Autoantibodies to islet antigen-2 are associated with HLA-DRB107 and DRB109 haplotypes as well as DRB1*04 at onset of type 1 diabetes: the possible role of HLA-DQA in autoimmunity to IA-2 (original) (raw)
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HLA‐DR‐DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity
Pediatric Diabetes, 2020
We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity. Methods: Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A) and zinc transporter 8 (ZnT8A) and genotyped for HLA DR/DQ alleles. In the DIPP study autoantibodies were regularly analyzed from birth up to 15 years of age. Results: In the DIPP cohort 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268 and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR. Conclusions: These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response.
Clinical and Vaccine …, 2011
The frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age-and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in the DRB1*030101 allele (P < 0.001), together with the DRB1*030101/DQB1*0201 (P < 0.001) and DRB1*040101/DQB1*0302 (P ؍ 0.002) haplotypes, while lower anti-GAD titers were associated with the DRB1*070101 (P ؍ 0.001) and DRB1*110101 (P < 0.001) alleles and DRB1*070101/DQB1*0201 (P ؍ 0.001) and DRB1*110101/DQB1*030101 (P ؍ 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in the DRB1*040101 allele (P ؍ 0.007) and DRB1*040101/DQB1*0302 (P ؍ 0.001) haplotypes but were lower in the DRB1*110101 allele (P ؍ 0.010) and the DRB1*110101 (P < 0.001) and DRB1*110101/DQB1*030101 (P ؍ 0.025) haplotypes. Multinomial regression analysis confirmed the positive association of DRB1*030101 and the negative association of DRB1*110101 and DQB1*030101, along with the DRB1*070101/DQB1*0201 and DRB1*110101/DQB1*030101 haplotypes, with anti-GAD levels. In contrast, only the DRB1*040101/DQB1*0302 haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D.
Diabetologia, 1993
Demographic and biological data were collected from all Caucasian Type 1 diabetic patients (n = 279) who were recruited at clinical onset by the Belgian Diabetes Registry over 34 months. The male/female ratio was significantly higher for onset between age 20 and 40 years (2.4) than before age 20years (1.0); no age-or sex-differences were noticed in serum fructosamine concentration. Total and high concentrations of insulin autoantibodies and islet cell antibodies were preferentially associated with the HLA DQAI*0301-DQBI*0302 susceptibility haplotype. The occurrence of both types of antibodies was also correlated, irrespective of haplotype. At onset before age 10 years, the high risk genotype DQAI*0301-DQBI*0302/DQAI*0501-DQBI*0201 was more prevalent than all other DQA1-DQB1 genotypes taken together, leading to a higher prevalence of the DQAI*0301-DQBI*0302 haplotype in this age group (75 %) than in the 10-39 years age group (54 %). Under age 10years, the presence of DQAI*0301-DQBI*0302 was strongly associated with insulin autoantibodies (90 %) and islet cell autoantibodies (92 % with 85 % of high titre), whereas patients without this haplotype were less frequently positive for insulin autoantibodies (31%) or islet cell autoantibodies (38 % high titre). In the group with onset at age 10.39years, the DQAI*0301-DQBI*0302 haplotype presented a lower association with insulin autoantibodies (-40 %) and islet cell autoantibodies (50 to 65 % high titre), prevalences which no longer differed from those in subjects lacking this haplotype. The present data demonstrate that variations in prevalence of insulin autoantibodies and islet cell autoantibodies at onset of Type 1 diabetes can result from differences in age and in the fraction of patients with the HLA DQAI*0301-DQBI*0302 haplotype. The presence of this susceptibility haplotype at onset under age 10 years identifies a sub-group of patients with more than 90% positivity for insulin autoantibodies and more than 90 % positivity for islet cell autoantibodies. It is conceivable that this sub-group can be recognized in the pre-diabetic phase through screening for immunological and genetic markers.
Clinical and Experimental Immunology, 1999
The possible relation between HLA-DQ genotypes and both frequencies and levels of autoantibodies associated with IDDM was assessed by examining HLA-DQB1 alleles and antibodies to islet cells (ICA), insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphataserelated IA-2 molecule (IA-2A) in 631 newly diagnosed diabetic children under the age of 15 years. ICA were found in 530 children (84•0%), while close to half of the subjects (n ¼ 307; 48•7%) tested positive for IAA. GADA were detected in 461 index cases (73•1%), with a higher frequency in those older than 10 years (78•9% versus 69•2% in the younger ones; P ¼ 0•006). More than 85% of the children (n ¼ 541; 85•7%) tested positive for IA-2A. Altogether there were only 11 children (1•7%) who had no detectable autoantibodies at diagnosis. There were no differences in the prevalence of ICA or GADA between four groups formed according to their HLA-DQB1 genotype (DQB1*0302/02, *0302/X (X ¼ other than *02), *02/Y (Y ¼ other than *0302) and other DQB1 genotypes). The children with the *0302/X genotype had a higher frequency of IA-2A and IAA than those carrying the *02/Y genotype (93•8% versus 67•3%, P < 0•001; and 49•0% versus 33•6%, P ¼ 0•002, respectively). The children with the *02/ Y genotype had the highest GADA levels (median 36•2 relative units (RU) versus 14•9 RU in those with *0302/X; P ¼ 0•005). Serum levels of IA-2A and IAA were increased among subjects carrying the *0302/X genotype (median 76•1 RU versus 1•6 RU, P ¼ 0•001; and 50 nU/ml versus 36 nU/ml, P ¼ 0•004) compared with those positive for *02/Y. Only three out of 11 subjects homozygous for *02 (27•3%) tested positive for IA-2A, and they had particularly low IA-2A (median 0•23 RU versus 47•6 RU in the other subjects; P < 0•001). The distribution of HLA-DQB1 genotypes among autoantibody-negative children was similar to that in the other patients. These results show that DQB1*0302, the most important single IDDM susceptibility allele, is associated with a strong antibody response to IA-2 and insulin, while GAD-specific humoral autoimmunity is linked to the *02 allele, in common with a series of other autoimmune diseases as well as IDDM. We suggest that IA-2A may represent b cell-specific autoimmunity, while GADA may represent a propensity to general autoimmunity. Keywords insulin-dependent diabetes mellitus HLA-DQB1 islet cell antibodies insulin autoantibodies antibodies to the 65-kD isoform of glutamic acid decarboxylase antibodies to the protein tyrosine phosphatase-related IA-2 antigen ᭧ 1999 Blackwell Science ¶The members of the Childhood Diabetes in Finland Study Group are listed in the Acknowledgements.
Immunogenetics of HLA class II in Israeli patients with adult-onset Type 1 diabetes mellitus
Human Immunology, 2007
The distribution of HLA class II alleles and genotypes in Israelis of different ethnic origin with adult-onset type 1 diabetes (T1D) was examined. The results were compared with published findings in healthy Israelis and childhood-onset T1D Israelis. An additional comparison was made between subgroups of patients with rapidly and slowly progressive adult-onset T1D (LADA). A DNA-based low-resolution analysis was performed for DRB1* and DQB1* alleles and a high-resolution analysis for DRB1*04 and DQB1*1 alleles. In all, 87% of the study group was positive for DRB1*03 or DRB1*04 compared with 36% of the healthy controls. The main alleles accounting for susceptibility to T1D were DRB1*0402, found in 77.9% of carriers of DRB1*04 and DQB1*0302, found in 74.6% of carriers of DQB1*03.
The Journal of clinical endocrinology and metabolism, 2017
A declining first phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes (T1D). It is not known whether reduced FPIR depends on class II HLA type, islet autoimmunity, or both. To dissect the role of class II HLA genotypes and biochemical islet autoantibodies in the compromised FPIR. A total of 438 HLA DR-DQ genotyped children in the prospective Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests (IVGTT) and categorized by their class II HLA genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. The associations between class II HLA genotype, islet autoantibody status and FPIR. A strong association between the degree of risk conferred by class II HLA genotype and positivity for islet autoantibodies existed (P<0...
Annals of the New York Academy of Sciences, 2004
The HLA DQB1 * 0302 allele on DR4 haplotypes is a well-known marker for T1D susceptibility. The contribution of this DQ molecule to overall disease susceptibility may be genotype dependent. On Asian DR4 haplotypes, not only DQB1 * 0302, but also DQB1 * 0401 confer susceptibility to T1D, which is mediated by DRB1 * 0405 on the same haplotype. To analyze further the association of DQB1 * 0302 and DQB1 * 0401 haplotypes in Asian patients with T1D, we investigated HLA DR and DQ alleles with the presence or the persistence of GAD, ICA, and IA-2 autoantibodies in 121 Korean T1D patients. In Korean patients, there was an association of IA-2 autoantibodies with DR4 as well as DR3, but not with DQA1 * 0301-DQB1 * 0302. GAD autoantibodies were not associated with the DR3-DQB1 * 0201, DQA1 * 0301-DQB1 * 0302, or DR4. In this low-risk population, autoantibodies to islet-cell antigens were associated with different HLA molecules. In different populations, the immune response to different  cell autoantigens is mediated via varying HLA class II molecules from different loci. Design of the antigen-specific immunointervention trials should take into account such HLA DR and DQ association.
HLA-DR, DQ and anti-GAD antibodies in first degree relatives of type I diabetes mellitus
Diabetes Research and Clinical Practice, 1996
The differential antibody response to glutamic acid decarboxylase (anti-GAD) and to islet cell cytoplasm (ICA) according to HLA-DR and DQ genotypes were examined in 28 Spanish patients with Type I diabetes mellitus (11.1 _+ 10,4 year diabetes duration) and their 41 first degree non-diabetic relatives. Anti-GAD was detected by radioimmunoprecipitation and ICA by indirect immunofluorescence and HLA-DR/DQ alleles were assigned by PCR and sequence specific oligonucleotide probes. The frequency in patients of positivity for ICA was 7.1% and of anti-GAD + 64.3%, and in relatives, the frequency of ICA ~ was 4.9%, and anti-GAD 4 9.8%. Concurrent positivity for ICA and anti-GAD existed in only one patient, and in none of the relatives. We confirm for a Spanish population the high frequency of risk genotypes t\~r Type 1. involving DR3, DR4 and DQBI*0302 (DQS), which were present in 26 of 28 (93%) patients and 32 of 41 (78%) relatives. The most frequent genotypes were DR3/DQB1 *0201/DQA 1 *0501-DR4/DQB 1 *0302/DQA 1"0301 (9 patients, 32%; 6 relatives, 15%), DR3/DQBl*0201 / DQA 1 *0501-DR3/DQB 1 "0201/DQA 1 '0501 (5 patients, 18%; 7 relatives, 17%) and DR3/DQB 1 *0201/DQA 1 *050 I-DRI/DQBI*0501/DQAI*0101(5 patients, 18%; 1 relative, 2%), Positivity for anti-GAD or for ICA did not correlate with gender, or age at onset or duration of DM. The distribution of high risk HLA genotypes were similar regardless the anti-GAD or anti-ICA status either in patients or in their relatives.
HLA-DR, HLA-DQ Haplotypes and Diabetic Autoantibodies in Nondiabetic Siblings of Type I Diabetes
Journal of Diabetes & Metabolism, 2015
The screening of non-diabetic siblings of Saudi type 1 diabetes mellitus (T1DM) patients (n=54) and 50 healthy controls was undertaken for glutamic acid decarboxylase (anti-GAD) and antibodies to tyrosine phosphatse (IA-2) using radioimmunoprecipitation. HLA-DRB1, DQB1 and DQA1 alleles were tested by PCR and sequence-specific oligonucleotide probes. HLA analysis showed that susceptible alleles were DRB1*03:01 (61.1%) *04:01 (22.02%), DQA1*05:01 (61.1%), DQA1*03:03 (33.3%) and DQB1*02:01 (72.2%). The DRB1*03:01-DQA1*05:01-DQB1*02:01 haplotype was significantly higher among siblings (61%). The protective alleles were DRB1*04:03 (1.8%), DRB1*13 (11.1%), DQA1*02:01 (5.6%), DQA1*05:05 (5.6%), DQB1*03:01 (5.6%) and DQB1*05:01 (11.1%). GADA (22.2%) and anti-IA-2 (11.1%) were significantly higher among siblings, both antibodies present in 27.8% of siblings. The frequency of GADA was higher in those aged 5 to 10 years (50%), while IA-2 positive children were > 5years old (100%). 36.4 % of DRB1*03:01-DQA1*05:01-DQB1*02:01 sibling were positive for GADA, 18.2% were positive for IA-2 and 9.1% were positive for both antibodies. 27.8% of siblings were HLA-identical to the proband, 61.1% were haploidentical, and 11.1% were not identical. GADA was significantly higher among the HLA-identical siblings (60%) than haploidentical (9.1%) and non-identical siblings (zero). IA-2 was higher in HLA-identical (20%) from haploidentical (9.1%) and non-identical HLA (zero) but not to significant level. Both antibodies were present in 20% of HLA-identical siblings, and in none of the haplo-or non-identical HLA. In conclusion, the immunogenetic screening of nondiabetic sibling identifies individuals at risk of developing T1DM.