title: Association of variants in HLA-DQA1-DQB1, PTPN22, INS, and CTLA4 with GAD autoantibodies and insulin secretion in nondiabetic adults of the Botnia Prospective Study.
abstract: OBJECTIVE
  Previously, we observed an association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. The aims of this study were to assess whether type 1 diabetes susceptibility gene variants explain this association and investigate the effect of the variants on insulin secretion and presence of glutamic acid decarboxylase autoantibodies (GADA) in nondiabetic adults.
  
  
  METHODS
  Polymorphisms in INS (rs689), PTPN22 (rs2476601), CTLA4 (rs3087243), and the HLA-DQA1-DQB1 regions (rs2187668 and rs7454108 tagging HLA-DQ2.5 and HLA-DQ8 respectively) were genotyped in the Botnia Prospective Study (n=2764), in which initially nondiabetic participants were followed for a mean of 8.1 years.
  
  
  RESULTS
  The variants did not explain the association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. In these nondiabetic adults, HLA-DQ AND PTPN22 risk genotypes were associated with GADA (HLA-DQ2.5/HLA-DQ8 or HLA-DQ8: OR (95% CI): 1.7 (1.3-2.3), P=0.0004; PTPN22 CT/TT: OR: 1.6 (1.2-2.2), P=0.003; P values were adjusted for sex, age, BMI, and follow-up time). A higher genetic risk score was associated with lower insulin secretion (insulinogenic index: 13.27 (16.27) vs 12.69 (15.27) vs 10.98 (13.06), P=0.02) and better insulin sensitivity index (risk score of 0-1 vs 2-3 vs 4-6: 142 (111) vs 144 (118) vs 157 (127), P=0.01) at baseline and a poorer capacity to compensate for the increased insulin demand after follow-up.
  
  
  CONCLUSIONS
  In nondiabetic adults, HLA-DQ2.5/HLA-DQ8 and PTPN22 CT/TT genotypes were associated with GADA.
authors.affiliation: Research Program for Molecular Medicine, Helsinki University and Department of Medicine, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Mette K
authors.initials: MK
authors.lastname: Andersen
authors.forename: Virve
authors.initials: V
authors.lastname: Lundgren
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
mesh_terms: D000483:Alleles; D001323:Autoantibodies / Q000032:analysis*; D060908:CTLA-4 Antigen / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology*; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008137:Longitudinal Studies; D008297:Male; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D007328:Insulin; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D005968:Glutamate Decarboxylase