AIMS/HYPOTHESIS: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. SUBJECTS AND METHODS: We analysed the effect of HLA class II, insulin (INS; -23 HphI variant) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies [IA-2A]). Those who developed beta-cell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). RESULTS: IAA emerged at a higher rate in children with the -23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. CONCLUSIONS/ INTERPRETATION: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.
AIMS/HYPOTHESIS: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. SUBJECTS AND METHODS: We analysed the effect of HLA class II, insulin (INS; -23 HphI variant) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies [IA-2A]). Those who developed beta-cell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). RESULTS: IAA emerged at a higher rate in children with the -23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. CONCLUSIONS/ INTERPRETATION: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.
Authors: A Kupila; P Muona; T Simell; P Arvilommi; H Savolainen; A M Hämäläinen; S Korhonen; T Kimpimäki; M Sjöroos; J Ilonen; M Knip; O Simell Journal: Diabetologia Date: 2001-03 Impact factor: 10.122
Authors: H Donner; H Rau; P G Walfish; J Braun; T Siegmund; R Finke; J Herwig; K H Usadel; K Badenhoop Journal: J Clin Endocrinol Metab Date: 1997-01 Impact factor: 5.958
Authors: T Abe; H Takino; H Yamasaki; M Ozaki; Y Sera; H Kondo; H Sakamaki; E Kawasaki; T Awata; Y Yamaguchi; K Eguchi Journal: Diabetes Res Clin Pract Date: 1999-11 Impact factor: 5.602
Authors: Mikko Laaksonen; Tomi Pastinen; Minna Sjöroos; Satu Kuokkanen; Juhani Ruutiainen; Marja Liisa Sumelahti; Helena Reijonen; Reijo Salonen; Juhani Wikström; Martin Panelius; Jukka Partanen; Pentti J Tienari; Jorma Ilonen Journal: J Neuroimmunol Date: 2002-01 Impact factor: 3.478
Authors: E Sabbah; K Savola; P Kulmala; H Reijonen; R Veijola; P Vähäsalo; J Karjalainen; J Ilonen; H K Akerblom; M Knip Journal: Clin Exp Immunol Date: 1999-04 Impact factor: 4.330
Authors: S Genovese; R Bonfanti; E Bazzigaluppi; V Lampasona; E Benazzi; E Bosi; G Chiumello; E Bonifacio Journal: Diabetologia Date: 1996-10 Impact factor: 10.122
Authors: L B Nielsen; H B Mortensen; F Chiarelli; R Holl; P Swift; C de Beaufort; F Pociot; P Hougaard; S Gammeltoft; M Knip; L Hansen Journal: Diabetologia Date: 2005-11-23 Impact factor: 10.122
Authors: R Hermann; K Lipponen; M Kiviniemi; T Kakko; R Veijola; O Simell; M Knip; J Ilonen Journal: Diabetologia Date: 2006-04-14 Impact factor: 10.122
Authors: Johanna Lempainen; Robert Hermann; Riitta Veijola; Olli Simell; Mikael Knip; Jorma Ilonen Journal: Diabetes Date: 2012-02-22 Impact factor: 9.461
Authors: Andrea K Steck; Weiming Zhang; Teodorica L Bugawan; Katherine J Barriga; Alan Blair; Henry A Erlich; George S Eisenbarth; Jill M Norris; Marian J Rewers Journal: Diabetes Date: 2009-02-02 Impact factor: 9.461
Authors: Anna J Threlfall; Alisdair M Boag; Francesca Soutter; Barbara Glanemann; Harriet M Syme; Brian Catchpole Journal: Canine Genet Epidemiol Date: 2015-06-09