(19) TZZ ¥_T (11) EP 2 257 643 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/68 (2006.01) 08.04.2015 Bulletin 2015/15 (86) International application number: (21) Application number: 09712711.2 PCT/US2009/034586 (22) Date of filing: 19.02.2009 (87) International publication number: WO 2009/105590 (27.08.2009 Gazette 2009/35) (54) IDENTIFICATION OF PEDIATRIC ONSET INFLAMMATORY BOWEL DISEASE LOCI AND METHODS OF USE THEREOF FOR THE DIAGNOSIS AND TREATMENT OF THE SAME IDENTIFIZIERUNG DES AUSBRUCHS VON ENTZÜNDLICHEN DARMERKRANKUNGS-LOCI BEI KINDERN UND VERFAHREN ZUR VERWENDUNG DAVON BEI DEREN DIAGNOSE UND BEHANDLUNG IDENTIFICATION DE LOCI DE MALADIE INTESTINALE INFLAMMATOIRE À DÉBUT PÉDIATRIQUE ET SES PROCÉDÉS D’UTILISATION POUR SON DIAGNOSTIC ET SON TRAITEMENT (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A2-2007/073478 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR • YAMAZAKI KEIKO ET AL: "Single nucleotide polymorphisms in TNFSF15 confer susceptibility (30) Priority: 19.02.2008 US 29841 P to Crohn’s disease", HUMAN MOLECULAR 06.06.2008 US 59486 P GENETICS, vol. 14, no. 22, 15 November 2005 (2005-11-15), pages 3499-3506, XP009132501, (43) Date of publication of application: OXFORD UNIVERSITY PRESS, SURREY ISSN: 08.12.2010 Bulletin 2010/49 0964-6906, DOI: 10.1093/HMG/DDI379 [retrieved on 2005-10-13] (73) Proprietor: The Children’s Hospital Of • DATABASE dbSNP 25 May 2006 (2006-05-25), Philadelphia "SINGLE NUCLEOTIDE POLYMORPHISM", Philadelphia, PA 19104 (US) XP008140832, retrieved from ncbi Database accession no. rs2315008 (72) Inventors: • DATABASE dbsnp [Online] 12 February 2003 • HAKONARSON, Hakon (2003-02-12), XP002678946, retrieved from ncbi Malvern, PA 19355 (US) Database accession no. rs4809330 • BRADFIELD, Jonathan • BURTON PAUL R ET AL: "Genome-wide Philadelphia, PA 19103 (US) association study of 14,000 cases of seven • IMIELINSKI, Marcin common diseases and 3,000 shared controls", Cambridge, MA 02139 (US) NATURE: INTERNATIONAL WEEKLY JOURNAL • GRANT, Struan OF SCIENCE, vol. 447, no. 7145, 1 June 2007 Philadelphia, PA 19104 (US) (2007-06-01), pages 661-683, XP002542263, NATURE PUBLISHING GROUP, UNITED (74) Representative: Cripps, Joanna Elizabeth et al KINGDOM ISSN: 0028-0836, DOI: Mewburn Ellis LLP 10.1038/NATURE05911 33 Gutter Lane London EC2V 8AS (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 257 643 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 257 643 B1 • FAYAD RAJA ET AL: "Apoptosis resistance in • BAI ET AL.: ’Overexpression of M68/DcR3 in ulcerative colitis: High expression of decoy humangastrointestinal tract tumors independent receptors by lamina propria T cells", EUROPEAN of gene amplification and its location in a four- JOURNAL OF IMMUNOLOGY, vol. 36, no. 8, 1 gene cluster.’ PROC NAT ACAD SCI vol. 97, no. August 2006 (2006-08-01) , pages 2215-2222, 3, 01 February 2000, pages 1230 - 1235, XP008127265, WILEY - V C H VERLAG GMBH & XP002938755 CO. KGAA, DE ISSN: 0014-2980, DOI: 10.1002/EJI. • PITTI ET AL.: ’Genomic amplification of a decoy 200535477 [retrieved on 2006-07-20] receptor for Fas ligand in lung and colon cancer. • KIM S ET AL: "Increased expression of soluble ’ NATURE vol. 396, no. 6712, 17 December 1998, decoy receptor 3 in acutely inflamed intestinal pages 699 - 703, XP002929444 epithelia", CLINICAL IMMUNOLOGY, vol. 115, no. • DATABASE OMIM 30 January 2009 ONLINE 3, 1 June 2005 (2005-06-01), pages 286-294, MENDELIAN INHERITANCE IN MAN (OMIM) XP004887958, ACADEMIC PRESS, US ISSN: (online).: ’INFLAMMATORY BOWEL DISEASE 24 1521-6616, DOI: 10.1016/J.CLIM.2005.02.014 IBD24’ Database accession no. 612566 • SUBRA KUGATHASAN ET AL: "Loci on 20q13 • KUGATHASAN ET AL.: ’Loci on 20q13 and 21q22 and 21q22 are associated with pediatric-onset areassociated withpediatric- onsetinflammatory inflammatory bowel disease", NATURE bowel disease.’ NATURE GENETICS vol. 40, no. GENETICS, vol. 40, no. 10, 1 October 2008 10, October 2008, pages 1211 - 1215, (2008-10-01), pages 1211-1215, XP008140834, XP008140834 NATURE PUBLISHING GROUP, NEW YORK, US • HirokoSashio ET AL: "Polymorphisms of theTNF ISSN: 1061-4036, DOI: 10.1038/NG.203 gene and the TNF receptor superfamily member • DATABASE SNP [Online] 25 May 2006 ’SINGLE 1B gene are associated with susceptibility to NUCLEOTIDE POLYMORPHISM’, XP008140832 ulcerative colitis and Crohn’s disease, Database accession no. rs2315008 respectively", Immunogenetics, vol. 53, no. 12, 1 • THE WELLCOME TRUST CASE CONTROL March 2002 (2002-03-01) , pages 1020-1027, CONSORTIUM.:’Genome- wideassociation study XP55077483, ISSN: 0093-7711, DOI: of 14,000 cases of seven common diseases and 10.1007/s00251-001-0423-7 3,000 shared controls. ’ NATURE vol. 447, 07 June 2007, pages 661 - 678, XP002542263 • YAMAZAKI ET AL.: ’Single nucleotide polymorphisms in TNFSF15 confer susceptibility toCrohn’s disease. ’HUM MOL GENETICS vol.14, no. 22, 15 November 2005, pages 3499 - 3506, XP009132501 2 EP 2 257 643 B1 Description FIELD OF THE INVENTION 5 [0001] This invention relates to the fields of inflammatory disorders and genetic testing. More specifically, the invention provides compositions and methods for the diagnosis and treatment inflammatory bowel disease (IBD) in pediatric and adult patients. BACKGROUND OF THE INVENTION 10 [0002] Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. [0003] Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, a defective mucosal barrier 15 and persistent dysregulation of the immune response to commensal intestinal bacteria 1-3. I BD is characterized by two distinct phenotypes: Crohn’s disease (CD) and ulcerative colitis (UC). Among children, CD is twice as common as UC. CD can affect any part of the gut with discontinuous penetrating lesions and is characterized by full thickness (transmural), discrete inflammation which leads to stricturing and fistulization, and can occur in the large and small bowel, whereas in UC, the impact is as a confluent inflammation of the colon, nearly always involving the rectum, ranging from proctitis 20 to a pancolitis and is characterized by mucosal inflammation4; CD impacts 100-250/100,000 and UC impacts 80-100/100,000 in the UK and the USA. Recurrence of both CD and UC among families 5-7,8, twin studies9, phenotype concordance among families10-12, identification of specific genetic risk factors, and environmental components all dem- onstrate that both disorders are complex genetic diseases. [0004] Linkage studies facilitated the ’positional cloning’ of the first two genes involved in the pathogenesis of the 25 disease13, including CARD15 (caspase recruitment domain family, member 15; also known as NOD2), which is now considered the first and most widely replicated CD susceptibility gene14-16 . The IBD5 locus, a site on chromosome 5q31, and its association with CD 17-19. has not been further resolved due to extensive linkage disequilibrium (LD) in the region20. [0005] With the more recent introduction of the GWA technology, several genes involved in the pathogenesis of IBD 30 have been uncovered. Duerr et al were the first to report a highly significant association between CD and sequence variants in the interleukin 23 receptor (IL23R) gene on chromosome 1p31 in non-Jewish, ileal CD cases of European ancestry using the HumanHap 317K gene chip from Illumina 20. A coding variant, rs11209026 (Arg381Gln), was shown to confer a strong protective effect against the disease and was then replicated in the same study in separate cohorts of patients with CD or UC. Others have replicated this finding, including our own laboratory in a cohort with pediatric 35 onset CD21, lending further support for the protective role of the IL23R gene in IBD 21. Around the same time, Hampe et al22 reported an independent association of a nsSNP in the autophagy-related 16-like 1 gene ( ATG16L1) on chromosome 2q37.122 (a threonine-to-alanine substitution at amino acid position 300 of the protein - T300A) and confirmed the previously reported variants in the SLC22A4 and CARD15 genes. [0006] Rioux et al23 presented a follow-up GWA study to their IL23R finding in ileal CD and two independent replication 40 studies, identifying several new regions of association to CD. Specifically, in addition to the previously established CARD15 and IL23R associations, they also reported strong association with independent replication to variation within an intergenic region on 10q21.1, in the genomic regions encoding PHOX2B, NCF4 and FAM92B.They also independently identified strong and significantly replicated association with the coding variant in ATG16L1. [0007] The Wellcome Trust Case Control Consortium24 described a joint GWA study (using the Affymetrix GeneChip 45 500K platform) carried out in the British population, which examined 2,000 individuals for each of seven major diseases, including CD, against a shared set of approximately 3,000 controls; they identified in the case-control comparison nine independent association signals at P<5x10-7 thereby corroborating the ATG16L1, 5q31, IL23R, 10q21 and 5p13.1 loci 25. Their study also identified four further new strong association signals, located on chromosomes 3p21, 5q33, 10q24 and 18p11. Parkes et al also reported eplication for the signals in the ATG16L and IRGM genes27. We have also successfully 50 demonstrated the association of ATG16L1 variation in our cohort of pediatric onset CD 28.