Genetic Alterations Associated with Type I Diabetes and Methods of Use Thereof for Diagnosis and Treatment

Abstract

Compositions and methods for the detection and treatment of T1D are provided.

1 . A method for detecting the presence or absence of at least one genetic alteration in a target nucleic acid isolated from a patient for assessing susceptibility for developing type 1 diabetes (T1D), said method comprising:
 a) providing a target nucleic acid from a patient sample, said target nucleic acid having a predetermined sequence in the normal population;   b) assessing said target nucleic acid for the presence of a copy number variation which is indicative of an increased susceptibility of developing T1D.   
     
     
         2 . The method as claimed in  claim 1 , wherein said genetic alteration is selected from the group consisting of a deletion, or a duplication of at least one nucleotide in said sequence. 
     
     
         3 . The method of  claim 1 , wherein said target nucleic acid is assessed for genetic alterations via a method selected from the group consisting of size analysis, hybridization of allele specific probes, allele-specific primer extension, oligomer ligation, DNA sequencing, single-stranded conformation polymorphism, and quantitative PCR. 
     
     
         4 . The method as claimed in  claim 1 , wherein said genetic alteration is at least one copy number variation (CNV) present in a gene listed in Table 1. 
     
     
         5 . A kit for practicing the method of  claim 1 . 
     
     
         6 . A nucleic acid comprising at least one CNV identified in Table 1. 
     
     
         7 . A microarray comprising the at least one nucleic acid of  claim 6 , said nucleic acid optionally being between 10 and 50 nucleotides in length. 
     
     
         8 . A method of management for T1D comprising:
 a) identifying a patient who is at an increased risk of developing T1D by detecting at least one of the CNVs in Table 1;   b) administering to said patient a therapeutic agent in a therapeutically effective amount to manage T1D.   
     
     
         9 . The method according to  claim 8 , wherein said therapeutic agent is selected from the group consisting of a small molecule, an antibody, a protein, an oligonucleotide, or an siRNA molecule. 
     
     
         10 . The method of  claim 9 , wherein said therapeutic agent is delivered to an inflammatory cell. 
     
     
         11 . The method of  claim 9 , wherein said therapeutic agent modulates natural killer cell activity. 
     
     
         12 . The method of  claim 9 , wherein said therapeutic agent modulates signaling in an insulin-producing beta cell. 
     
     
         13 . The method of  claim 12 , wherein modulatory effects of said agent are assessed on a parameter selected from the group consisting of insulin secretion, glucagon secretion and glucosamine induced beta cell apoptosis is determined. 
     
     
         14 . The method as claimed in  claim 4  wherein said gene is selected from the group consisting of CCND1, REGL, TRPM1 and KCNS3. 
     
     
         15 . The method as claimed in  claim 8  wherein said gene is selected from the group consisting of CCND1, REGL, TRPM1 and KCNS3. 
     
     
         16 . The method as claimed in  claim 4  wherein said gene is IGFBP4. 
     
     
         17 . The method as claimed in  claim 8  wherein said gene is selected from the group consisting of IGFBP4.