(19) TZZ _¥¥_T (11) EP 2 134 863 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) 21.05.2014 Bulletin 2014/21 (86) International application number: (21) Application number: 08732132.9 PCT/US2008/056869 (22) Date of filing: 13.03.2008 (87) International publication number: WO 2008/112903 (18.09.2008 Gazette 2008/38) (54) GENETIC ALTERATIONS ON CHROMOSOME 16 AND METHODS OF USE THEREOF FOR THE DIAGNOSIS OF TYPE 1 DIABETES GENETISCHE VERÄNDERUNGENAUF CHROMOSOM 16 UND VERFAHREN ZUR VERWENDUNG DAVON BEI DER DIAGNOSE VON TYP-1-DIABETES MODIFICATIONS GÉNÉTIQUES SUR LE CHROMOSOME 16 ET PROCÉDÉS D’UTILISATION DE CELLES-CI POUR LE DIAGNOSTIC DU DIABÈTE DE TYPE I (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • KANTAROVA D ET AL: "Genetic susceptibility to HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT type 1 diabetes mellitus in humans", RO SE SI SK TR PHYSIOLOGICAL RESEARCH, vol. 56, no. 3, 22 June 2006 (2006-06-22), pages 255-266, (30) Priority: 13.03.2007 US 894649 P XP002608749, ISSN: 0862-8408 04.04.2007 US 910019 P • BARTSOCAS C S ET AL: "Genetics of type 1 25.05.2007 US 940274 P diabetes mellitus", PEDIATRIC ENDOCRINOLOGY REVIEWS, XX, IL, vol. 3, no. (43) Date of publication of application: suppl. 3, 1 August 2006 (2006-08-01), pages 23.12.2009 Bulletin 2009/52 508-513, XP001525620, ISSN: 1565-4753 • LEE Y H ET AL: "The PTPN22 C1858T functional (73) Proprietors: polymorphism and autoimmune diseases - a • The Children’s Hospital Of Philadelphia meta-analysis", RHEUMATOLOGY (OXFORD), Philadelphia, PA 19104 (US) vol. 46, no. 1, January 2007 (2007-01), pages • The Royal Institution for the Advancement of 49-56, XP002608750, ISSN: 1462-0324 Learning / McGill University • SMYTH DEBORAH J ET AL: "A genome-wide Montreal, Québec H3A 2T5 (CA) association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon- (72) Inventors: induced helicase (IFIH1) region", NATURE • HAKONARSON, Hakon GENETICS, NATURE PUBLISHING GROUP, NEW Malvern, PA 19355 (US) YORK, US LNKD- DOI:10.1038/NG1800, vol. 38, • GRANT, Struan, F.A. no. 6, 1 June 2006 (2006-06-01), pages 617-619, Swarthmore, PA 10981 (US) XP009096717, ISSN: 1061-4036 • BRADFIELD, Johnathan, P. • OSTERHOLM A -M ET AL: "Genome-wide scan Philadelphia, PA 19103 (US) for type 1 diabetic nephropathy in the Finnish • POLYCHRONAKOS, Constantin population reveals suggestive linkage to a single Côte Saint Luc, Quèbec H3H 1P3 (CA) locus on chromosome 3q", KIDNEY INTERNATIONAL, vol. 71, no. 2, January 2007 (74) Representative: Boult Wade Tennant (2007-01), pages 140-145, XP002608751, ISSN: Verulam Gardens 0085-2538 70 Gray’s Inn Road London WC1X 8BT (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 2 134 863 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 134 863 B1 • HAKONARSON HAKON ET AL: "A genome- wide • ’Sequence-specific oliognucleotide (SSO) Probe association study identifies KIAA0350 as a type for Homo sapines variation rs2903692’, [Online] 1 diabetes gene.", NATURE 2 AUG 2007 LNKD- 06 March 2006, NCBI : Probe Retrieved from the PUBMED:17632545, vol. 448, no. 7153, 2 August Internet: <URL:http://www.ncbi.nlm.nih.gov/ 2007 (2007-08-02), pages 591-594, XP002608752, projects/g enome/probe/reports/ ISSN: 1476-4687 probereport.cgi?uid=532 0763> • HAKONARSON HAKON ET AL: "A novel • ’Sequence-specific oligonucleotide /SSO) probe susceptibility locus for type 1 diabetes on for Homo sapiens variation rs17673553’, [Online] Chr12q13 identified by a genome-wide 06 March 2006, NCBI : Probe Retrieved from the association study.", DIABETES APR 2008 LNKD- Internet: <URL:http://www.ncbi.nlm.nih.gov/ PUBMED:18198356, vol. 57, no. 4, April 2008 projects/g enome/probe/reports/ (2008-04), pages 1143-1146, XP002608753, ISSN: probereport.cgi?uid=530 1954> 1939-327X • ’rs2903692’, [Online] 02 October 2001, NCBI: • IYENGAR S K ET AL: "Mining the Genome for dbSNP Retrieved from the Internet: <URL:http: Susceptibility to Diabetic Nephropathy: The Role //www.ncbi.nlm.nih.gov/projects/S NP/snp_ of Large-Scale Studies and Consortia", ss.cgi?subsnp_id=4098259> SEMINARS IN NEPHROLOGY - DIABETIC NEPHROPATHY 200703 US LNKD- DOI: Remarks: 10.1016/J.SEMNEPHROL.2007.01.004, vol. 27, Thefile contains technical information submitted after no. 2, March 2007 (2007-03), pages 208-222, the application was filed and not included in this XP9140917, ISSN: 0270-9295 specification • BEKRIS L.M. ET AL.: ’Glutathione-s-transferase M1 and T1 polymorphisms and associations with type 1 diabetes age-at-onset’ AUTOIMMUNITY vol. 38, no. 8, December 2005, pages 567 - 575, XP008118755 • MEI RUI ET AL: "Genome- wide detection of allelic imbalance using human SNPs and high-density DNA arrays", GENOME RESEARCH, vol. 10, no. 8, August 2000 (2000-08), pages 1126-1137, ISSN: 1088-9051 2 EP 2 134 863 B1 Description FIELD OF THE INVENTION 5 [0001] This invention relates to the fields of glucose metabolism, genetics and pathology associated with diabetes, particularly type I diabetes. More specifically, the invention provides a panel of genes containing single nucleotide polymorphisms which had heretofore not been associated with this disease. Methods and kits for using the sequences so identified for diagnostic and therapeutic treatment purposes are also provided, as are therapeutic compositions for management of diabetes. 10 BACKGROUND OF THE INVENTION [0002] Type I diabetes (TID) results from the autoimmune destruction of pancreatic beta cells, a process believed to be strongly influenced by multiple genes and environmental factors. The incidence of T1D has been increasing in Western 15 countries and has more than doubled in the United States over the past 30 years. The disease shows a strong familial component, with first-degree relatives of cases being at 15 times greater risk of T1D than a randomly selected member of the general population and monozygotic twins being concordant for T1D at a frequency of approximately 50%. However, while the genetic evidence is strong, the latter data suggests that an interplay with environmental factors also plays a key role in influencing T1D outcome. 20 [0003] The familial clustering of T1D is influenced by multiple genes. Variation in four loci has already been established to account for a significant proportion of the familial aggregation of T1D. These include the major histocompatibility complex (MHC) region on 6p21 (including theHLA-DRB1 , -DQA1 and -DRQ1 genes1); the insulin/insulin-like growth factor 2 gene complex (INS-IGF2) on 11p152-4, the protein tyrosine phosphatase-22 (PTPN22) gene on 1p135,6 and the gene encoding cytotoxic T-lymphocyte-associated protein 4 (CTLA4) on 2q317,8. The interleukin-2 receptor alpha 25 (CD25) locus on 10p15 9 has also been implicated in the pathogenesis of T1D but remains to be replicated by independent studies. In addition, spontaneous mouse model studies of T1D have implicated numerous other regions that have been confirmed in replication studies10. Several other loci have also been implicated in human association studies with T1D but the effects of these implicated genes remain controversial and are subject to confirmation in independent studies utilizing sufficient sample sizes. Together, these studies suggest that many more T1D susceptibility genes remain to be 30 discovered. It is also clear that there are differences in genetic susceptibility to T1D between populations. An explanation for this variation may be related to differing frequencies of T1D causative and protective variants between different populations and ethnic groups, a hypothesis that needs to be addressed in multi-center, multi-national studies that are truly transcontinental. [0004] Kantárová and co-workers (Kantárová et al., 2006, Physiological Research, 56(3):255-266) have described 35 SNPs at HLA, INS (Insuline), CTLA-4, PTPN22 and other genes associated with susceptibility to T1D. Association of alterations at 16p13 region or at the KIA0350 locus of chromosome 16 with susceptibility to T1D was not described. [0005] Bartsocas and co-workers (Bartsocas et al., 2006, Pediatric Endocrinology Reviews, 3 (suppl. 3):508-523) have described SNPs at HLA, INS and PTPN22 among other genes associated with T1D. Association of alterations at 16p13 region or at the KIA0350 locus of chromosome 16 with susceptibility to T1D was not described. 40 SUMMARY OF THE INVENTION [0006] In accordance with the present invention, T1D-associated SNPs have been identified which are indicative of an increased or reduced risk of developing T1D. Thus, described herein are nuleic acids comprising at least one genetic 45 alteration identified in Tables 1-3 are provided. Such nucleic acids and the proteins encoded thereby have utility in the diagnosis and management of type 1 diabetes (T1D). [0007] In one aspect of the invention, methods for assessing susceptibility for developing T1D are provided. An ex- emplary method entails providing a target nucleic acid from a patient sample, said target nucleic acid having a prede- termined sequence in the normal population, and assessing said target nucleic acid for the presence of a single nucleotide 50 polymorphism which is indicative of an increased or decreased risk of developing T1D. Such genetic alterations include, without limitation, inversion, deletion, duplication, and insertion of at least one nucleotide in said sequence. [0008] The genetic alteration is a single nucleotide polymorphism at the KIAA0350 locus region of chromosome 16.