Abstract
The human leucocyte antigen (HLA) association with type 1 diabetes (T1D) is well known but there are limited studies investigating the association between β-cell autoantibodies and HLA genes. We evaluated the prevalence of GAD65 and IA-2 autoantibodies (GADA and IA2A) in 252 T1D patients from North India and investigated the genetic association of GADA and IA2A with HLA class I and class II genes/haplotypes. GADA and IA2A were detected in 50.79% and 15.87% of T1D patients, respectively, while only 8.73% had both GADA and IA2A. HLA-DRB1∗03 was observed to be significantly higher in GADA+ T1D patients as compared to GADA– (91.41% vs. 66.13%, Bonferroni-corrected P (Pc) = 1.11 × 10−5; OR = 5.45; 95% CI: 2.67-11.08). Similarly, HLA-DQB1∗02 was found to be significantly increased in GADA+ patients (94.53%, Pc = 2.19 × 10−5; OR = 6.27; 95% CI: 2.7-14.49) as compared to GADA– (73.39%). The frequencies of HLA-DRB1∗04 and DQB1∗03 were increased in IA2A+ patients (45.0% and 52.5%, respectively) as compared to that in IA2A– (25.94% and 33.96%, respectively). Further, the frequency of DRB1∗03-DQB1∗02 haplotype was found to be significantly increased in GADA+ T1D patients as compared to GADA- (60.55% vs. 41.94%, P = 3.94 × 10−5; OR = 2.13; 95%CI = 1.49-3.03). Similarly, HLA-DRB1∗04-DQB1∗03 haplotype was found to be significantly increased in IA2A+ T1D patients compared to IA2A– patients (22.5% vs. 12.97%; P = 0.041; OR = 1.95; 95%CI = 1.08-3.52). None of the HLA class I genes (HLA-A, B, and Cw) was found to be associated with GADA or IA2A in people with T1D. Our findings suggest that HLA-DRB1∗03/DQB1∗02 and HLA-DRB1∗04/DQB1∗03 might play an important role in the development of GADA and IA2A, respectively.
Highlights
Type 1 diabetes (T1D) is a multifaceted autoimmune disorder, which is caused by immune-mediated destruction of insulin producing islet β-cells and is characterised by insulin deficiency and the presence of islet autoantibodies in the peripheral blood [1, 2]
Out of 252 T1D patients tested for the presence of autoantibodies against GAD65 (GADA) and tyrosine phosphatase-related islet antigen 2 (IA2A), Glutamic acid decarboxylase (GADA) was present in 128 (50.79%) patients while IA2A was detected in 40 patients (15.87%) (Table 1)
When we analysed the genotypic distribution of HLADRB1 genes in GADA+, GADA, IA2A+, and IA2A– people with T1D (Table 2), we observed a significant increase in the frequency of DRB1∗03/∗03 homozygote in GADA+ vs. GADA– patients (29.69% vs. 17.74%; P = 0:038; odds ratios (ORs) = 1:96; 95% confidence interval (CI): 1.08-3.54); the statistical significance was lost after Bonferroni correction (Pc = 0:228)
Summary
Type 1 diabetes (T1D) is a multifaceted autoimmune disorder, which is caused by immune-mediated destruction of insulin producing islet β-cells and is characterised by insulin deficiency and the presence of islet autoantibodies in the peripheral blood [1, 2]. T1D is strongly associated with Human Leukocyte Antigen (HLA) genes present on the humans’. HLA-DR2 (DRB1∗15:01DQA1∗01:02-DQB1∗06:02) haplotype was reported to be negatively associated with T1D [8,9,10,11]. Our previous studies on North Indian population have revealed a strong genetic association of HLA-DRB1∗03 allele and its haplotypes with T1D, while DRB1∗07, ∗11, ∗13, and ∗15 were found to be negatively associated [12, 13]. HLA-A∗02, A∗26, B∗08, and B∗50 at the class I locus were observed to be strongly associated with T1D but this association was suggested to be secondary because of linkage disequilibrium of these alleles with the HLA-DRB1∗03 gene [13, 14]
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