A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes

Abstract

Autoimmune-mediated destruction of pancreatic islet β cells results in type 1 diabetes (T1D). Serum islet autoantibodies usually develop in genetically susceptible individuals in early childhood before T1D onset, with multiple islet autoantibodies predicting diabetes development. However, most at-risk children remain islet-antibody negative, and no test currently identifies those likely to seroconvert. We sought a genomic signature predicting seroconversion risk by integrating longitudinal peripheral blood gene expression profiles collected in high-risk children included in the BABYDIET and DIPP cohorts, of whom 50 seroconverted. Subjects were followed for 10 years to determine time of seroconversion. Any cohort effect and the time of seroconversion were corrected to uncover genes differentially expressed (DE) in seroconverting children. Gene expression signatures associated with seroconversion were evident during the first year of life, with 67 DE genes identified in seroconverting children relative to those remaining antibody negative. These genes contribute to T cell-, DC-, and B cell-related immune responses. Near-birth expression of ADCY9, PTCH1, MEX3B, IL15RA, ZNF714, TENM1, and PLEKHA5, along with HLA risk score predicted seroconversion (AUC 0.85). The ubiquitin-proteasome pathway linked DE genes and T1D susceptibility genes. Therefore, a gene expression signature in infancy predicts risk of seroconversion. Ubiquitination may play a mechanistic role in diabetes progression.Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517); Blood. 2007 Sep 15;110(6):1814-23. (PMID: 17536012); MAGMA. 2006 Dec;19(6):281-96. (PMID: 17171386); J Autoimmun. 2008 Aug;31(1):1-6. (PMID: 18450419); Mol Psychiatry. 2014 Mar;19(3):294-301. (PMID: 23439483); Pediatr Diabetes. 2011 Dec;12(8):733-43. (PMID: 21564455); Exp Cell Res. 2015 Jan 1;330(1):212-21. (PMID: 25305500); Ann N Y Acad Sci. 2008 Dec;1150:61-7. (PMID: 19120269); Trends Biochem Sci. 2010 Nov;35(11):618-26. (PMID: 20685123); J Immunol. 2002 Jun 1;168(11):5491-8. (PMID: 12023343); Diabetes Care. 2013 Jun;36(6):1597-603. (PMID: 23340888); J Immunol. 2002 Jan 1;168(1):188-96. (PMID: 11751962); Annu Rev Genet. 2012;46:43-68. (PMID: 22934649); Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9. (PMID: 16381927); BMC Bioinformatics. 2006 Mar 02;7:106. (PMID: 16512900); Genome Res. 2003 Nov;13(11):2498-504. (PMID: 14597658); Curr Opin Chem Biol. 2014 Dec;23:71-7. (PMID: 25461388); Diabetes. 2005 Dec;54(12):3402-9. (PMID: 16306355); FASEB J. 2007 Feb;21(2):427-37. (PMID: 17172638); Biochim Biophys Acta. 2014 Apr;1843(4):694-702. (PMID: 24389248); Immunology. 2017 Jun;151(2):198-210. (PMID: 28190264); Mol Syst Biol. 2008;4:167. (PMID: 18277383); JAMA. 2013 Jun 19;309(23):2473-9. (PMID: 23780460); Diabetes. 2014 Jul;63(7):2402-14. (PMID: 24550192); Bioinformatics. 2009 Apr 15;25(8):1091-3. (PMID: 19237447); J Biol Chem. 2002 Mar 15;277(11):9307-17. (PMID: 11748237); Nat Genet. 2003 Jul;34(3):267-73. (PMID: 12808457); Diabetes. 2014 Jul;63(7):2506-15. (PMID: 24595351); Transl Res. 2016 Feb;168:96-106.e1. (PMID: 26397425); Adv Immunol. 2008;100:79-124. (PMID: 19111164); Clin Transl Immunology. 2015 Aug 28;4(8):e41. (PMID: 26366287); J Immunol. 2013 Mar 1;190(5):2080-9. (PMID: 23345330); Med Res Rev. 2016 Jan;36(1):92-118. (PMID: 26010985); Cold Spring Harb Perspect Biol. 2010 Mar;2(3):a003350. (PMID: 20300215); J Immunol. 2008 Mar 1;180(5):3166-75. (PMID: 18292540); Biochem Pharmacol. 2008 Jun 1;75(11):2183-91. (PMID: 18455150); Physiol Rev. 2011 Jan;91(1):79-118. (PMID: 21248163); Diabetes. 2011 Mar;60(3):918-24. (PMID: 21270237); Science. 2006 Sep 29;313(5795):1929-35. (PMID: 17008526); Nat Immunol. 2008 Dec;9(12 ):1356-63. (PMID: 18931680); Genes Immun. 2013 Mar;14(2):67-82. (PMID: 23190644); Sci Transl Med. 2017 Feb 22;9(378):. (PMID: 28228602); Diabetes. 2014 Jul;63(7):2538-50. (PMID: 24561305); PLoS Biol. 2004 Jan;2(1):E9. (PMID: 14737187); Mol Cell Biochem. 2005 Jul;275(1-2):117-25. (PMID: 16335791); Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8560-5. (PMID: 7567975); Lancet. 2014 Jan 4;383(9911):69-82. (PMID: 23890997); Curr Opin Endocrinol Diabetes Obes. 2015 Aug;22(4):270-6. (PMID: 26087338); J Clin Invest. 2006 Apr;116(4):996-1004. (PMID: 16543950); Diabetes. 2008 Aug;57(8):2234-44. (PMID: 18477811); Curr Opin Immunol. 2013 Feb;25(1):4-12. (PMID: 23312890); Nat Genet. 2000 May;25(1):25-9. (PMID: 10802651); Biochem Biophys Res Commun. 2015 Oct 2;465(4):851-6. (PMID: 26319551); Nat Methods. 2015 May;12(5):453-7. (PMID: 25822800); J Immunol. 2009 Jun 15;182(12 ):7451-8. (PMID: 19494268); Diabetes Care. 2012 Dec;35(12):2515-20. (PMID: 23173134). Linking ISSN: 23793708. Subset: MEDLINE; Date of Electronic Publication: 2018 Mar 08. ; Original Imprints: Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- <br />