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- Graham, Jinko, et al.
(author)
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Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset
- 1999
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In: European Journal of Immunogenetics. - : Wiley. - 0960-7420 .- 1365-2370. ; 26, s. 117-
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Journal article (peer-reviewed)abstract
- HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201-A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype ether than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.
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| 2. |
- Gupta, Manu, et al.
(author)
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MHC class I chain-related gene-A is associated with IA2 and IAA but not GAD in Swedish type 1 diabetes mellitus
- 2006
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In: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1079, s. 229-239
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Journal article (peer-reviewed)abstract
- In type I diabetes mellitus (T1DM), the frequency of antibodies against insulin (IAA), glutamic acid decarboxylase-65 (GAD65), ICA512/IA2 (IA2), and islet cell antigens (ICA) vary with human leukocyte antigen (HLA) composition of the patient. IAA, IA2 autoantibodies, and ICA are increased in DQ8 positives; GAD65 antibodies are increased in DQ2 positives. MHC class I chain-related gene-A (MICA) is another genetic marker that has been proposed to be associated with T1DM. In this article, we looked at microsatellite polymorphism of MICA and its association with autoantibodies (IAA, IA2, and GAD65) in Swedish T1DM patients and if the association explains its importance in early events in autoimmune response. We studied 635 T1DM patients between 0-35 years. Frequency of MICA5/5 was positively associated with the formation of IAA and IA2 antibodies considered individually or in combination (odds ratio 10111, 95% Cl, Pc: [IAA+ versus IAA-] : 4.94, 2.09-11.62, < 0.0005; [IA2+ versus IA2-] : 2.65,1.52-4.59,0.0015; [IAA and/or IA2+ versus rest]: 9.83, 2.37-40.78, < 0.0015; [IAA and IA2+ versus rest]: 3.51, 2.01-6.15, < 0.0015). Also, -5.115.1 was increased in IAA+ patients compared to IAA- patients (2.82, 1.64-4.83, < 0.0005). All patients positive for -5/5 developed at least one of the three antibodies. Frequency of MICA5.1 was decreased in IAA+ (0.54, 0.36-0.81, 0.017), in IA2A+ (0.63, 0.45-0.88, 0.04), in IAA and/or IA2A+ (0.52, 0.33-0.84, 0.044), and in IAA and IA2A+ (0.55, 0.39-0.78, 0.0055) patients when compared with patients negative for corresponding antibodies. Frequency of MICA9, 5/5.1, and 5.1/9 was decreased in IAA+ compared to IAA- patients (0.51, 0.32-0.79,0.021; 0.22, 0.11-0.44, < 0.005; and 0.39, 0.22-0.69, 0.026, respectively). Frequency of MICA9 and -5.1/9 was also decreased in IAA and/or IA2 antibody-positive patients while MICA5/5.1 decreased in patients positive for IAA and IA2 antibody both together. IAA and IA2 antibodies are believed to appear early during the autoimmune reaction against beta cells. Thus, according to our data, MICA-5/5 and -5.1/5.1 is associated with early autoimmunity in T1DM patients. Our study suggests that MICA gene polymorphism is associated with autoantibody formation and that the polymorphism especially MICA5/5 and -5.1/5.1 are important in early events of autoimmune reaction.
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