Resolving TYK2 locus genotype-To-phenotype differences in autoimmunity

Science Translational Medicine

Volumn 8, Issue 363, 2016, Pages

  Dendrou, Calliope A ^a   Cortes, Adrian ^a,b   Shipman, Lydia ^a   Evans, Hayley G ^a   Attfield, Kathrine E ^c   Jostins, Luke ^b   Barber, Thomas ^a   Kaur, Gurman ^c   Kuttikkatte, Subita Balaram ^c   Leach, Oliver A ^a   Desel, Christiane ^a   Faergeman, Soren L ^a,d   Cheeseman, Jane ^a   Neville, Matt J ^a,e   Sawcer, Stephen ^f   Compston, Alastair ^f   Johnson, Adam R ^g   Everett, Christine ^g   Bell, John I ^c   Karpe, Fredrik ^a,e   Ultsch, Mark ^g   Eigenbrot, Charles ^g   McVean, Gil ^b   Fugger, Lars ^a,c,d   more..

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c UNIVERSITY OF OXFORD   (United Kingdom)

^d AARHUS UNIVERSITY HOSPITAL   (Denmark)

^e NIHR OXFORD BIOMEDICAL RESEARCH CENTRE   (United Kingdom)

^f UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^g GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA INTERFERON; INTERFERON; INTERLEUKIN 10; INTERLEUKIN 6; PROTEIN KINASE TYK2; CYTOKINE; JAK2 PROTEIN, HUMAN; JANUS KINASE 2; TRANSCRIPTOME; TYK2 PROTEIN, HUMAN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANKYLOSING SPONDYLITIS; ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CONTROLLED STUDY; CROHN DISEASE; FEMALE; GENE; GENE EXPRESSION; GENE FREQUENCY; GENE FUNCTION; GENE LOCUS; GENE MAPPING; GENE TARGETING; GENETIC ASSOCIATION; GENETIC VARIABILITY; HOMOZYGOSITY; HUMAN; HUMAN CELL; ICAM1 GENE; ICAM4 GENE; IMMUNOCOMPETENT CELL; MISSENSE MUTATION; MOUSE; MULTIPLE SCLEROSIS; NONHUMAN; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN PHOSPHORYLATION; PSORIASIS; SINGLE NUCLEOTIDE POLYMORPHISM; TYK2 GENE; ULCERATIVE COLITIS; ZGLP1 GENE; ANIMAL; CD4+ T LYMPHOCYTE; CHEMISTRY; CYTOLOGY; GENETIC ASSOCIATION STUDY; GENETIC EPIGENESIS; GENETIC RECOMBINATION; GENETIC VARIATION; GENETICS; GENOMICS; GENOTYPE; HEK293 CELL LINE; HOMOZYGOTE; IMMUNE SYSTEM; MALE; METABOLISM; MONONUCLEAR CELL; PHENOTYPE; PROTEIN CONFORMATION; QUANTITATIVE TRAIT LOCUS; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION;

ANIMALS; AUTOIMMUNE DISEASES; AUTOIMMUNITY; CD4-POSITIVE T-LYMPHOCYTES; CYTOKINES; EPIGENESIS, GENETIC; FEMALE; GENETIC ASSOCIATION STUDIES; GENETIC VARIATION; GENOMICS; GENOTYPE; HEK293 CELLS; HOMOZYGOTE; HUMANS; IMMUNE SYSTEM; JANUS KINASE 2; LEUKOCYTES, MONONUCLEAR; MALE; MICE; MUTATION, MISSENSE; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEIN CONFORMATION; QUANTITATIVE TRAIT LOCI; RECOMBINATION, GENETIC; SEQUENCE ANALYSIS, RNA; SIGNAL TRANSDUCTION; TRANSCRIPTOME; TYK2 KINASE;

EID: 84994528744     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aag1974     Document Type: Article

References (50)

1. T. A. Manolio, Bringing genome-wide association findings into clinical use. Nat. Rev. Genet. 14, 549-558 (2013).
2. M. Hay, D. W. Thomas, J. L. Craighead, C. Economides, J. Rosenthal, Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40-51 (2014).
3. M. R. Nelson, H. Tipney, J. L. Painter, J. Shen, P. Nicoletti, Y. Shen, A. Floratos, P. C. Sham, M. J. Li, J. Wang, L. R. Cardon, J. C. Whittaker, P. Sanseau, The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856-860 (2015).
4. R. M. Plenge, E. M. Scolnick, D. Altshuler, Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581-594 (2013).
5. International Genetics of Ankylosing Spondylitis Consortium (IGAS), A. Cortes, J. Hadler, J. P. Pointon, P. C. Robinson, T. Karaderi, P. Leo, K. Cremin, K. Pryce, J. Harris, S. Lee, K. B. Joo, S.-C. Shim, M. Weisman, M. Ward, X. Zhou, H.-J. Garchon, G. Chiocchia, J. Nossent, B. A. Lie, O. Førre, J. Tuomilehto, K. Laiho, L. Jiang, Y. Liu, X. Wu, L. A. Bradbury, D. Elewaut, R. Burgos-Vargas, S. Stebbings, L. Appleton, C. Farrah, J. Lau, T. J. Kenna, N. Haroon, M. A. Ferreira, J. Yang, J. Mulero, J. L. Fernandez-Sueiro, M. A. Gonzalez-Gay, C. Lopez-Larrea, P. Deloukas, P. Donnelly; Australo-Anglo-American Spondyloarthritis Consortium (TASC); Groupe Française d'Etude Génétique des Spondylarthrites (GFEGS); Nord-Trøndelag Health Study (HUNT); Spondyloarthritis Research Consortium of Canada (SPARCC), Wellcome Trust Case Control Consortium 2 (WTCCC2), P. Bowness, K. Gafney, H. Gaston, D. D. Gladman, P. Rahman, W. P. Maksymowych, H. Xu, J. B. Crusius, I. E. van der Horst-Bruinsma, C.-T. Chou, R. Valle-Oñate, C. Romero-Sánchez, I. M. Hansen, F. M. Pimentel-Santos, R. D. Inman, V. Videm, J. Martin, M. Breban, J. D. Reveille, D. M. Evans, T. H. Kim, B. P. Wordsworth, M. A. Brown, Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related. Nat. Genet. 45, 730-738 (2013).
6. L. Jostins, S. Ripke, R. K. Weersma, R. H. Duerr, D. P. McGovern, K. Y. Hui, J. C. Lee, L. P. Schumm, Y. Sharma, C. A. Anderson, J. Essers, M. Mitrovic, K. Ning, I. Cleynen, E. Theatre, S. L. Spain, S. Raychaudhuri, P. Goyette, Z. Wei, C. Abraham, J.-P. Achkar, T. Ahmad, L. Amininejad, A. N. Ananthakrishnan, V. Andersen, J. M. Andrews, L. Baidoo, T. Balschun, P. A. Bampton, A. Bitton, G. Boucher, S. Brand, C. Büning, A. Cohain, S. Cichon, M. D'Amato, D. De Jong, K. L. Devaney, M. Dubinsky, C. Edwards, D. Ellinghaus, L. R. Ferguson, D. Franchimont, K. Fransen, R. Gearry, M. Georges, C. Gieger, J. Glas, T. Haritunians, A. Hart, C. Hawkey, M. Hedl, X. Hu, T. H. Karlsen, L. Kupcinskas, S. Kugathasan, A. Latiano, D. Laukens, I. C. Lawrance, C. W. Lees, E. Louis, G. Mahy, J. Mansfield, A. R. Morgan, C. Mowat, W. Newman, O. Palmieri, C. Y. Ponsioen, U. Potocnik, N. J. Prescott, M. Regueiro, J. I. Rotter, R. K. Russell, J. D. Sanderson, M. Sans, J. Satsangi, S. Schreiber, L. A. Simms, J. Sventoraityte, S. R. Targan, K. D. Taylor, M. Tremelling, H. W. Verspaget, M. De Vos, C. Wijmenga, D. C. Wilson, J. Winkelmann, R. J. Xavier, S. Zeissig, B. Zhang, C. K. Zhang, H. Zhao; International IBD Genetics Consortium (IIBDGC), M. S. Silverberg, V. Annese, H. Hakonarson, S. R. Brant, G. Radford-Smith, C. G. Mathew, J. D. Rioux, E. E. Schadt, M. J. Daly, A. Franke, M. Parkes, S. Vermeire, J. C. Barrett, J. H. Cho, Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124 (2012).
7. A. Franke, D. P. McGovern, J. C. Barrett, K. Wang, G. L. Radford-Smith, T. Ahmad, C. W. Lees, T. Balschun, J. Lee, R. Roberts, C. A. Anderson, J. C. Bis, S. Bumpstead, D. Ellinghaus, E. M. Festen, M. Georges, T. Green, T. Haritunians, L. Jostins, A. Latiano, C. G. Mathew, G. W. Montgomery, N. J. Prescott, S. Raychaudhuri, J. I. Rotter, P. Schumm, Y. Sharma, L. A. Simms, K. D. Taylor, D. Whiteman, C. Wijmenga, R. N. Baldassano, M. Barclay, T. M. Bayless, S. Brand, C. Büning, A. Cohen, J.-F. Colombel, M. Cottone, L. Stronati, T. Denson, M. DeVos, R. D'Inca, M. Dubinsky, C. Edwards, T. Florin, D. Franchimont, R. Gearry, J. Glas, A. Van Gossum, S. L. Guthery, J. Halfvarson, H. W. Verspaget, J. P. Hugot, A. Karban, D. Laukens, I. Lawrance, M. Lemann, A. Levine, C. Libioulle, E. Louis, C. Mowat, W. Newman, J. Panés, A. Phillips, D. D. Proctor, M. Regueiro, R. Russell, P. Rutgeerts, J. Sanderson, M. Sans, F. Seibold, A. H. Steinhart, P. C. F. Stokkers, L. Torkvist, G. Kullak-Ublick, D. Wilson, T. Walters, S. R. Targan, S. R. Brant, J. D. Rioux, M. D'Amato, R. K. Weersma, S. Kugathasan, A. M. Griffiths, J. C. Mansfield, S. Vermeire, R. H. Duerr, M. S. Silverberg, J. Satsangi, S. Schreiber, J. H. Cho, V. Annese, H. Hakonarson, M. J. Daly, M. Parkes, Genome-wide meta-Analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42, 1118-1125 (2010).
8. A. H. Beecham, N. A. Patsopoulos, D. K. Xifara, M. F. Davis, A. Kemppinen, C. Cotsapas, T. S. Shah, C. Spencer, D. Booth, A. Goris, A. Oturai, J. Saarela, B. Fontaine, B. Hemmer, C. Martin, F. Zipp, S. D'Alfonso, F. Martinelli-Boneschi, B. Taylor, H. F. Harbo, I. Kockum, J. Hillert, T. Olsson, M. Ban, J. R. Oksenberg, R. Hintzen, L. F. Barcellos; Wellcome Trust Case Control Consortium 2 (WTCCC2); International IBD Genetics Consortium (IIBDGC), C. Agliardi, L. Alfredsson, M. Alizadeh, C. Anderson, R. Andrews, H. B. Søndergaard, A. Baker, G. Band, S. E. Baranzini, N. Barizzone, J. Barrett, C. Bellenguez, L. Bergamaschi, L. Bernardinelli, A. Berthele, V. Biberacher, T. M. C. Binder, H. Blackburn, I. L. Bomfim, P. Brambilla, S. Broadley, B. Brochet, L. Brundin, D. Buck, H. Butzkueven, S. J. Caillier, W. Camu, W. Carpentier, P. Cavalla, E. G. Celius, I. Coman, G. Comi; International Multiple Sclerosis Genetics Consortium (IMSGC), Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat. Genet. 45, 1353-1360 (2013).
9. L. C. Tsoi, S. L. Spain, J. Knight, E. Ellinghaus, P. E. Stuart, F. Capon, J. Ding, Y. Li, T. Tejasvi, J. E. Gudjonsson, H. M. Kang, M. H. Allen, R. McManus, G. Novelli, L. Samuelsson, J. Schalkwijk, M. Ståhle, A. D. Burden, C. H. Smith, M. J. Cork, X. Estivill, A. M. Bowcock, G. G. Krueger, W. Weger, J. Worthington, R. Tazi-Ahnini, F. O. Nestle, A. Hayday, P. Hoffmann, J. Winkelmann, C. Wijmenga, C. Langford, S. Edkins, R. Andrews, H. Blackburn, A. Strange, G. Band, R. D. Pearson, D. Vukcevic, C. C. A. Spencer, P. Deloukas, U. Mrowietz, S. Schreiber, S. Weidinger, S. Koks, K. Kingo, T. Esko, A. Metspalu, H. W. Lim, J. J. Voorhees, M. Weichenthal, H. E. Wichmann, V. Chandran, C. F. Rosen, P. Rahman, D. D. Gladman, C. E. M. Griffiths, A. Reis, J. Kere; Collaborative Association Study of Psoriasis (CASP); Genetic Analysis of Psoriasis Consortium; Psoriasis Association Genetics Extension; Wellcome Trust Case Control Consortium 2, R. P. Nair, A. Franke, J. N. Barker, G. R. Abecasis, J. T. Elder, R. C. Trembath, Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat. Genet. 44, 1341-1348 (2012).
10. D. Diogo, L. Bastarache, K. P. Liao, R. R. Graham, R. S. Fulton, J. D. Greenberg, S. Eyre, J. Bowes, J. Cui, A. Lee, D. A. Pappas, J. M. Kremer, A. Barton, M. J. Coenen, B. Franke, L. A. Kiemeney, X. Mariette, C. Richard-Miceli, H. Canhão, J. E. Fonseca, N. de Vries, P. P. Tak, J. B. Crusius, M. T. Nurmohamed, F. Kurreeman, T. R. Mikuls, Y. Okada, E. A. Stahl, D. E. Larson, T. L. Deluca, M. O'Laughlin, C. C. Fronick, L. L. Fulton, R. Kosoy, M. Ransom, T. R. Bhangale, W. Ortmann, A. Cagan, V. Gainer, E. W. Karlson, I. Kohane, S. N. Murphy, J. Martin, A. Zhernakova, L. Klareskog, L. Padyukov, J. Worthington, E. R. Mardis, M. F. Seldin, P. K. Gregersen, T. Behrens, S. Raychaudhuri, J. C. Denny, R. M. Plenge, TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of pleiotropic effects on non-Autoimmune complex traits. Plos One 10, e0122271 (2015).
11. S. Onengut-Gumuscu, W.-M. Chen, O. Burren, N. J. Cooper, A. R. Quinlan, J. C. Mychaleckyj, E. Farber, J. K. Bonnie, M. Szpak, E. Schofield, P. Achuthan, H. Guo, M. D. Fortune, H. Stevens, N. M. Walker, L. D. Ward, A. Kundaje, M. Kellis, M. J. Daly, J. C. Barrett, J. D. Cooper, P. Deloukas; Type 1 Diabetes Genetics Consortium, J. A. Todd, C. Wallace, P. Concannon, S. S. Rich, Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat. Genet. 47, 381-386 (2015).
12. D. M. Schwartz, M. Bonelli, M. Gadina, J. J. O'Shea, Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12, 25-36 (2016).
13. M. H. Tomasson, Z. Xiang, R. Walgren, Y. Zhao, Y. Kasai, T. Miner, R. E. Ries, O. Lubman, D. H. Fremont, M. D. McLellan, J. E. Payton, P. Westervelt, J. F. DiPersio, D. C. Link, M. J. Walter, T. A. Graubert, M. Watson, J. Baty, S. Heath, W. D. Shannon, R. Nagarajan, C. D. Bloomfield, E. R. Mardis, R. K. Wilson, T. J. Ley, Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 111, 4797-4808 (2008).
14. N. Couturier, F. Bucciarelli, R. N. Nurtdinov, M. Debouverie, C. Lebrun-Frenay, G. Defer, T. Moreau, C. Confavreux, S. Vukusic, I. Cournu-Rebeix, R. H. Goertsches, U. K. Zettl, M. Comabella, X. Montalban, P. Rieckmann, F. Weber, B. Müller-Myhsok, G. Edan, B. Fontaine, L. T. Mars, A. Saoudi, J. R. Oksenberg, M. Clanet, R. S. Liblau, D. Brassat, Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility. Brain 134, 693-703 (2011).
15. Z. Li, M. Gakovic, J. Ragimbeau, M.-L. Eloranta, L. Rönnblom, F. Michel, S. Pellegrini, Two rare disease-Associated Tyk2 variants are catalytically impaired but signaling competent. J. Immunol. 190, 2335-2344 (2013).
16. The Wellcome Trust Case Control Consortium, J. B. Maller, G. McVean, J. Byrnes, D. Vukcevic, K. Palin, Z. Su, J. M. M. Howson, A. Auton, S. Myers, A. Morris, M. Pirinen, M. A. Brown, P. R. Burton, M. J. Caulfield, A. Compston, M. Farrall, A. S. Hall, A. T. Hattersley, A. V. Hill, C. G. Mathew, M. Pembrey, J. Satsangi, M. R. Stratton, J. Worthington, N. Craddock, M. Hurles, W. Ouwehand, M. Parkes, N. Rahman, A. Duncanson, J. A. Todd, D. P. Kwiatkowski, N. J. Samani, S. C. Gough, M. I. McCarthy, P. Deloukas, P. Donnelly, Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294-1301 (2012).
17. 1000 Genomes Project Consortium, A. Auton, L. D. Brooks, R. M. Durbin, E. P. Garrison, H. M. Kang, J. O. Korbel, J. L. Marchini, S. McCarthy, G. A. McVean, G. R. Abecasis, A global reference for human genetic variation. Nature 526, 68-74 (2015).
18. L. Jostins, G. McVean, Trinculo: Bayesian and frequentist multinomial logistic regression for genome-wide association studies of multi-category phenotypes. Bioinformatics 32, 1898-1900 (2016).
19. J. H. Cho, M. Feldman, Heterogeneity of autoimmune diseases: Pathophysiological insights from genetics and implications for new therapies. Nat. Med. 21, 730-738 (2015).
20. M. Ban, A. Goris, A. R. Lorentzen, A. Baker, T. Mihalova, G. Ingram, D. R. Booth, R. N. Heard, G. J. Stewart, E. Bogaert, B. Dubois, H. F. Harbo, E. G. Celius, A. Spurkland, R. Strange, C. Hawkins, N. P. Robertson, F. Dudbridge, J. Wason, P. L. De Jager, D. Hafler, J. D. Rioux, A. J. Ivinson, J. L. McCauley, M. Pericak-Vance, J. R. Oksenberg, S. L. Hauser, D. Sexton, J. Haines, S. Sawcer; Wellcome Trust Case-Control Consortium (WTCCC), A. Compston, Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor. Eur. J. Hum. Genet. 17, 1309-1313 (2009).
21. T. Raj, K. Rothamel, S. Mostafavi, C. Ye, M. N. Lee, J. M. Replogle, T. Feng, M. Lee, N. Asinovski, I. Frohlich, S. Imboywa, A. Von Korff, Y. Okada, N. A. Patsopoulos, S. Davis, C. McCabe, H.-I. Paik, G. P. Srivastava, S. Raychaudhuri, D. A. Hafler, D. Koller, A. Regev, N. Hacohen, D. Mathis, C. Benoist, B. E. Stranger, P. L. De Jager, Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 344, 519-523 (2014).
22. B. P. Fairfax, P. Humburg, S. Makino, V. Naranbhai, D. Wong, E. Lau, L. Jostins, K. Plant, R. Andrews, C. McGee, J. C. Knight, Innate immunity activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343, 1246949 (2014).
23. M. N. Lee, C. Ye, A.-C. Villani, T. Raj, W. Li, T. M. Eisenhaure, S. H. Imboywa, P. I. Chipendo, F. A. Ran, K. Slowikowski, L. D. Ward, K. Raddassi, C. McCabe, M. H. Lee, I. Y. Frohlich, D. A. Hafler, M. Kellis, S. Raychaudhuri, F. Zhang, B. E. Stranger, C. O. Benoist, P. L. De Jager, A. Regev, N. Hacohen, Common genetic variants modulate pathogensensing responses in human dendritic cells. Science 343, 1246980 (2014).
24. B. P. Fairfax, S. Makino, J. Radhakrishnan, K. Plant, S. Leslie, A. Dilthey, P. Ellis, C. Langford, F. O. Vannberg, J. C. Knight, Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat. Genet. 44, 502-510 (2012).
25. GTEx Consortium, The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science 348, 648-660 (2015).
26. A. Battle, S. Mostafavi, X. Zhu, J. B. Potash, M. M. Weissman, C. McCormick, C. D. Haudenschild, K. B. Beckman, J. Shi, R. Mei, A. E. Urban, S. B. Montgomery, D. F. Levinson, D. Koller, Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals. Genome Res. 24, 14-24 (2014).
27. T. S. Nair, K. E. Kozma, N. L. Hoefling, P. K. Kommareddi, Y. Ueda, T.-W. Gong, M. I. Lomax, C. D. Lansford, S. A. Telian, B. Satar, H. A. Arts, H. K. El-Kashlan, W. E. Berryhill, Y. Raphael, T. E. Carey, Identification and characterization of choline transporter-like protein 2, an inner ear glycoprotein of 68 and 72 kDa that is the target of antibody-induced hearing loss. J. Neurosci. 24, 1772-1779 (2004).
28. P. J. Lupardus, M. Ultsch, H. Wallweber, P. Bir Kohli, A. R. Johnson, C. Eigenbrot, Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc. Natl. Acad. Sci. U.S.A. 111, 8025-8030 (2014).
29. A. Y. Kreins, M. J. Ciancanelli, S. Okada, X.-F. Kong, N. Ramírez-Alejo, S. S. Kilic, J. El Baghdadi, S. Nonoyama, S. A. Mahdaviani, F. Ailal, A. Bousfiha, D. Mansouri, E. Nievas, C. S. Ma, G. Rao, A. Bernasconi, H. Sun Kuehn, J. Niemela, J. Stoddard, P. Deveau, A. Cobat, S. El Azbaoui, A. Sabri, C. K. Lim, M. Sundin, D. T. Avery, R. Halwani, A. V. Grant, B. Boisson, D. Bogunovic, Y. Itan, M. Moncada-Velez, R. Martinez-Barricarte, M. Migaud, C. Deswarte, L. Alsina, D. Kotlarz, C. Klein, I. Muller-Fleckenstein, B. Fleckenstein, V. Cormier-Daire, S. Rose-John, C. Picard, L. Hammarstrom, A. Puel, S. Al-Muhsen, L. Abel, D. Chaussabel, S. D. Rosenzweig, Y. Minegishi, S. G. Tangye, J. Bustamante, J.-L. Casanova, S. Boisson-Dupuis, Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. J. Exp. Med. 212, 1641-1662 (2015).
30. N. Hogg, I. Patzak, F. Willenbrock, The insider's guide to leukocyte integrin signalling and function. Nat. Rev. Immunol. 11, 416-426 (2011).
31. Roadmap Epigenomics Consortium, A. Kundaje, W. Meuleman, J. Ernst, M. Bilenky, A. Yen, A. Heravi-Moussavi, P. Kheradpour, Z. Zhang, J. Wang, M. J. Ziller, V. Amin, J. W. Whitaker, M. D. Schultz, L. D. Ward, A. Sarkar, G. Quon, R. S. Sandstrom, M. L. Eaton, Y. C. Wu, A. R. Pfenning, X. Wang, M. Claussnitzer, Y. Liu, C. Coarfa, R. A. Harris, N. Shoresh, C. B. Epstein, E. Gjoneska, D. Leung, W. Xie, R. D. Hawkins, R. Lister, C. Hong, P. Gascard, A. J. Mungall, R. Moore, E. Chuah, A. Tam, T. K. Canfield, R. S. Hansen, R. Kaul, P. J. Sabo, M. S. Bansal, A. Carles, J. R. Dixon, K.-H. Farh, S. Feizi, R. Karlic, A.-R. Kim, A. Kulkarni, D. Li, R. Lowdon, G. Elliott, T. R. Mercer, S. J. Neph, V. Onuchic, P. Polak, N. Rajagopal, P. Ray, R. C. Sallari, K. T. Siebenthall, N. A. Sinnott-Armstrong, M. Stevens, R. E. Thurman, J. Wu, B. Zhang, X. Zhou, A. E. Beaudet, L. A. Boyer, P. L. De Jager, P. J. Farnham, S. J. Fisher, D. Haussler, S. J. Jones, W. Li, M. A. Marra, M. T. McManus, S. Sunyaev, J. A. Thomson, T. D. Tlsty, L.-H. Tsai, W. Wang, R. A. Waterland, M. Q. Zhang, L. H. Chadwick, B. E. Bernstein, J. F. Costello, J. R. Ecker, M. Hirst, A. Meissner, A. Milosavljevic, B. Ren, J. A. Stamatoyannopoulos, T. Wang, M. Kellis, Integrative analysis of 111 reference human genomes. Nature 518, 317-330 (2015).
32. D. Adams, L. Altucci, S. E. Antonarakis, J. Ballesteros, S. Beck, A. Bird, C. Bock, B. Boehm, E. Campo, A. Caricasole, F. Dahl, E. T. Dermitzakis, T. Enver, M. Esteller, X. Estivill, A. Ferguson-Smith, J. Fitzgibbon, P. Flicek, C. Giehl, T. Graf, F. Grosveld, R. Guigo, I. Gut, K. Helin, J. Jarvius, R. Küppers, H. Lehrach, T. Lengauer, Å. Lernmark, D. Leslie, M. Loeffler, E. Macintyre, A. Mai, J. H. Martens, S. Minucci, W. H. Ouwehand, P. G. Pelicci, H. Pendeville, B. Porse, V. Rakyan, W. Reik, M. Schrappe, D. Schübeler, M. Seifert, R. Siebert, D. Simmons, N. Soranzo, S. Spicuglia, M. Stratton, H. G. Stunnenberg, A. Tanay, D. Torrents, A. Valencia, E. Vellenga, M. Vingron, J. Walter, S. Willcocks, BLUEPRINT to decode the epigenetic signature written in blood. Nat. Biotechnol. 30, 224-226 (2012).
33. M. W. L. Teng, E. P. Bowman, J. J. McElwee, M. J. Smyth, J.-L. Casanova, A. M. Cooper, D. J. Cua, IL-12 and IL-23 cytokines: From discovery to targeted therapies for immunemediated inflammatory diseases. Nat. Med. 21, 719-729 (2015).
34. L. B. Ivashkiv, L. T. Donlin, Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36-49 (2014).
35. P. A. Calabresi, B. C. Kieseier, D. L. Arnold, L. J. Balcer, A. Boyko, J. Pelletier, S. Liu, Y. Zhu, A. Seddighzadeh, S. Hung, A. Deykin; ADVANCE Study Investigators, Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): A randomised, phase 3, double-blind study. Lancet Neurol. 13, 657-665 (2014).
36. D. J. Cua, J. Sherlock, Y. Chen, C. A. Murphy, B. Joyce, B. Seymour, L. Lucian, W. To, S. Kwan, T. Churakova, S. Zurawski, M. Wiekowski, S. A. Lira, D. Gorman, R. A. Kastelein, J. D. Sedgwick, Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744-748 (2003).
37. A. Awasthi, L. Riol-Blanco, A. Jäger, T. Korn, C. Pot, G. Galileos, E. Bettelli, V. K. Kuchroo, M. Oukka, Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. J. Immunol. 182, 5904-5908 (2009).
38. M. Prinz, H. Schmidt, A. Mildner, K.-P. Knobeloch, U.-K. Hanisch, J. Raasch, D. Merkler, C. Detje, I. Gutcher, J. Mages, R. Lang, R. Martin, R. Gold, B. Becher, W. Brück, U. Kalinke, Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28, 675-686 (2008).
39. R. C. Axtell, B. A. de Jong, K. Boniface, L. F. van der Voort, R. Bhat, P. De Sarno, R. Naves, M. Han, F. Zhong, J. G. Castellanos, R. Mair, A. Christakos, I. Kolkowitz, L. Katz, J. Killestein, C. H. Polman, R. de Waal Malefyt, L. Steinman, C. Raman, T helper type 1 and 17 cells determine efficacy of interferon-b in multiple sclerosis and experimental encephalomyelitis. Nat. Med. 16, 406-412 (2010).
40. F. Altare, A. Durandy, D. Lammas, J.-F. Emile, S. Lamhamedi, F. Le Deist, P. Drysdale, E. Jouanguy, R. Döffinger, F. Bernaudin, O. Jeppsson, J. A. Gollob, E. Meinl, A. W. Segal, A. Fischer, D. Kumararatne, J.-L. Casanova, Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280, 1432-1435 (1998).
41. C. J. A. Duncan, S. M. B. Mohamad, D. F. Young, A. J. Skelton, T. R. Leahy, D. C. Munday, K. M. Butler, S. Morfopoulou, J. R. Brown, M. Hubank, J. Connell, P. J. Gavin, C. McMahon, E. Dempsey, N. E. Lynch, T. S. Jacques, M. Valappil, A. J. Cant, J. Breuer, K. R. Engelhardt, R. E. Randall, S. Hambleton, Human IFNAR2 deficiency: Lessons for antiviral immunity. Sci. Transl. Med. 7, 307ra154 (2015).
42. J. E. Chrencik, A. Patny, I. K. Leung, B. Korniski, T. L. Emmons, T. Hall, R. A. Weinberg, J. A. Gormley, J. M. Williams, J. E. Day, J. L. Hirsch, J. R. Kiefer, J. W. Leone, H. D. Fischer, C. D. Sommers, H.-C. Huang, E. J. Jacobsen, R. E. Tenbrink, A. G. Tomasselli, T. E. Benson, Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J. Mol. Biol. 400, 413-433 (2010).
43. M. Siu, R. Pastor, W. Liu, K. Barrett, M. Berry, W. S. Blair, C. Chang, J. Z. Chen, C. Eigenbrot, N. Ghilardi, P. Gibbons, H. He, C. A. Hurley, J. R. Kenny, S. Cyrus Khojasteh, H. Le, L. Lee, J. P. Lyssikatos, S. Magnuson, R. Pulk, V. Tsui, M. Ultsch, Y. Xiao, B.-y. Zhu, D. Sampath, 2-Amino-[1, 2, 4]triazolo[1, 5-A]pyridines as JAK2 inhibitors. Bioorg. Med. Chem. Lett. 23, 5014-5021 (2013).
44. V. Tsui, P. Gibbons, M. Ultsch, K. Mortara, C. Chang, W. Blair, R. Pulk, M. Stanley, M. Starovasnik, D. Williams, M. Lamers, P. Leonard, S. Magnuson, J. Liang, C. Eigenbrot, A new regulatory switch in a JAK protein kinase. Proteins 79, 393-401 (2011).
45. K. Reich, R. G. Langley, K. A. Papp, J.-P. Ortonne, K. Unnebrink, M. Kaul, J. M. Valdes, A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis. N. Engl. J. Med. 365, 1586-1596 (2011).
46. A. Grant, S. S. Ponia, S. Tripathi, V. Balasubramanian, L. Miorin, M. Sourisseau, M. C. Schwarz, M. P. Sánchez-Seco, M. J. Evans, S. M. Best, A. García-Sastre, Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19, 882-890 (2016).
47. F. S. Collins, H. Varmus, A new initiative on precision medicine. N. Engl. J. Med. 372, 793-795 (2015).
48. J. D. Buenrostro, P. G. Giresi, L. C. Zaba, H. Y. Chang, W. J. Greenleaf, Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213-1218 (2013).
49. F. A. Ran, P. D. Hsu, J. Wright, V. Agarwala, D. A. Scott, F. Zhang, Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281-2308 (2013).
50. J. J. Kulagowski, W. Blair, R. J. Bull, C. Chang, G. Deshmukh, H. J. Dyke, C. Eigenbrot, N. Ghilardi, P. Gibbons, T. K. Harrison, P. R. Hewitt, M. Liimatta, C. A. Hurley, A. Johnson, T. Johnson, J. R. Kenny, P. Bir Kohli, R. J. Maxey, R. Mendonca, K. Mortara, J. Murray, R. Narukulla, S. Shia, M. Steffek, S. Ubhayakar, M. Ultsch, A. van Abbema, S. I. Ward, B. Waszkowycz, M. Zak, Identification of imidazo-pyrrolopyridines as a novel and potent JAK1 inhibitors. J. Med. Chem. 55, 5901-5922 (2012).