poole, Dorset, England

Power, S:
 Poole Hosp NHS Fdn Trust, Poole, Dorset, England

Barham, H:
 Poole Hosp NHS Fdn Trust, Poole, Dorset, England

Pathan, N:
 Cambridge Univ Hosp NHS Trust, Cambridge, England

Ridout, J:
 Cambridge Univ Hosp NHS Trust, Cambridge, England

White, D:
 Cambridge Univ Hosp NHS Trust, Cambridge, England

Thurston, S:
 Cambridge Univ Hosp NHS Trust, Cambridge, England

Faust, S:
 Univ Hosp Southampton, Southampton, Hants, England

Patel, S:
 Univ Hosp Southampton, Southampton, Hants, England

McCorkell, J:
 Univ Hosp Southampton, Southampton, Hants, England

Davies, P:
 Nottingham Univ Hosp NHS Trust, Nottingham, England

Cratev, L:
 Nottingham Univ Hosp NHS Trust, Nottingham, England

Navarra, H:
 Nottingham Univ Hosp NHS Trust, Nottingham, England

Carter, S:
 Nottingham Univ Hosp NHS Trust, Nottingham, England

Ramaiah, R:
 Univ Hosp Leicester NHS Trust, Leicester, Leics, England

Patel, R:
 Univ Hosp Leicester NHS Trust, Leicester, Leics, England

Tuffrey, C:
 Portsmouth Hosp NHS Trust, London, England

Gribbin, A:
 Portsmouth Hosp NHS Trust, London, England

McCready, S:
 Portsmouth Hosp NHS Trust, London, England

Peters, M:
 Portsmouth Hosp NHS Trust, London, England

Hardy, K:
 Portsmouth Hosp NHS Trust, London, England

Standing, F:
 Portsmouth Hosp NHS Trust, London, England

O'Neill, L:
 Portsmouth Hosp NHS Trust, London, England

Abelake, E:
 Portsmouth Hosp NHS Trust, London, England

Deep, A:
 Kings Coll Hosp NHS Fdn Trust, London, England

Nsirim, E:
 Kings Coll Hosp NHS Fdn Trust, London, England

Willis, L:
 Univ Oxford, Dept Pediat, Oxford Vaccine Grp, Oxford, England

 NIHR Oxford Biomed Res Ctr, Oxford, England

Young, Z:
 Univ Oxford, Dept Pediat, Oxford Vaccine Grp, Oxford, England

 NIHR Oxford Biomed Res Ctr, Oxford, England

Royad, C:
 Kettering Gen Hosp NHS Fdn Trust, Kettering, England

White, S:
 Kettering Gen Hosp NHS Fdn Trust, Kettering, England

Fortune, PM:
 Cent Manchester NHS Trust, Manchester, Lancs, England

Hudnott, P:
 Cent Manchester NHS Trust, Manchester, Lancs, England

Gonzalez, FA:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Barral-Arca, R:
 Univ Santiago Compostela, Fac Med, Inst Ciencias Forenses, Dept Anat PatolOx & Ciencias Forenses, Galicia, Spain

 Hosp Clin Univ Santiago, Inst Invest Sanitarias IDIS, GenPoB Res Grp, Galicia, Spain

 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Cebey-Lopez, M:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Curras-Tuala, MJ:
 Univ Santiago Compostela, Fac Med, Inst Ciencias Forenses, Dept Anat PatolOx & Ciencias Forenses, Galicia, Spain

 Hosp Clin Univ Santiago, Inst Invest Sanitarias IDIS, GenPoB Res Grp, Galicia, Spain

 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Garcia, N:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Vicente, LG:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Gomez-Carballa, A:
 Univ Santiago Compostela, Fac Med, Inst Ciencias Forenses, Dept Anat PatolOx & Ciencias Forenses, Galicia, Spain

 Hosp Clin Univ Santiago, Inst Invest Sanitarias IDIS, GenPoB Res Grp, Galicia, Spain

 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Rial, JG:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Beiroa, AG:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Grande, AJ:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Iglesias, PL:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Santos, AEM:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Martinon-Torres, N:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Sanchez, JMM:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Perez, BM:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Pacheco, PO:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Pardo-Seco, J:
 Univ Santiago Compostela, Fac Med, Inst Ciencias Forenses, Dept Anat PatolOx & Ciencias Forenses, Galicia, Spain

 Hosp Clin Univ Santiago, Inst Invest Sanitarias IDIS, GenPoB Res Grp, Galicia, Spain

 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Pischedda, S:
 Univ Santiago Compostela, Fac Med, Inst Ciencias Forenses, Dept Anat PatolOx & Ciencias Forenses, Galicia, Spain

 Hosp Clin Univ Santiago, Inst Invest Sanitarias IDIS, GenPoB Res Grp, Galicia, Spain

 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Calle, IR:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Rodriguez-Tenreiro, C:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Redondo-Collazo, L:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Fernandez, SS:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Silva, MDP:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

Vega, A:
 Hosp Clin Univ Santiago, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

 Inst Invest Sanitaria Santiago, GENVIP Res Grp, Galicia, Spain

 Univ Santiago Compostela, Fdn Publ Galega Med Xenom, Inst Invest Sanitarias IDIS, Serv Galego Saude SERGAS,CIBERER, Santiago De Compostela, Spain

 Univ Santiago Compostela, Ctr Invest Biomed Red Enfermedades Raras, Grp Med Xenom, Santiago De Compostela, Spain

Reyes, SB:
 Hosp Clin Univ Virgen Arrixaca, Murcia, Spain

Leon, MCL:
 Hosp Clin Univ Virgen Arrixaca, Murcia, Spain

Mingorance, AN:
 Hosp Clin Univ Virgen Arrixaca, Murcia, Spain

Barrios, XG:
 Hosp Clin Univ Virgen Arrixaca, Murcia, Spain

Vergara, EO:
 Hosp Donostia, San Sebastian, Spain

Torre, AC:
 Hosp Univ Cent Asturias, Asturias, Spain

Vivanco, A:
 Hosp Univ Cent Asturias, Asturias, Spain

Fernandez, R:
 Hosp Univ Cent Asturias, Asturias, Spain

Sanchez, FG:
 Complejo Hosp Torrecardenas, Almeria, Spain

Forte, MS:
 Complejo Hosp Torrecardenas, Almeria, Spain

Rojo, P:
 Hosp Univ 12 Octubre, Madrid, Spain

Contreras, JR:
 Hosp Univ 12 Octubre, Madrid, Spain

Palacios, A:
 Hosp Univ 12 Octubre, Madrid, Spain

Navarro, M:
 Hosp Gen Univ Gregorio Maranon, Madrid, Spain

Alvarez, CA:
 Hosp Gen Univ Gregorio Maranon, Madrid, Spain

Lozano, MJ:
 Hosp Gen Univ Gregorio Maranon, Madrid, Spain

Carreras, E:
 Hosp Santa Creu & Sant Pau, Barcelona, Spain

Sanagustin, SB:
 Hosp Santa Creu & Sant Pau, Barcelona, Spain

Neth, O:
 Hosp Univ Virgen Rodo, Seville, Spain

Padilla, MDM:
 Complejo Hosp Jaen, Jaen, Spain

Tato, LMP:
 Hosp Univ Getafe, Madrid, Spain

Guillen, S:
 Hosp Univ Getafe, Madrid, Spain

Silveira, LF:
 Hosp Univ & Politecn La Fe, Valencia, Spain

Moreno, D:
 Hosp Reg Univ Carlos Haya, Malaga, Spain

van Furth, AMT:
 Vrije Univ Univ, Med Ctr, Amsterdam, Netherlands

van der Flier, M:
 Radboud Univ Nijmegen, Dept Pediat, Med Ctr, Nijmegen, Netherlands

 Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands

Boeddha, NP:
 Univ Med Ctr, Erasmus Med Ctr, Dept Pediat, Sophia Childrens Hosp, Rotterdam, Netherlands

Driessen, GJA:
 Univ Med Ctr, Erasmus Med Ctr, Dept Pediat, Sophia Childrens Hosp, Rotterdam, Netherlands

Pajkrt, D:
 Emma Childrens Hosp Acad, Div Pediat Hematol, Immunol & Infect Dis, Med Ctr, Amsterdam, Netherlands

Sanders, EAM:
 Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Utrecht, Netherlands

van de Beek, D:
 Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands

van der Ende, A:
 Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands

Philipsen, HLA:
 Radboud Univ Nijmegen, Dept Pediat, Med Ctr, Nijmegen, Netherlands

 Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands

Adeel, AOA:
 Kennemer Gasthuis, Haarlem, Netherlands

Breukels, MA:
 Elkerliek Hosp, Helmond, Netherlands

Brinkman, DMC:
 Alrijne Hosp, Leiderdorp, Netherlands

de Korte, CCMM:
 Beatrix Hosp, Gorinchem, Netherlands

de Vries, E:
 Jeroen Bosch Hosp, Shertogenbosch, Netherlands

de Waal, WJ:
 Diakonessen Hosp, Utrecht, Netherlands

Dekkers, R:
 Maasziekenhuis Pantein, Boxmeer, Netherlands

Dings-Lammertink, A:
 Gelre Hosp, Zutphen, Netherlands

Doedens, RA:
 Martini Hosp, Groningen, Netherlands

Donker, AE:
 Maxima Med Ctr, Veldhoven, Netherlands

Dousma, M:
 Gemini Hosp, Den Helder, Netherlands

Faber, TE:
 Med Ctr Leeuwarden, Leeuwarden, Netherlands

Gerrits, GPJM:
 Canisius Wilhelmina Hosp, Nijmegen, Netherlands

Gerver, JAM:
 Rode Kruis Hosp, Beverwijk, Netherlands

Heidema, J:
 St Antonius Hosp, Nieuwegein, Netherlands

Homan-van der Veen, J:
 Deventer Hosp, Deventer, Netherlands

Jacobs, MAM:
 Slingeland Hosp, Doetinchem, Netherlands

Jansen, NJG:
 Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Utrecht, Netherlands

Kawczynski, P:
 Refaja Hosp, Stadskanaal, Netherlands

Klucovska, K:
 Bethesda Hosp, Hoogeveen, Netherlands

Kneyber, MCJ:
 Univ Med Ctr Groningen, Beatrix Childrens Hosp, Groningen, Netherlands

Koopman-Keemink, Y:
 Juliana Childrens Hosp, Naga Hosp, The Hague, Netherlands

Langenhorst, VJ:
 Isala Hosp, Zwolle, Netherlands

Leusink, J:
 Bernhoven Hosp, Uden, Netherlands

Loza, BF:
 VieCuri Med Ctr, Venlo, Netherlands

Merth, IT:
 Ziekenhuisgrp Twente, Almelo Hengelo, Netherlands

Miedema, CJ:
 Catharina Hosp, Eindhoven, Netherlands

Neeleman, C:
 Radboud Univ Nijmegen, Dept Pediat, Med Ctr, Nijmegen, Netherlands

 Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands

Noordzij, JG:
 Reinier Graaf Gasthuis, Delft, Netherlands

Obihara, CC:
 ETZ Elisabeth, Tilburg, Netherlands

van Overbeek-van Gils, ALT:
 Scheper Hosp, Emmen, Netherlands

Poortman, GH:
 St Jansdal Hosp, Hardewijk, Netherlands

Potgieter, ST:
 Laurentius Hosp, Roermond, Netherlands

Potjewijd, J:
 Isala Diaconessenhuis, Meppel, Netherlands

Rosias, PPR:
 Zuyderland Med Ctr, Sittard Geleen, Netherlands

Sprong, T:
 Canisius Wilhelmina Hosp, Nijmegen, Netherlands

ten Tussher, GW:
 Westfriesgasthuis, Hoorn, Netherlands

Thio, BJ:
 Med Spectrum Twente, Enschede, Netherlands

Tramper-Stranders, GA:
 St Franciscus Gasthuis, Rotterdam, Netherlands

van Deuren, M:
 Radboud Univ Nijmegen, Dept Pediat, Med Ctr, Nijmegen, Netherlands

 Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands

van der Meer, H:
 Vrije Univ Univ, Med Ctr, Amsterdam, Netherlands

van Kuppevelt, AJM:
 Streekziekenhuis Koningin Beatrix, Winterswijk, Netherlands

van Wermeskerken, AM:
 Flevo Hosp, Almere, Netherlands

Verwijs, WA:
 Zuwe Hofpoort Hosp, Woerden, Netherlands

Wolfs, TFW:
 Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Utrecht, Netherlands

Agyeman, P:
 Univ Bern, Bern Univ Hosp, Dept Pediat, Inselspital, Bern, Switzerland

Aebi, C:
 Univ Bern, Bern Univ Hosp, Dept Pediat, Inselspital, Bern, Switzerland

Berger, C:
 Univ Bern, Bern Univ Hosp, Dept Pediat, Inselspital, Bern, Switzerland

 Univ Childrens Hosp Zurich, Div Infect Dis, Zurich, Switzerland

 Univ Childrens Hosp Zurich, Hosp Epidemiol, Zurich, Switzerland

 Univ Childrens Hosp Zurich, Childrens Res Ctr, Zurich, Switzerland

Giannoni, E:
 Lausanne Univ Hosp, Serv Neonatol, Lausanne, Switzerland

 Lausanne Univ Hosp, Infect Dis Serv, Lausanne, Switzerland

Stocker, M:
 Childrens Hosp Lucerne, Dept Pediat, Luzern, Switzerland

Posfay-Barbe, KM:
 Univ Hosp Geneva, Childrens Hosp Geneva, Pediat Infect Dis Unit, Geneva, Switzerland

Heininger, U:
 Univ Basel Childrens Hosp, Infect Dis & Vaccinol, Basel, Switzerland

 Univ Kinderspital Beider Basel, Abt Infektiol, Basel, Switzerland

Bernhard-Stirnemann, S:
 Childrens Hosp Aarau, Aarau, Switzerland

Niederer-Loher, A:
 Childrens Hosp Eastern Switzerland, Div Infect Dis, St Gallen, Switzerland

 Childrens Hosp Eastern Switzerland, Hosp Epidemiol, St Gallen, Switzerland

Kahlert, C:
 Childrens Hosp Eastern Switzerland, Div Infect Dis, St Gallen, Switzerland

 Childrens Hosp Eastern Switzerland, Hosp Epidemiol, St Gallen, Switzerland

Hasters, P:
 Univ Hosp Zurich, Dept Neonatol, Zurich, Switzerland

Relly, C:
 Univ Childrens Hosp Zurich, Div Infect Dis, Zurich, Switzerland

 Univ Childrens Hosp Zurich, Hosp Epidemiol, Zurich, Switzerland

 Univ Childrens Hosp Zurich, Childrens Res Ctr, Zurich, Switzerland

Baer, W:
 Childrens Hosp Chur, Chur, Switzerland

Paulus, S:
 Alder Hey Childrens Hosp, Dept Infect Dis, Eaton Rd, Liverpool, Merseyside, England

Frederick, H:
 Alder Hey Childrens Hosp, Dept Infect Dis, Eaton Rd, Liverpool, Merseyside, England

Jennings, R:
 Alder Hey Childrens Hosp, Dept Infect Dis, Eaton Rd, Liverpool, Merseyside, England

Johnston, J:
 Alder Hey Childrens Hosp, Dept Infect Dis, Eaton Rd, Liverpool, Merseyside, England

Kenwright, R:
 Alder Hey Childrens Hosp, Dept Infect Dis, Eaton Rd, Liverpool, Merseyside, England

Agbeko, R:
 Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

 Newcastle Tyne Hosp Fdn Trust, Great North Childrens Hosp, Paediat Intens Care Unit, Newcastle Upon Tyne, Tyne & Wear, England

Bojang, K:
 Med Res Council Unit Gambia, Banjul, Gambia

Sarr, I:
 Med Res Council Unit Gambia, Banjul, Gambia

Kebbeh, N:
 Med Res Council Unit Gambia, Banjul, Gambia

Sey, G:
 Med Res Council Unit Gambia, Banjul, Gambia

Saidykhan, M:
 Med Res Council Unit Gambia, Banjul, Gambia

Cole, F:
 Med Res Council Unit Gambia, Banjul, Gambia

Thomas, G:
 Med Res Council Unit Gambia, Banjul, Gambia

Antonio, M:
 Med Res Council Unit Gambia, Banjul, Gambia

Walcher, W:
 Med Univ Graz, Dept Obstet & Gynecol, Graz, Austria

Geishofer, G:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Klobassa, D:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Martin, M:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Pfurtscheller, K:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Reiter, K:
 Kinderklin LMU Munchen Dr von Haunerschen Kinders, Munich, Germany

Rodl, S:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Zobel, G:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Zohrer, B:
 Med Univ Graz, Dept Gen Pediat, Graz, Austria

Topke, B:
 Ostalb Klinikum, Aalen, Germany

Fucik, P:
 Krankenhaus Amstetten, Amstetten, Austria

Gabriel, M:
 Klinikum Aschaffenburg, Aschaffenburg, Germany

Penzien, JM:
 Zentralklinikum Kinderkliniken, Augsburg, Germany

Diab, G:
 Kreiskrankenhaus Bad Hersfeld, Bad Hersfeld, Germany

Miething, R:
 Diakonie Krankenhaus, Bad Kreuznach, Germany

Deeg, KH:
 Klinikum Bamberg, Bamberg, Germany

Hammer, J:
 Univ Kinderspital Beider Basel, Padiatr Intensivmed, Basel, Switzerland

Varnholt, V:
 Univ Klinikum Charite, Campus Virchow Klinikum, Berlin, Germany

Schmidt, A:
 St Agnes Hosp, Bocholt, Germany

Bindl, L:
 Rheinische Friedrich Wilhelms Univ, Bonn, Germany

Sillaber, U:
 Landeskrankenhaus Bregenz, Abt Innere Med, Bregenz, Austria

Huemer, C:
 Landeskrankenhaus Bregenz, Abt Kinderheilkunde, Bregenz, Austria

Meier, P:
 Zentralkrankenhaus Links Weser, Bremen, Germany

Simic-Schleicher, G:
 Zentralkrankenhaus Bremen Nord, Bremen, Germany

Markart, M:
 Osped Bressanone, Brixen, Italy

Pfau, E:
 DRK Krankenhaus Chemnitz Rabenstein, Chemnitz, Germany

Broede, H:
 Klinikum Lippe Detmold GmbH, Detmold, Germany

Ausserer, B:
 Krankenhaus Dornbirn, Dornbirn, Austria

Kalhoff, H:
 Stadt Kliniken Dortmund, Dortmund, Germany

Arpe, V:
 St Marien Hosp Duren Birkesdorf, Duren, Germany

Schweitzer-Krantz, S:
 Evangel Krankenhaus, Dusseldorf, Germany

Kasper, JM:
 St Georg Klinikum Eisenach gGmbH, Eisenach, Germany

Loranth, K:
 Krankenhaus Barmherzigen Bruder, Eisenstadt, Austria

Bittrich, HJ:
 Helios Klinikum Erfurt, Erfurt, Germany

Simma, B:
 Landeskrankenhaus Feldkirch, Feldkirch, Austria

Klinge, J:
 Klinikum Furth, Furth, Germany

Fedlmaier, M:
 Klinikum Garm Partenkirchen, Garmisch Partenkirchen, Germany

Weigand, N:
 Klinikum Justus Liebig Uni O, Giessen, Germany

Herting, E:
 Georg August Univ Kinderklin, Gottingen, Germany

Grube, R:
 Univ Klin Neurol, Graz, Austria

Fusch, C:
 Klinikum Ernst Moritz Arndt Univ, Greifswald, Germany

Gruber, A:
 Krankenhaus Schulschwestern Grieskirchen, Grieskirchen, Germany

Schimmel, U:
 Allg Krankenhaus Hagen GmbH, Hagen, Germany

Knaufer-Schiefer, S:
 Ohrekreis Klinikum, Haldensleben, Germany

Lassig, W:
 Stadt Krankenhaus Martha Maria Halle Dolau gGmbH, Halle, Germany

Hennenberger, A:
 Kinderkrankenhaus Wilhelmstift, Hamburg, Germany

von der Wense, A:
 Altonaer Kinderkrankenhaus, Hamburg, Germany

Tillmann, R:
 Klinikum Kreis Herford, Herford, Germany

Schwarick, J:
 Kreiskrankenhaus Herzberg, Herzberg, Germany

Sitzmann, FC:
 Univ Klin Kinder & Jugendmed, Homburg Saar, Germany

Streif, W:
 Univ Klin Kinder & Jugendheilkunde Innsbruck, Innsbruck, Austria

Muller, H:
 Klin Robert Weixler Str, Kempten, Germany

Kurnik, P:
 Landeskrankenhaus Klagenfurt, Klagenfurt, Austria

Groneck, P:
 Kinderklin Stadt Koln, Cologne, Germany

Weiss, U:
 Achenbach Kreiskrankenhaus, Konigs Wusterhause, Germany

Groblacher-Roth, H:
 Landeskrankenhaus Krems a d Donau, Krems Ad Donau, Austria

Bensch, J:
 Vinzentius Krankenhaus, Landau, Germany

Moser, R:
 Landeskrankenhaus Leoben, Leoben, Austria

Schwarz, R:
 Landes Kinderklin Linz, Linz, Austria

Lenz, K:
 Konventhosp Barmherzigen Bruder, Linz, Austria

Hofmann, T:
 Evangel Krankenhaus, Lippstadt, Germany

Gopel, W:
 Med Univ Lubeck, Lubeck, Germany

Schulz, D:
 Stadt Klinikum Luneburg, Luneburg, Germany

Berger, T:
 Kantonspital Luzern, Luzern, Switzerland

Hauser, E:
 Landeskrankenhaus Modling, Modling, Austria

Forster, KM:
 Stadt Krankenhaus Harlaching, Munich, Germany

Peters, J:
 Kinderklin TU Munchen, Munich, Germany

Nicolai, TH:
 Kinderklin Dr v Haunerschen Kinderspital, Munich, Germany

Kumlien, B:
 Kinderklin Dritten Ordens, Munich, Germany

Beckmann, R:
 Dietrich Bonhoeffer Klinikum, Neubrandenburg, Germany

Seitz, C:
 FEK Friedrich Ebert Krankenhaus Neumunster GmbH, Neumunster, Germany

Huseman, D:
 Ruppiner Kliniken GmbH, Neuruppin, Germany

Schurmann, R:
 Stadt Kliniken Neuss Lukaskrankenhaus GmbH, Neuss, Germany

Ta, VH:
 Evangel Krankenhaus, Oberhausen, Germany

Weikmann, E:
 Landeskrankenhaus Oberwart, Oberwart, Austria

Evert, W:
 Stadt Kliniken Offenbach, Offenbach, Germany

Hautz, J:
 Klinikum Offenburg, Offenburg, Germany

Seidenberg, J:
 Elisabeth Kinderkrankenhaus, Oldenburg, Germany

Wocko, L:
 Krankenhaus Oranienburg, Oranienburg, Germany

Luigs, P:
 St Vincenz Krankenhaus Frauen Kinderklin, Paderborn, Germany

Reiter, HL:
 Klin Kinder & Jugendl Stadt Klinikum, Pforzheim, Germany

Quietzach, J:
 Vogtland Klinikum Plauen GmbH, Plauen, Germany

Konig, M:
 Oerschwaben Klin gGmbH, Ravensburg, Germany

Herrmann, J:
 Kreiskrankenhaus Rendsburg, Rendsburg, Germany

Mitter, H:
 Krankenhaus Barmherzigen Schwestern Ried, Ried, Austria

 Krankenhaus Barmherzigen Schwestern Ried, Innkreis, Austria

Seidler, E:
 Kreiskrankenhaus Obergoltzsch Rodew, Rodewisch, Germany

Maak, B:
 Thuringen Klin Georgius Agr gGmbH, Saalfeld, Germany

Sperl, W:
 Landeskrankenanstalten Salzburg, Salzburg, Austria

Zwiauer, K:
 Landesklinikum Sankt Polten, Sankt Polten, Austria

Meissl, M:
 Landeskrankenhaus Scharding, Scharding, Austria

Koch, R:
 Leopoldina Krankenhaus, Schweinfurt, Germany

Cremer, M:
 DRK Kinderklin Siegen, Siegen, Germany

Breuer, HA:
 Stadt Klinikum Solingen, Solingen, Germany

Gorke, W:
 Johanniter Kinderklin, Stendal, Germany

Nossal, R:
 Olga Hosp Stuttgart, Stuttgart, Germany

Pernice, W:
 Kreiskrankenhaus Torgau, Torgau, Germany

Brangenberg, R:
 Klinikum Traunstein, Traunstein, Germany

Salzer, HR:
 Landeskrankenhaus Tulin, Tulin, Austria

Koch, H:
 St Marien Hosp, Vechta, Germany

Schaller, G:
 Landeskrankenhaus Villach, Villach, Austria

Paky, F:
 Landeskrankenhaus Vocklabruck, Vocklabruck, Austria

Strasser, F:
 Klinikum Weiden, Weiden, Germany

Eitelberger, F:
 Krankenhaus Barmherzigen Schwestern v Heiligen Kr, Wels, Austria

Sontheimer, D:
 Harz Klinikum Wernigerode GmbH, Wernigerode, Germany

Lischka, A:
 Wilhelminenspital Wien, Vienna, Austria

Kronberger, M:
 St Anna Childrens Hosp, Vienna, Austria

Dilch, A:
 Gottfried Preyersches Kinderspital Stadt Wien, Vienna, Austria

Scheibenpflug, C:
 Donauspital SMZ Ost Stadt Wien, Vienna, Austria

Bruckner, R:
 Krankenhaus Wiener Neustadt, Wiener Neustadt, Austria

Mahler, K:
 St Elizabeth Hosp, Wittlich, Germany

Runge, K:
 Zentrum Kinder & Jugendmed, Wuppertal, Germany

Kunze, W:
 Krankenhaus Muldentalkreis Wurzen, Wurzen, Germany

Schermann, P:
 Krankenhaus Zwettl, Zwettl, Austria
ISSN: 20452322





Scientific Reports
Editorial
NATURE RESEARCH, HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY, Reino Unido
Tipo de documento: Article
Volumen: 9 Número:
Páginas:
WOS Id: 000466878900066
ID de PubMed: 31061469
imagen Green Published, Green Accepted, gold

MÉTRICAS