Person: Ng, Aylwin
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Publication Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans
(2013) Smeekens, Sanne P.; Ng, Aylwin; Kumar, Vinod; Johnson, Melissa D.; Plantinga, Theo S.; van Diemen, Cleo; Arts, Peer; Verwiel, Eugéne T.P.; Gresnigt, Mark S.; Fransen, Karin; van Sommeren, Suzanne; Oosting, Marije; Cheng, Shih-Chin; Joosten, Leo A.B.; Hoischen, Alexander; Kullberg, Bart-Jan; Scott, William K.; Perfect, John R.; van der Meer, Jos W.M.; Wijmenga, Cisca; Netea, Mihai G.; Xavier, Ramnik J.Candida albicans is the most common human fungal pathogen causing mucosal and systemic infections. However, human antifungal immunity remains poorly defined. Here, by integrating transcriptional analysis and functional genomics, we identified Candida-specific host defense mechanisms in humans. Candida induced significant expression of genes from the type I interferon (IFN) pathway in human peripheral blood mononuclear cells. This unexpectedly prominent role of type I IFN pathway in anti-Candida host defense was supported by additional evidence. Polymorphisms in type I IFN genes modulated Candida-induced cytokine production and were correlated with susceptibility to systemic candidiasis. In in-vitro experiments, type I IFNs skewed Candida-induced inflammation from a Th17-response toward a Th1-response. Patients with chronic mucocutaneaous candidiasis displayed defective expression of genes in the type I IFN pathway. These findings indicate that the type I IFN pathway is a main signature of Candida-induced inflammation and plays a crucial role in anti-Candida host defense in humans.
Publication IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
(Nature Publishing Group UK, 2018) Momozawa, Yukihide; Dmitrieva, Julia; Théâtre, Emilie; Deffontaine, Valérie; Rahmouni, Souad; Charloteaux, Benoît; Crins, François; Docampo, Elisa; Elansary, Mahmoud; Gori, Ann-Stephan; Lecut, Christelle; Mariman, Rob; Mni, Myriam; Oury, Cécile; Altukhov, Ilya; Alexeev, Dmitry; Aulchenko, Yuri; Amininejad, Leila; Bouma, Gerd; Hoentjen, Frank; Löwenberg, Mark; Oldenburg, Bas; Pierik, Marieke J.; vander Meulen-de Jong, Andrea E.; Janneke van der Woude, C.; Visschedijk, Marijn C.; Abraham, Clara; Achkar, Jean-Paul; Ahmad, Tariq; Ananthakrishnan, Ashwin; Andersen, Vibeke; Anderson, Carl A.; Andrews, Jane M.; Annese, Vito; Aumais, Guy; Baidoo, Leonard; Baldassano, Robert N.; Bampton, Peter A.; Barclay, Murray; Barrett, Jeffrey C.; Bayless, Theodore M.; Bethge, Johannes; Bitton, Alain; Boucher, Gabrielle; Brand, Stephan; Brandt, Berenice; Brant, Steven R.; Büning, Carsten; Chew, Angela; Cho, Judy H.; Cleynen, Isabelle; Cohain, Ariella; Croft, Anthony; Daly, Mark; D’Amato, Mauro; Danese, Silvio; Jong, Dirk De; Denapiene, Goda; Denson, Lee A.; Devaney, Kathy L.; Dewit, Olivier; D’Inca, Renata; Dubinsky, Marla; Duerr, Richard H.; Edwards, Cathryn; Ellinghaus, David; Essers, Jonah; Ferguson, Lynnette R.; Festen, Eleonora A.; Fleshner, Philip; Florin, Tim; Franke, Andre; Fransen, Karin; Gearry, Richard; Gieger, Christian; Glas, Jürgen; Goyette, Philippe; Green, Todd; Griffiths, Anne M.; Guthery, Stephen L.; Hakonarson, Hakon; Halfvarson, Jonas; Hanigan, Katherine; Haritunians, Talin; Hart, Ailsa; Hawkey, Chris; Hayward, Nicholas K.; Hedl, Matija; Henderson, Paul; Hu, Xinli; Huang, Hailiang; Hui, Ken Y.; Imielinski, Marcin; Ippoliti, Andrew; Jonaitis, Laimas; Jostins, Luke; Karlsen, Tom H.; Kennedy, Nicholas A.; Khan, Mohammed Azam; Kiudelis, Gediminas; Krishnaprasad, Krupa; Kugathasan, Subra; Kupcinskas, Limas; Latiano, Anna; Laukens, Debby; Lawrance, Ian C.; Lee, James C.; Lees, Charlie W.; Leja, Marcis; Limbergen, Johan Van; Lionetti, Paolo; Liu, Jimmy Z.; Mahy, Gillian; Mansfield, John; Massey, Dunecan; Mathew, Christopher G.; McGovern, Dermot P. B.; Milgrom, Raquel; Mitrovic, Mitja; Montgomery, Grant W.; Mowat, Craig; Newman, William; Ng, Aylwin; Ng, Siew C.; Ng, Sok Meng Evelyn; Nikolaus, Susanna; Ning, Kaida; Nöthen, Markus; Oikonomou, Ioannis; Palmieri, Orazio; Parkes, Miles; Phillips, Anne; Ponsioen, Cyriel Y.; Potocnik, Urõs; Prescott, Natalie J.; Proctor, Deborah D.; Radford-Smith, Graham; Rahier, Jean-Francois; Raychaudhuri, Soumya; Regueiro, Miguel; Rieder, Florian; Rioux, John D.; Ripke, Stephan; Roberts, Rebecca; Russell, Richard K.; Sanderson, Jeremy D.; Sans, Miquel; Satsangi, Jack; Schadt, Eric E.; Schreiber, Stefan; Schulte, Dominik; Schumm, L. Philip; Scott, Regan; Seielstad, Mark; Sharma, Yashoda; Silverberg, Mark S.; Simms, Lisa A.; Skieceviciene, Jurgita; Spain, Sarah L.; Steinhart, A. Hillary; Stempak, Joanne M.; Stronati, Laura; Sventoraityte, Jurgita; Targan, Stephan R.; Taylor, Kirstin M.; ter Velde, Anje; Torkvist, Leif; Tremelling, Mark; Sommeren, Suzanne van; Vasiliauskas, Eric; Verspaget, Hein W.; Walters, Thomas; Wang, Kai; Wang, Ming-Hsi; Wei, Zhi; Whiteman, David; Wijmenga, Cisca; Wilson, David C.; Winkelmann, Juliane; Xavier, Ramnik; Zhang, Bin; Zhang, Clarence K.; Zhang, Hu; Zhang, Wei; Zhao, Hongyu; Zhao, Zhen Z.; Lathrop, Mark; Hugot, Jean-Pierre; Weersma, Rinse K.; De Vos, Martine; Franchimont, Denis; Vermeire, Severine; Kubo, Michiaki; Louis, Edouard; Georges, MichelGWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.