Class II HLA Genotype Association with First Phase Insulin Response Is Explained by Islet Autoantibodies (original) (raw)
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Diabetes, 2012
We assessed the effects of non-HLA gene polymorphisms on the risk of islet autoimmunity (IA) and progression to type 1 diabetes in the Diabetes Autoimmunity Study in the Young. A total of 1,743 non-Hispanic, white children were included: 861 first-degree relatives and 882 general population children identified as having high-risk HLA-DR/DQ genotypes for type 1 diabetes. Of those, 109 developed IA and 61 progressed to diabetes. Study participants were genotyped for 20 non-HLA polymorphisms, previously confirmed as type 1 diabetes susceptibility loci. PTPN22 and UBASH3A predicted both IA and diabetes in regression models controlling for family history of type 1 diabetes and presence of HLA-DR3/4-DQB1*0302 genotype. In addition, PTPN2 predicted IA whereas INS predicted type 1 diabetes. The final multivariate regression models for both IA and type 1 diabetes included PTPN22, UBASH3A, and INS, in addition to family history of type 1 diabetes and HLA-DR3/4. In general population children,...
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.
Diabetes Care
offspring or siblings of patients with type 1 diabetes. Participants were enrolled at birth and followed with type 1 diabetes-related autoantibody testing at age 9 months, at 2 years, and every 3 years thereafter. Those who became islet autoantibody-positive were subsequently followed six-monthly. A subgroup of 150 children participated in the BABYDIET dietary intervention study and had 3-monthly follow-up visits until the age of 3 years, and yearly thereafter (ClinicalTrials.gov Identifier: NCT01115621). The intervention (delay of exposure to gluten) failed to show an effect on islet autoimmunity or type 1 diabetes risk. After completion of the trial, participants were followed further in BABYDIAB/BABYDIET. Written informed consent was provided by participating families. BABYDIAB was approved by the Bavarian ethical committee (Bayerische Landesärztekammer; No. 95357) and the BABYDIET was approved by the ethics committee of the
Diabetologia, 2017
In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9-21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Altogether, 1550 children (21%) tested positive for at least one diabetes...
Diabetes Care, 2018
We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single-to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ,-A*24,-B*18, and-B*39 status. Genetic markers were determined by PCR sequence-specific oligotyping. RESULTS Unlike HLA-B*18 or-B*39, HLA-A*24 was associated with delayed progression from single-to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurred independently from older age (P < 0.001) and absence of HLA-DQ2/DQ8 or-DQ8 (P < 0.001 and P = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, HLA-A*24 was associated with accelerated progression from multiple-autoantibody positivity to clinical onset (P = 0.006), but its effects wererestricted to HLA-DQ8 + relatives with IA-2 or zinc transporter 8 autoantibodies (P = 0.002). HLA-B*18, but not-B*39, was also associated with more rapid progression, but only in HLA-DQ2 carriers with double positivity for GAD and insulin autoantibodies (P = 0.004). CONCLUSIONS HLA-A*24 predisposes to a delayed antigen spreading of humoral autoimmunity, whereas HLA-A*24 and-B*18 are associated with accelerated progression of advanced subclinical autoimmunity in distinct risk groups. The relation of these alleles to the underlying disease process requires further investigation. Their typing should be relevant for the preparation and interpretation of observational and interventional studies in asymptomatic type 1 diabetes.
Diabetologia, 2003
Aims/hypothesis. To assess the role of HLA-defined genetic diabetes susceptibility in the appearance of signs of beta-cell autoimmunity in a series of children derived from the general population. Methods. Tests for five HLA DQB1 alleles and four diabetes-associated autoantibodies were carried out on 1,584 older sibs of infants with an increased HLA-defined genetic risk of Type 1 diabetes. The DQB1 genotypes were classified into those conferring high (*02/0302), moderate (*0302/x; where x indicates *0302 or a non-defined allele), low (*0301/0302, *02/0301, *02/x, *0302/0602, *0302/0603; where x indicates *02 or a non-defined allele) or decreased risk (other genotypes). Results. Both islet cell antibodies (ICA) and GAD65 antibodies (GADA) were more frequent among the sibs with the high-risk genotype than among those with a low or decreased risk. Insulin autoantibodies and IA-2 antibodies (IA-2A) were more prevalent in the high-risk than low-risk sibs. Sibs with moderaterisk genotypes tested positive for ICA, GADA and IA-2A more often than sibs with genotypes conferring decreased risk. Autoantibody titres were also dependent on the genetic risk with high risk sibs having the highest values. Sibs carrying high-risk or moderaterisk genotypes tested positive for multiple antibodies (≥2) more often than did the sibs with low or decreased genetic risk. Conclusions/interpretation. The data show that HLAdefined susceptibility to Type 1 diabetes has an effect on both the quality and quantity of humoral beta-cell autoimmunity in unaffected children derived from the general population. [Diabetologia (2003) 46:65-70]
The Journal of Clinical Endocrinology & Metabolism, 2019
Context Characterization of slow progression to type 1 diabetes (T1D) may reveal novel means for prevention of T1D. Slow progressors might carry natural immunomodulators that delay β-cell destruction and mediate preservation of β-cell function. Objective To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D. Design HLA-susceptible children (n = 7410) were observed from birth for islet cell antibody (ICA), insulin autoantibody (IAA), glutamic acid decarboxylase (GADA), and islet antigen-2 autoantibodies (IA-2A), and for clinical T1D. Disease progression that lasted ≥7.26 years (slowest) quartile from initial seroconversion to diagnosis was considered slow. Autoantibody and genetic characteristics including 45 non-HLA single nucleotide polymorphisms (SNPs) predisposing to T1D were analyzed. Results By the end of 2015, 1528 children (21%) had tested autoantibody positive and 247 (16%) had progressed to T1D. The media...