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WO 2014/008426 A2 9 January 2014 (09.01.2014) P O P C T

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WO 2014/008426 A2 9 January 2014 (09.01.2014) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/008426 A2 9 January 2014 (09.01.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/68 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US2013/049371 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, 3 July 20 13 (03.07.2013) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/668,939 6 July 2012 (06.07.2012) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: IGNYTA, INC. [US/US]; 271 1 Centerville GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Road, Suite 400, Wilmington, DE 19808 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: LIM, Jonathan; 5457 Meadows Del Mar, San EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Diego, CA 92130 (US). SHOEMAKER, Robert; 3140 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Thorn Street, San Diego, CA 92104 (US). BOOKBIND¬ TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ER, Louis; 14823 Gable Ridge Road, San Diego, CA KM, ML, MR, NE, SN, TD, TG). 92128 (US). ANDERSON, David; 15768 Boulder Moun tain Road, Poway, CA 92064 (US). Published: (74) Agent: MILLER, Kimberly, J.; KNOBBE MARTENS without international search report and to be republished OLSON & BEAR LLP, 2040 Main Street, 14th Floor, upon receipt of that report (Rule 48.2(g)) Irvine, CA 92614 (US). (54) Title: DIAGNOSIS OF SYSTEMIC LUPUS ERYTHEMATOSUS (57) Abstract: Loci having methylation sites relevant to the diagnosis of SLE, Error Percentages per DML Set Sizes as well as related methods and reagents, are disclosed. 60% 50% SVM Error (no noise) 40% SVM Error (2 Noisy Samples) g 30% SVM Error (8 Noisy Samples) 20% SVM Error Linear Regression Line (2 Noisy Samples) SVM Error Linear Regression 10% Line (8 Noisy Samples) < 0% 2 4 6 8 10 12 14 16 18 20 22 24 DML Set Size ∞ o o o DIAGNOSIS OF SYSTEMIC LUPUS ERYTHEMATOSUS REFERENCE TO SEQUENCE LISTING, TABLE, OR COMPUTER PROGRAM LISTING [0001] Tables 1A, IB, 2A, 2B, 3A, 3B, and 4 precede the listing of the claims of this application. RELATED APPLICATIONS [0002] The present application claims priority to Provisional U.S. Application Serial No. 61/668,939, filed July 6, 2012, and also claims priority to Provisional U.S. Application Serial No. 61/776,729, filed March 11, 2013. FIELD OF THE INVENTION [0003] Embodiments of the present invention include methods, compositions and kits for the diagnosis of a subject with a disorder such as Systemic Lupus Erythematosus. BACKGROUND OF THE INVENTION [0004] Epigenetic mechanisms such as DNA methylation play a fundamental role in the etiology of autoimmune diseases by modulating the methylation state and transcriptional activity of critical genes that affect immune maturation and function and lead to the development of autoimmunity. The identification of the key differentially methylated loci may provide novel biomarkers for diagnostics. [0005] Systemic Lupus Erythematosus (SLE) or lupus is an autoimmune disorder where immune cell abnormalities lead to the production of autoantibodies by B-cells and auto-reactive T-cells that contribute to disease pathology (Crispin J.C., Liossis S.N., Kis- Toth K., et al. (2010) Pathogenesis of human systemic lupus erythematosus: recent advances. Trends Mol. Med. 16: 47-57; Kammer G.M., Perl A., Richardson B.C., Tsokos G.C. (2002) Abnormal T cell signal transduction in systemic lupus erythematosus. Arthritis Rheum. 46:1 139-1 154; Tsokos G.C, (201 1) Systemic Lupus Erythematosus. N . Engl. J. Med. 365: 2 110-2121; Perl A., Fernandez D.R., Telarico T., Doherty E., Francis L., Phillips P.E. (2009) T-cell and B-cell signaling biomarkers and treatment targets in lupus. Curr. Opin. Rheumatol. 21: 454^-64; Perl A. (2010) Systems biology of lupus: mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targetsfor treatment. Autoimmunity 43: 32-47; Pernis A.B. (2009) Th 17 cells in rheumatoid arthritis and systemic lupus erythematosus. J. Intern. Med. 265: 644-652). The aberrant autoimmune response of lupus spares no organ or tissue, with the involvement of the skin, brain, blood, cardiovascular system, and kidneys in most patients. The chronic, uncontrolled autoimmune attack on the body's vital organs is often accompanied by life threatening complications (Tsokos G.C., (201 1) Systemic Lupus Erythematosus. N . Engl. J. Med. 365: 2 110-2121). The prevalence of SLE ranges from 20 to 150 cases per 100,000 individuals and appears to be increasing as the disease is recognized more readily and survival increases. In the United States, people of African, Hispanic, or Asian ancestry, as compared with those of other racial or ethnic groups, tend to have an increased prevalence of SLE with greater severity. Furthermore, the vast majority of SLE patients are women of childbearing age (nine out of ten patients are women), making it even more critical to develop diagnostic tools that enable earlier and more precise treatment (Pons-Estel G.J., Alarcon G.S., Scofield L., Reinlib L., Cooper G.S. (2010) Understanding the epidemiology and progression of systemic lupus erythematosus. Semin. Arthritis Rheum 39:257-68; Mindy S. Lo and George C. Tsokos, (2012) Treatment of systemic lupus erythematosus: new advances in targeted therapy. Ann. N.Y. Acad. Sci. 1247:138-152). [0006] The complex etiology and pathogenesis of autoimmune diseases such as lupus is known to involve both genetic predisposition and environmental factors (Duarte C , Couto M., Ines L., Liang M.H. Epidemiology of systemic lupus erythematosus. In: Lahita RG, Tsokos G, Buyon J, Koike T, eds. (201 1) Systemic lupus erythematosus. 5th ed. London: Elsevier, 673-96). Because concordance rates for SLE in genetically identical twins are only 11 - 40%, there is an upper limit to the genetic contribution to SLE. Thus, factors other than genetics, such as environmental and lifestyle factors (infections, toxins, inflammation, diet, chemicals, hormones) that can cause epigenetic changes may play a role in SLE pathogenesis (Wesley H. Brooks, Christelle Le Dantec, Jacques-Olivier Pers, Pierre Youinou, Yves Renaudineau, (2010) Epigenetics and autoimmunity. Journal of Autoimmunity 34:J207-J219; Ballestar, Esteban (2010) Epigenetics Lessons from Twins: Prospects for Autoimmune Disease. Clinic. Rev. Allerg. Immunol. 39:30^1-1; Farga M.F., Ballestar E., Paz M.F., Ropero S., Setien F., Ballestar M.L., et al. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA 102: 10604-9; Jaenisch R., Bird A., (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33:245-54; Biola M. Javierre, Agustin F. Fernandez, Julia Richter, Fatima Al-Shahrour, J. Ignacio Martin-Subero, Javier Rodriguez-Ubreva, Maria Berdasco, Mario F. Fraga, Terrance P. O'Hanlon, Lisa G. Rider, Filipe V. Jacinto, F. Javier Lopez-Longo, Joaquin Dopazo, Marta Forn, Miguel A . Peinado, Luis Carreno, Amr H. Sawalha, John B. Harley, Reiner Siebert, Manel Esteller, Frederick W. Miller, and Esteban Ballestar, (2010) Changes in the pattern ofDNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 20: 170-179). [0007] Epigenetics or non-coding DNA changes affect the potential of the genome to be expressed and may have a significant impact on human diseases as a result of environmental factors that cause epigenetic changes (Bjornsson, H. T., M. D. Fallin, A. P. Feinberg, (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet. 20: 350-358; Torst, Jorg, (2010) DNA methylation: An introduction to the biology and the disease-associated changes of a promising biomarker. Mol. Biotechnol. 44:71-81; Manel Esteller, (2008) Epigenetics in Cancer. NEJM 358(1 1): 1148-1 159; Vardhman K. Rakyan, Thomas A. Down, David J. Balding and Stephan Beck, (201 1) Epigenome-wide association studies for common human diseases. Nature Reviews Genetics 12:529-541; Anna Portela and Manel Esteller, (2010) Epigenetic modifications and human disease. Nature Biotechnology 28(10): 1057-1068; Richardson, B. (2007) Primer: epigenetics of autoimmunity. Nature Clin. Practice Rheum. 3(9):521-527; Van der Maarel S.M. (2008) Epigenetic mechanisms in health and disease. Ann Rheum Dis 67:97-100; Pons D., de Vries F.R., van den Elsen P.J., Heijmans B.T., Quax P.H., Jukema J.W. (2009) Epigenetic histone acetylation modifiers in vascular remodeling: new targets for therapy in cardiovascular disease. Eur. Heart J. 30:266-77) including SLE (Feinberg A.P. (2007) Phenotypic plasticity and the epigenetics of human disease. Nature. 447:433-40; Q. Lua, X. Qiu, A. N . Hua, H.
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