title: Improving prediction of type 1 diabetes by testing non-HLA genetic variants in addition to HLA markers.
abstract: OBJECTIVE
  The purpose of this study was to explore whether non-human leukocyte antigen (non-HLA) genetic markers can improve type 1 diabetes(T1D) prediction in a prospective cohort with high-risk HLA-DR,DQ genotypes.
  
  
  METHODS
  The Diabetes Autoimmunity Study in the Young (DAISY) follows prospectively for the development of T1D and islet autoimmunity (IA)children at increased genetic risk. A total of 1709 non-Hispanic White DAISY participants have been genotyped for 27 non-HLA single nucleotide polymorphisms (SNPs) and one microsatellite.
  
  
  RESULTS
  In multivariate analyses adjusting for family history and HLA-DR3/4 genotype, PTPN22 (rs2476601) and two UBASH3A (rs11203203 and rs9976767) SNPs were associated with development of IA [hazard ratio(HR)=1.87, 1.55, and 1.54, respectively, all p ≤ 0.003], while GLIS3 and IL2RA showed borderline association with development of IA. INS,UBASH3A, and IFIH1 were significantly associated with progression from IA to diabetes (HR=1.65, 1.44, and 1.47, respectively, all p ≤ 0.04), while PTPN22 and IL27 showed borderline association with progression from IA to diabetes. In survival analysis, 45% of general population DAISY children with PTPN22 rs2476601 TT or HLA-DR3/4 and UBASH3A rs11203203 AA developed diabetes by age 15, compared with 3% of children with all other genotypes (p<0.0001). Addition of non-HLA markers to HLA-DR3/4,DQ8 did not improve diabetes prediction in first-degree relatives.
  
  
  CONCLUSIONS
  Addition of PTPN22 and UBASH3A SNPs to HLA-DR,DQ genotyping can improve T1D risk prediction.
authors: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver (UCD), Aurora, CO, USA. andrea.steck@ucdenver.edu
authors: Andrea K
authors: AK
authors: Steck
authors: Fran
authors: F
authors: Dong
authors: Randall
authors: R
authors: Wong
authors: Alexandra
authors: A
authors: Fouts
authors: Edwin
authors: E
authors: Liu
authors: Jihane
authors: J
authors: Romanos
authors: Cisca
authors: C
authors: Wijmenga
authors: Jill M
authors: JM
authors: Norris
authors: Marian J
authors: MJ
authors: Rewers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D015551:Autoimmunity / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006680:HLA Antigens / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006680:HLA Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; C423262:UBASH3A protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: islet autoimmunity; non-HLA genetic markers; prediction; type 1 diabetes