Genetic Effects on Age-Dependent Onset and Islet Cell Autoantibody Markers in Type 1 Diabetes

Abstract

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0 -34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P ‫؍‬ 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P ‫؍‬ 0.03) and with INS VNTR (P ‫؍‬ 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P ‫؍‬ 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P ‫؍‬ 0.04), and all four autoantibody markers (P ‫؍‬ 0.004). The CTLA-4 3 end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development. Diabetes 51: 1346 -1355, 2002

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

“…Data on the effect of the CTLA4 gene region on beta cell autoimmunity are similarly ambiguous. The CTLA4-3′(AT)n microsatellite and the +49A/G polymorphism showed no association with humoral autoimmunity in Swedish and Belgian cohorts, whereas IA-2A showed association with the G allele of the +49A/G polymorphism in a Japanese study [7,24,25].…”

“…An early study observed no association between the INS VNTR genotype and insulin-specific cellular and humoral autoimmunity [19], while class I alleles of the VNTR were found to contribute to the emergence of IAA in a larger case-control comparison [7]. It has also been suggested that the INS locus confers increased disease risk only in subjects with moderate-risk HLA genotypes [20].…”

“…Although cellular immunity is perceived to play a central role in the effector phase of islet destruction, a combination of humoral markers (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies [IA-2A]) has proved to be a useful tool for monitoring the development of islet autoimmunity and for prediction of progression to clinical disease [1][2][3][4]. Although the association of certain HLA haplotypes with the appearance of IAA, GADA and IA-2A seems to be consistent in various studies [5][6][7][8], it is still unclear at what stage of the autoimmune process the HLA genes exert their effect.…”

Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes

“…13 DISS2: HLA genotyping for DQB1, DQA1 and DRB1 was performed with PCR amplification followed by dot blot hybridizations and by restriction fragment length polymorphism as previously described, 13 except that allele-specific PCR amplification (PCR-SSP) of DRB1 alleles was also used. 40 BDD: A method based on an asymmetrical PCR and a subsequent hybridization of allele-specific probes was used, as described previously.…”

“…11 The HLA association to T1D is also known to vary with age at onset, such that the association is stronger in younger patients compared with older patients. 3,12,13 Genome-wide significant association to celiac disease has recently been reported for markers in the CIITA gene. 14 In addition, increased susceptibility to myocardial infarction (MI), rheumatoid arthritis (RA) and multiple sclerosis (MS) has been demonstrated for a polymorphism (rs3087456) in the 5 0 region of type III CIITA.…”