Differential HLA Association of GAD65 and IA2 Autoantibodies in North Indian Type 1 Diabetes Patients

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 ${}^{\ast }$ 03 was observed to be significantly higher in GADA+ T1D patients as compared to GADA– (91.41% vs. 66.13%, Bonferroni- $\text{corrected}P\left(P_{\text{c}}\right)=1.11\times {10}^{-5}$ ; $\text{OR}=5.45$ ; 95% CI: 2.67-11.08). Similarly, HLA-DQB1 ${}^{\ast }$ 02 was found to be significantly increased in GADA+ patients (94.53%, $P_{\text{c}}=2.19\times {10}^{-5}$ ; $\text{OR}=6.27$ ; 95% CI: 2.7-14.49) as compared to GADA– (73.39%). The frequencies of HLA-DRB1 ${}^{\ast }$ 04 and DQB1 ${}^{\ast }$ 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 ${}^{\ast }$ 03-DQB1 ${}^{\ast }$ 02 haplotype was found to be significantly increased in GADA+ T1D patients as compared to GADA- (60.55% vs. 41.94%, $P=3.94\times {10}^{-5}$ ; $\text{OR}=2.13$ ; $95\%\text{CI}=1.49$ -3.03). Similarly, HLA-DRB1 ${}^{\ast }$ 04-DQB1 ${}^{\ast }$ 03 haplotype was found to be significantly increased in IA2A+ T1D patients compared to IA2A– patients (22.5% vs. 12.97%; $P=0.041$ ; $\text{OR}=1.95$ ; $95\%\text{CI}=1.08$ -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 ${}^{\ast }$ 03/DQB1 ${}^{\ast }$ 02 and HLA-DRB1 ${}^{\ast }$ 04/DQB1 ${}^{\ast }$ 03 might play an important role in the development of GADA and IA2A, respectively.