High prevalence of humoral autoimmunity in first-degree relatives of Mexican type 1 diabetes patients (original) (raw)
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HLA-Class II in Latin American patients with type 1 diabetes
Autoimmunity Reviews, 2010
Objective: To identify and estimate the common effect size of HLA-Class II contributing to susceptibility on T1D in Latin America (LA) through a meta-analysis. Methods: A systematic review of the literature searching for all HLA-Class II alleles and susceptibility for T1D case-control studies performed in LA was made up to October 2009. Effect summary ORs and 95% CI were obtained by means of the random effect model. A prediction model that identifies peptides binding to HLA-DR alleles that were significantly associated with T1D throughout the meta-analysis was done. Results: 21 studies were included (1138 cases and 1920 controls). DRB1*0301 (OR: 9.65; 95% CI: 5.69-16.36; p b 0.0001), DRB1*1201 (OR: 4.84; 95% CI: 1.97-11.91; p = 0.001), DQB1*0302 (OR: 4.58; 95% CI: 3.36-6.26; p b 0.0001), DQA1*0301(OR: 3.02; 95% CI: 1.37-6.65; p = 0.0059) and DQB1*0602 (OR: 0.19; 95% CI: 0.11-0.33; p b 0.0001), DRB1*14 (OR: 0.18; 95% CI: 0.06-0.55; p = 0.0024), and DQB1*0501 (OR: 0.47; 95% CI: 0.26-0.83; p = 0.0097) were the most significant alleles associated with T1D. DRB1*0301-DQA1*0501-DQB1*0201 (OR: 13.50; 95% CI: 3.85-47.28; p b 0.0001) and DRB1*1301-DQB1*0603 (OR: 0.25; 95% CI: 0.1-0.65; p = 0.004) were the most significant risk and protective haplotypes associated, respectively. There were peptides binding to significantly HLA-DRB1 alleles and haplotypes found through the meta-analysis from islet cell protein tyrosine phosphatase and glutamic acid decarboxylase. Conclusions: These results strengthen the effect of HLA-Class II on T1D in LA similar to Caucasians regardless of the latitudinal gradient and admixture. The shared chemical characteristics in critical pockets could explain the predisposition to present a "diabetogenic peptide" to T cells in this population.
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.
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.
ANALYSIS OF HLA HAPLOTYPES IN FAMILIES WITH TYPE 1 DIABETES MELLITUS IN LA R�UNION ISLAND
European Journal of Immunogenetics, 1996
To analyse HLA and insulin-dependent diabetes mellitus (IDDM) association in the ethnically mixed population of La RCunion island, we carried out a family study on 70 diabetic subjects. HLA-DQAI, -DQB 1 and -DRB 1 typing was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), completed by PCRsequence-specific oligonucleotide (SSO) and PCR-sequence-specific priming (SSP). Haplotype-relative risks (HRR) were determined with the non-transmitted parental haplotypes as controls, and relative risks (RR) were calculated with a classical case-control study. The most significant risks were found for the cis and trans combinations between DQA1*03 or *0501 (Arg52') and DQB1*02 or *0302 (Asp57-) alleles, suggesting a direct role for the HLA-DQ heterodimer in IDDM susceptibility. Interestingly, due to the mixed origin of the population, the trans-encoded DQ molecules in the (DR3)-DQAl*O50 I -DQB 1*02/(DR4)-DQA1*03-DQB 1 *0302 subjects were also found cisencoded in patients with the (DR7 or 9)-DQA1*03-DQB1*02 haplotype and in a patient with the rare (DRI I)-DQA1*0501-DQB 1 *0302 haplotype. A relative predispositional effect (RPE) analysis gave significant haplotype-IDDM+ associations in the following order: (DR3)-DQAl*O5Ol-DQBl*O2 >(DR4)-DQAl*03-DQB1*0302> (DR9)-DQA1*03-DQB*02>(DR7)-DQA1*03-DQB1*02~(DR2)-DQAl*O1-DQB1*0502. No protective effect remained significant once the susceptible haplotypes were removed. A stratification study showed a stronger influence of the DQ genes than DRBl alleles within the DR7 haplotypes. On the other hand, IDDM subjects with only one susceptible haplotype had inherited this haplotype more often from their father than from their mother. This paternal effect could be related to the greater risk of IDDM in offspring of diabetic fathers than the risk in offspring of diabetic mothers.
2010
As part of a genetic study of type 1 diabetes in Mexican-Americans, 360 first-degree relatives of 108 type 1 diabetic probands were studied. Islet cell antibody (ICA), insulin autoantibody, glutamic acid decarboxylase (GAD 65 ), and protein tyrosine phosphatase autoantibodies were measured and human leucocyte antigen (HLA) class II alleles DRB1 and DQB1 genotyping was performed. ICA was positive in 37% of the probands and 5.8% of the relatives. A subgroup of 26 probands (12 ICA؉, 14 ICA؊) was tested for GAD 65 and was found positive. 4/14 ICA؉ first-degree relatives were GAD 65 positive. Four relatives, positive for two antibodies, subsequently developed type 1 diabetes. Life-Table analysis of first-degree relatives with autoantibodies indicated an 80% disease-free survival at 3.5 yr. HLA-DRB1 was found to be associated with the presence of ICA in both probands and relatives, whereas HLA-DPB1 was associated with autoantibody in relatives of type 1 diabetic probands.
Diabetes Care, 2004
OBJECTIVE—To assess possible differences in the frequency of HLA-DQB1 risk genotypes and the emergence of signs of β-cell autoimmunity among three geographical regions in Finland. RESEARCH DESIGN AND METHODS—The series comprised 4,642 children with increased HLA-DQB1–defined genetic risk of type 1 diabetes from the Diabetes Prediction and Prevention (DIPP) study: 1,793 (38.6%) born in Turku, 1,646 (35.5%) in Oulu, and 1,203 (25.9%) in Tampere. These children were examined frequently for the emergence of signs of β-cell autoimmunity, for the primary screening of which islet cell antibodies (ICA) were used. If the child developed ICA, all samples were also analyzed for insulin autoantibodies (IAA), GAD65 antibodies (GADA), and antibodies to the IA-2 molecule (IA-2A). RESULTS—The high- and moderate-risk genotypes were unevenly distributed among the three areas (P < 0.001); the high-risk genotype was less frequent in the Oulu region (20.4%) than in the Turku (28.4%; P < 0.001) or ...
American Journal of Epidemiology, 2001
The human leukocyte antigen (HLA) system plays a crucial role in the autoimmune process leading to childhood diabetes. The purpose of this study was to evaluate the association between type 1 diabetes and the polymorphism encoded by the HLA-DQB1 gene by using case-parents trios. The study area was the metropolitan region of Santiago, Chile, and cases were ascertained from March 1997 to August 1998. Genotyping was performed in 94 trios comprising incident cases less than 17 years of age at the time of diagnosis and their parents. The transmission/disequilibrium test was used to detect differential transmission in the HLA-DQB1 locus. The authors found that alleles DQB1*0302 and DQB1*0201 were strongly associated with the disease. By using 1:3 matched sets of cases-pseudosibs and conditional logistic regression models, allelic relative risks were estimated for DQB1*0302 (r = 7.2, 95% confidence interval: 2.8, 18.5) and DQB1*0201 (r = 4.7, 95% confidence interval: 1.9, 11.6); DQB1*0301 was considered the baseline allele. When case-parents trios were used, alleles DQB1*0302 and DQB1*0201 were strongly associated with a higher risk of type 1 diabetes in the population of Santiago. Am J Epidemiol 2001;153:794-8.