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The purpose of this study was to test the hypothesis that glutamate cysteine ligase catalytic subunit (GCLC) promoter polymorphisms are susceptibility factors for type 1 diabetes (T1D), T1D age-at-onset and T1D autoantibodies. T1D patients and control subjects from the Swedish Childhood Diabetes Registry and the Swedish Diabetes Incidence Study registry were genotyped for two GCLC promoter polymorphisms; the GCLC -129 C to T single nucleotide polymorphism (GCLC -129 SNP) and the GCLC GAG trinucleotide repeat polymorphism (GCLC TNR). Glutamate decarboxylase antibody (GAD65Ab) positive T1D patients with the GCLC -129 SNP C/T genotype have increased GAD65Ab levels (p-value, <0.05) compared to the GCLC -129 SNP C/C genotype. T1D patients with an age-at-onset of 14-35 years who possess the GCLC -129 SNP T/T genotype have a higher GAD65Ab index than T1D patients with the GCLC -129 SNP C/C genotype (p-value <0.05). In addition, T1D patients with an age-at-onset of 14-35 years possess the GCLC TNR 7/8 genotype at a lower frequency than the control subjects (OR, 0.33, 95% CI, 0.13-0.82). The GCLC -129 SNP and GCLC TNR appear to be in linkage disequilibrium (p-value<0.0001). These results suggest that GCLC promoter polymorphisms may influence GAD65Ab levels and may influence the age at which T1D is diagnosed.

In type 1 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 [OR], 95% CI, 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, -5.1/5.1 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.

Aims/hypothesis: The HLA class II DQB1*0602 allele confers strong dominant protection against type 1 diabetes but protection is not absolute. The aim of this study was to identify markers within the HLA region that differentiate DQB1*0602 haplotypes and show different associations with disease risk., Methods: We defined alleles at eight microsatellite markers spanning the HLA region in a case-control cohort from Sweden., Results: We found that allele 15 at marker D6S265 (109 kb centromeric of HLA-A) was over-represented among patients carrying DRB1*15, DQB1*0602. A detailed haplotype analysis showed that DRB1*15, DQB1*0602 haplotypes carrying D6S265*15 have a ten-fold higher odds ratio (OR) than those carrying other alleles and thus confer reduced protection [OR D6S265*15=0.186 (95% CI 0.074, 0.472) vs OR D6S265*15-=0.017 (95% CI 0.005, 0.062), p<0.001]., Conclusions/interpretation: Our data support the existence of a locus that modifies the protective effect associated with DQB1*0602. Typing for allele D6S265*15 can identify a less protective DQB1*0602 haplotype, thereby allowing a more accurate prediction of type 1 diabetes risk.

Major histocompatibility complex (MHC) class I chain related gene-A (MIC-A) is associated with type 1 diabetes mellitus (T1DM) in other populations. We tested the association of MIC-A gene polymorphism with T1DM in Swedish Caucasians; if it has an age-dependent association; and if the association has an effect on gender. We studied 635 T1DM patients and 503 matched controls in the age group of 0-35 years old. MIC-A5 was significantly increased in T1DM compared with controls (odds ratio [OR] =1.81, p(c) < 0.0005). Logistic regression analysis revealed MIC-A5 association was independent of HLA. MIC-A5 with DR4-DQ8 or MIC-A5 with DR3-DQ2 gave higher OR than the OR obtained with either of them alone (OR = 1.81, 7.1, and 3.6, respectively). MIC-A5 was positively (OR = 2.48, p(c) < 0.0005) and MIC-A6 negatively associated (OR = 0.61, p(c) = 0.035) with the disease in < or = 20 years of age. The negative association of MIC-A6 in young onset was confirmed by logistic regression analysis. MIC-A5 was associated with the disease in males (OR = 2.05, p(c) = 0.0005). MIC-A6 conferred protection (OR = 0.098, p(c) = 0.032) in females heterozygous for DR3/DR4. In conclusion, MIC-A5 is associated with T1DM; the association was higher in individuals < or = 20 years old; and negative association of MIC-A6 was stronger in younger onset patients than in older onset patients.

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.