Progression to type 1 diabetes and autoantibody positivity in relation to HLA-risk genotypes in children participating in the ABIS study

Background:  Autoantibodies against beta-cell antigens together with human leukocyte antigen (HLA)-risk genotypes are used as predictive markers for type 1 diabetes (T1D). In this study, we have investigated the role of HLA-risk and -protective genotypes for development of beta-cell autoantibodies and progression to T1D in healthy children.
Methods:  T1D-related HLA genotypes and autoantibodies against glutamic acid decarboxylase [glutamic acid decarboxylase antibodies (GADA)] and islet antigen-2 (IA-2A) were studied at 1, 2.5 and 5 yr of age in unselected healthy children and children with T1D participating in the All Babies In Southeast Sweden (ABIS) study.
Results:  GADA or IA-2A positivity at 5 yr of age was associated with DR4-DQ8 haplotype and DR3-DQ2/DR4-DQ8 genotype. By the age of 6–7 yr, we identified 32 children with T1D among the 17 055 participants in the ABIS study. Eight of 2329 (0.3%) non-diabetic children had permanent autoantibodies, and 143 of 2329 (6%) children had transient autoantibodies. HLA-risk genotypes associated with T1D, whereas protective genotypes were seldom found in children with T1D. Children with permanent autoantibodies had more often risk-associated DR4-DQ8 haplotype than autoantibody-negative children. No associations with HLA-risk or -protective genotypes were found for transient autoantibodies.
Conclusions:  The strong relation between HLA-risk alleles and T1D once again confirmed that HLA-risk genotypes play an important role for development of T1D. However, HLA genotypes seem not to explain induction of autoantibodies, especially transient autoantibodies, in the general population, emphasizing the role of environmental factors in the initiation of autoimmunity. It seems that HLA-risk genotypes are responsible for maturation of the permanent autoantibody response.     

Does the relative risk for type 1 diabetes conferred by HLA‐DQ,INS, and PTPN22 polymorphisms vary with maternal age,birth weight,or cesarean section?

Stene LC, Rønningen KS, Undlien DE, Joner G. Does the relative risk for type 1 diabetes conferred by HLA‐DQ, INS, and PTPN22 polymorphisms vary with maternal age, birth weight, or cesarean section? Background and objective: Maternal age at birth, birth weight, and cesarean section has been associated with a weak but significant increase in risk of type 1 diabetes. The objective was to assess whether the relative risk for type 1 diabetes conferred by established susceptibility loci human leukocyte antigen (HLA)‐DQ, INS, and PTPN22 differed depending on these perinatal factors. Methods: We employed a case–control study with 456 cases of type 1 diabetes diagnosed before 15 yr of age and 1377 population‐based control children. HLA genotypes were divided into high to moderate risk (DQ8/DQ2, DQ8/DQ8, DQ8/X, DQ2/DQ2) vs. all other genotypes. Case‐only analysis using logistic regression was used to test for significant interaction. Results: There was no significant difference in the relative risks conferred by HLA‐DQ, INS, or PTPN22 by maternal age, birth weight, or mode of delivery, except the relative risk conferred by PTPN22 which was 2.11 [95% confidence interval (CI): 1.64–2.72] for those born vaginally and 0.99 (95% CI: 0.50–1.99) for those born by cesarean section [p(interaction) = 0.028]. Conclusion: The relative risks conferred by the three established susceptibility genes investigated here were independent of the perinatal factors, apart from a possible interaction between PTPN22 and mode of delivery.     

Newborn HLA-DR,DQ genotype screening: age- and ethnicity-specific type 1 diabetes risk estimates

OBJECTIVE: Certain human leukocyte antigen (HLA)-DR,DQ genotypes have been associated with type 1 diabetes mellitus (T1DM) risk, although it is unknown whether the association is due to alleles, haplotypes, genotypes, the formation of heterodimers, or all of the above. To characterize the role of the HLA-DR,DQ genotype and ethnicity on the onset age of T1DM, we analyzed these factors in patients with T1DM and the general population. METHODS: One thousand three hundred twenty-two well-characterized patients with T1DM were compared with 3339 children from the general population of Denver, Colorado, USA. Because of the extensive available data across age and ethnic groups, this study population is unique. RESULTS: The HLA-DR3/4,DQB1*0302, DRX/4,DQB1*0302 (where X=1, 4, 8, and 9), and HLA--DR3/3 genotypes were associated with T1DM, supporting previous research. Additionally, the DR3/9 genotype showed a positive association with T1DM, which has not previously been described in Caucasian populations. The HLA-DR3/4*0302 genotype was most strongly associated with T1DM in diabetic individuals with the youngest onset age. Genotype frequencies were similar between Hispanics and non-Hispanic whites, except for the DR3/3 genotype, which was more likely to be found in non-Hispanic whites. CONCLUSIONS: These results indicate that there are multiple alleles and genotypes associated with T1DM and that the risk associated with different genetic markers depends on the age of disease onset, suggesting that some markers may be involved in more rapid disease progression.     

HLA A Class II (DR, DQ) in Japanese Patients with Type 1 Diabetes Mellitus

DNA restriction fragment length polymorphism (RFLP) typing of HLA-DR and DQ alleles of 60 Japanese type 1 (insulin dependent) diabetic patients and 115 controls was performed. RFLP typing of DRB1 showed increased frequency of DR9 and decreased frequencies of DR2 and DRW6 among patients compared to controls. In the RFLP typing of BamHI- digested DNA to DQ β probe (BamHI-DQB1), the incidence of the 10.26 kb fragment, which represents either DQW4, DQW8 or DQW9, was markedly elevated in the patients, whereas the incidence of DQW6 was reduced. The predicted DR-DQ haplotype study revealed that DR4-DQW4 or DQW8, DRW8-DQW4 or DQW8 and DR9-DQW9 may contribute to susceptibility to type 1 diabetes. When serological typing of the 13 DRW8 patients was performed, all the 11 DRW8 patients carrying DQW4 or DQW8 (BamHI-10.26 kb) were positive for DQW3.
These results indicated that the HLA-DQ locus may play an important role in the development of type 1 diabetes in the Japanese as well as other ethnic groups and that the DRW8- DQW8 haplotype may predispose to the disease in Japan.     

Cutaneous microvascular dysfunction is associated with human leukocyte antigen-DQ in youths with type 1 diabetes

Functional disturbances in microcirculation in juvenile type 1 diabetes (T1D) are believed to underlie, in part, the later occurrence of cardiovascular complications. Some epidemiologic studies suggested greater risk of microvascular complications in those with T1D-risk genotypes of human leukocyte antigen (HLA). We investigated whether HLA-DQ2/8, which is linked to highest T1D morbidity, influences microvascular function in young diabetic patients. Cutaneous microvascular endothelium-dependent and independent reactivity and HLA genotypes were assessed in young patients (age: 9-21 y) with T1D (duration: 2-20 y). HLA-DQ2/8 was identified in 29 of 75 patients. The DQ2/8 and non-DQ2/8 groups were similar in age, body mass index, diabetes duration, glycosylated hemoglobin, and C-reactive protein (CRP). Compared with the non-DQ2/8 group, the DQ2/8 group showed decreased endothelium-dependent responses (p = 0.03 after adjustment for age, diabetes duration, glycosylated hemoglobin, and CRP) and elevated soluble intercellular adhesion molecule-1 (p = 0.05). In these but not in non-DQ2/8 patients, CRP correlated with both systolic (r = 0.76; p < 0.001) and diastolic (r = 0.50; p = 0.01) blood pressure. HLA-DQ2/8 is associated with endothelial microvascular dysfunction in young patients with T1D, and future studies are needed to provide mechanistic insights. The findings could explain in part the previously reported epidemiologic link between T1D-risk HLA and microvascular complications.     

The importance of CTLA-4 polymorphism and human leukocyte antigen genotype for the induction of diabetes-associated cytokine response in healthy school children

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease associated with the destruction of pancreatic beta cells and genetically linked to human leukocyte antigen (HLA) class II DR3-DQ2 and DR4-DQ8 haplotypes. The +49A/G polymorphism of the immunoregulatory cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is also associated with T1D. Genetic and environmental risk factors precede the onset of T1D, which is characterized by a T helper 1 cell-dominating cytokine response to diabetes-related autoantigens. AIM: To investigate immunological differences between healthy children with and without CTLA-4 +49A/G and HLA genetic susceptibility for T1D. STUDY DESIGN: Young, 7-15 years of age, healthy subjects (n = 58) were investigated to test whether CTLA-4 +49A/G genotype was associated with enzyme-linked immunospot assay T-cell responses to T1D-related autoantigens. Because T1D is primarily HLA-DQ associated, we stratified the healthy subjects by HLA genotypes associated with the disease. RESULTS: Peptide of heat shock protein 60 induced a higher interferon-gamma (IFN-gamma) response in subjects with risk-associated CTLA-4 polymorphism (GG genotype) (p = 0.02) while glutamic acid decarboxylase 65-induced interleukin-4 (IL-4) secretion was lower in GG genotype subjects (p = 0.02). CONCLUSION: The increased IFN-gamma response and lower IL-4 response toward diabetes-related autoantigens shown in CTLA-4 +49 GG risk subjects show a possible mechanism for the association between CTLA-4 and T1D.     

Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention

Type 1 diabetes mellitus (T1DM) is the archetypal example of a T cell‐mediated autoimmune disease characterized by selective destruction of pancreatic β cells. The pathogenic equation for T1DM presents a complex interrelation of genetic and environmental factors, most of which have yet to be identified. On the basis of observed familial aggregation of T1DM, it is certain that there is a decided heritable genetic susceptibility for developing T1DM. The well‐known association of T1DM with certain human histocompatibility leukocyte antigen (HLA) alleles of the major histocompatibility complex (MHC) was a major step toward understanding the role of inheritance in T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (e.g., HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03‐DQB1*0201 (DR3/DQ2) or DRB1*04‐DQB1*0302 (DR4/DQ8)]. In addition, the HLA allele DQB1*0602 is associated with dominant protection from T1DM in multiple populations. A concordance rate lower than 100% between monozygotic twins indicates a potential involvement of environmental factors on disease development. The detection of at least two islet autoantibodies in the blood is virtually pre‐diagnostic for T1DM. The majority of children who carry these biomarkers, regardless of whether they have an a priori family history of the disease, will develop insulin‐requiring diabetes. Facilitating pre‐diagnosis is the timing of seroconversion which is most pronounced in the first 2 yr of life. Unfortunately the significant progress in improving prediction of T1DM has not yet been paralleled by safe and efficacious intervention strategies aimed at preventing the disease. Herein we summarize the chequered history of prediction and prevention of T1DM, describing successes and failures alike, and thereafter examine future trends in the exciting, partially explored field of T1DM prevention.     

Donor selection in pediatric kidney transplantation using DR and DQ eplet mismatching: A new histocompatibility paradigm

It is now appreciated that more HLA‐DR mismatching at the time of the first renal transplant is associated with higher degrees of sensitization, lower rates and longer times to retransplantation, and worse graft outcomes in children who are subsequently retransplanted. As such, our pediatric renal transplant program preferentially uses 0 or 1 HLA‐DR–mismatched kidneys and reserves 2 DR‐mismatched kidneys for recipients with an eminent need for a kidney. Based on a new HLA class II epitope matching strategy that is designed to minimize dnDSA production to DR and DQ antigens, we evaluated the prevalence of DR and DQ eplet mismatching for dd offers made to our pediatric wait‐listed candidates. Each candidate/dd pair were HLA‐DR (β1 and β3 and/or β5) and DQ (α1 and β1) allele typed by rSSO and were then evaluated for eplet mismatches by the HLAMatchmaker program. We evaluated 78 offers made to 16 children on our UNOS waiting list from 27 consecutive dd from 4/14/14 to 3/23/15. The data show that 40% (8/20) of the 1 DR‐mismatched dd offers and 64% (37/58) of the 2 DR‐mismatched offers were in the high‐risk category for both DR and DQ dnDSA development. Whereas only 15% (3/20) of the 1 DR‐mismatched offers and 5% (3/58) of the 2 DR‐mismatched offers were in the low‐risk category for both DR and DQ dnDSA development, 55% and 33% of the 1 DR‐ and 2 DR‐mismatched offers, respectively, had a favorable DQ eplet mismatch threshold. In summary, HLA class II eplet mismatching is common in potential pediatric transplant recipient/donor pairs. Additional study will be necessary to validate the DR and DQ eplet threshold levels in children and to determine whether eplet mismatching strategies in donor selection result in improved transplant outcome and decreased dnDSA production.     

Pattern of human leukocyte antigens in Turkish children with celiac disease

BACKGROUND: Regional variations in the human leukocyte antigen (HLA) distribution patterns of celiac disease (CD) have been reported. The aim of the present study was to assess the distribution of HLA class I and class II in Turkish children with CD and to compare the findings with a control group. METHODS: Human leukocyte antigen typing was performed in 33 children with CD and in 77 healthy individuals, who served as controls, by using standard National Institutes of Health lymphocytotoxicity techniques. RESULTS: A positive association was found between HLA A2 (42 vs 19% for sick subjects compared with healthy controls, respectively), B8 (39 vs. 9% for sick subjects compared with healthy controls, respectively), CW7 (45 vs. 25% for sick subjects compared with healthy controls, respectively), DR3 (70 vs. 17% for sick subjects compared with healthy controls, respectively), DR7 (30 vs. 13% for sick subjects compared with healthy controls, respectively) and DQ2 (52 vs. 34% for sick subjects compared with healthy controls, respectively). The combinations of DR3-DQ2 (30 vs. 12% for sick subjects compared with healthy controls, respectively), DR3-DR4 (21 vs. 1% for sick subjects compared with healthy controls, respectively) and DR7-DQ2 (21 vs. 6% for sick subjects compared with healthy controls, respectively) were also found to be significantly important in children with CD. The highest relative risk (RR) was for HLA B8 in class I (RR 6.50), for DR3 (RR 11.30) in class II and for combination of DR3-DR4 (RR 20.46). The highest etiologic fraction (EF) was for the DR3 antigen (EF 0.55). CONCLUSIONS: The present study emphasizes that HLA genotypes are an important background to CD development, but some additional susceptibility factors remain to be identified.     

Duration of breast feeding and bovine serum albumin antibody levels in type 1 diabetes: a case-control study

To compare the levels of bovine serum albumin (BSA) antibodies and their relationship with duration of breast feeding, age of exposure to cow's milk, and human leukocyte antigen (HLA‐DQ) genotype in children with and without type 1 diabetes. Methods: Serum samples from 143 (0.3–14.7 yr) newly diagnosed children with type 1 diabetes and 107 unrelated control children (0.8–13.5 yr) were evaluated for BSA antibodies. Duration of breast feeding and exposure to cow's milk were recorded on questionnaires. HLA‐DQ typing was determined by polymerase chain reaction. Results: One hundred percent of the diabetic children were positive for BSA antibodies compared to 1.9% for healthy controls (p < 0.001). Diabetic children also had higher levels of immunoglobulin G antibodies than unrelated controls (55.1 vs. 17.8 ng/mL, p < 0.0001). Duration of breast feeding (5.4 vs. 7.6 months, p < 0.02), but not age of exposure to cow's milk (8.3 vs. 9.2 months, p = 0.11), differed between cases and controls. There was no difference in antibody titer by duration of breast feeding or age of exposure to cow's milk in the cases or controls. Conclusion: Higher levels of antibodies to BSA were found in children recently diagnosed with type 1 diabetes compared to the controls, particularly those with high or moderate HLA‐DQ genotypes. The BSA profile, however, does not seem to depend on duration of breast feeding or age of exposure to cow's milk in this population.     

Genetics of insulin-dependent diabetes mellitus in children

Insulin-dependent diabetes in children is a heritable disease, although it does not fit into any simple genetic model. Research is not facilitated by the lack of knowledge of the different etiological mechanisms and the inability to classify the disease. Human leucocyte antigens (HLAs) coded for in the major histocompatibility complex on the 6th chromosome have given the most important insights into the genetics of diabetes, and these genes probably provide the majority of genetic susceptibility to type-I diabetes. Several facts indicate that there are at least two loci of importance, one associated with HLA B8, DR3 and another with HLA B15, DR4, which probably are usually included in extended haplotypes in linkage disequilibrium. There seems to be a substantial DNA polymorphism and further studies may detect fragments that are even more strongly associated with diabetes than the DR type. A combination of more detailed immunological, perhaps virological or other environmental investigations on diabetic patients and their families, together with the use of specific DNA probes for the HLA region, might reveal the susceptibility genes.     

An inverse association between history of childhood eczema and subsequent risk of type 1 diabetes that is not likely to be explained by HLA‐DQ,PTPN22, or CTLA4 polymorphisms

Stene LC, Rønningen KS, Bjørnvold M, Undlien DE, Joner G. An inverse association between history of childhood eczema and subsequent risk of type 1 diabetes that is not likely to be explained by HLA‐DQ, PTPN22, or CTLA4 polymorphisms. Background: Established genetic susceptibility loci for type 1 diabetes are important in immune regulation and may play a role also in atopic disorders, potentially explaining the inverse association between childhood eczema and subsequent risk for type 1 diabetes previously reported. Objective: We aimed to directly assess whether HLA‐DQ, CTLA4, and PTPN22 genes could explain the putative association between childhood eczema and lower subsequent risk of type 1 diabetes observed in several case–control studies. Methods: We designed a case–control study with 339 incident cases of type 1 diabetes identified in the Norwegian childhood diabetes registry, and 985 population‐based control children. DNA was collected, and physician‐diagnosed childhood eczema was ascertained by a questionnaire administered to the parents of children with and without type 1 diabetes. Results: The previously reported association between childhood eczema and lower risk of type 1 diabetes was confirmed (odds ratio,OR, 0.61, 95% confidence interval, CI, 0.40–0.95] and this was consistent in subgroups defined by HLA‐DQ, CTLA4, and PTPN22 genotypes. The OR was essentially not influenced by adjustment for genetic variation at these loci (OR simultaneously adjusted for the three genetic loci: 0.55, 95% CI: 0.32–0.92). The ratio of the unadjusted to adjusted OR was 1.12, with a corresponding 95% CI from 0.84 to 1.50. Conclusion: In this first study of its kind, we demonstrated directly that the observed inverse association between childhood eczema and type 1 diabetes is not likely to be explained by the established diabetes susceptibility genes HLA‐DQ, CTLA4, or PTPN22.     

HLA‐DRB, ‐DQA,and DQB alleles and haplotypes in Iranian patients with diabetes mellitus type I

Specific alleles at the HLA‐DRB1, ‐DQA1, and ‐DQB1 loci seem to be associated with variable risks of developing type 1 diabetes (T1D). This study assessed the distribution of HLA‐DR and ‐DQ alleles among Iranian T1D patients and healthy controls. In this study, HLA‐DRB1, ‐DQA1, and ‐DQB1 alleles were determined in 100 children with T1D and 100 unrelated healthy controls. The following alleles were found to have a strong positive association with T1D: DRB1*0301, DRB1*0401, DRB1*0402, DQA1*0301, DQA1*0501, DQB1*0201, and DQB1*0302. Meanwhile, protective associations were found for DRB1*1001, DRB1*1101, DRB1*15, DRB1*16, DQA1*0102, DQA1*0103, DQB1*0301, DQB1*0501, and DQB1*0602 alleles. The haplotypes found most frequently among patients with T1D were DRB1*0301‐DQA1*0501‐DQB1*0201, DRB1*0401‐DQA1*0301‐ DQB1*0302, and DRB1*0402‐DQA1*0301‐DQB1*0302, whereas DRB1*1101‐DQA1*0501‐DQB1*0301 and DRB1*16‐DQA1*0102‐ DQB1*0501 haplotypes were negatively associated with the disease. These results confirm the previously reported association of specific HLA‐DR and HLA‐DQ alleles and haplotypes with T1D in Iranian population. The notable difference was the identification of DRB1*16‐DQA1*0102‐DQB1*0501 as a protective haplotype and the absence of a negative association of DRB1*1301‐DQA1*0103‐DRB1*0603 with T1D.     

Prevalence and characteristics of diabetes among Somali children and adolescents living in Helsinki, Finland

Oilinki T, Otonkoski T, Ilonen J, Knip M, Miettinen PJ. Prevalence and characteristics of diabetes among Somali children and adolescents living in Helsinki, Finland. Objective: We compared the prevalence and characteristics of diabetes between Somali and Finnish children in the City of Helsinki. Subjects and methods: Ten Somali and 310 non‐Somali children <16 yr of age were treated for diabetes in Helsinki at the end of 2007. We analyzed autoantibodies, HLA alleles, and serum 25‐hydroxy‐vitamin D [S25(OH)D] concentrations. Results: The prevalence of diabetes was 40/10 000 (95% CI 19–73/10 000) for the Somali children and 37/10 000 (95% CI 33–41/10 000) for the background population. At least one autoantibody was detected in all seven Somali patients sampled within 18 months after the diagnosis. Most Somalis (75%) carried HLA‐conferred susceptibility to type 1 diabetes (T1D), DR3‐DQ2 being the dominating HLA haplotype. Low S25(OH)D levels (<40 nmol/L) were seen in 83% of the Somali patients and in 60% of their siblings. Conclusions: These data show that (i) Somali children have autoimmune diabetes, (ii) the prevalence of T1D is similar among Somali and Finnish children, and (iii) both affected and unaffected Somali children have low concentrations of S25(OH)D.     

Simultaneous onset of type 1 diabetes in monozygotic twins younger than 1 year

This report describes type 1 insulin deficient diabetes mellitus (IDDM) arising in identical twins aged under one year. One twin presented with symptoms and was diagnosed with type 1 IDDM; the diagnosis of type 1 IDDM was simultaneously made in the second twin without clinical symptoms. Both twins were positive for anti-GAD (glutamic acid decarboxylase) antibody at first, and then positive for islet cell antibodies. Interestingly, the twins have four susceptible HLA DR and DQ genes together that are usually recognized separately in IDDM patients in Japan.     

Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies

Delli AJ, Lindblad B, Carlsson A, Forsander G, Ivarsson S‐A, Ludvigsson J, Marcus C, Lernmark Å; for the Better Diabetes Diagnosis (BDD) Study Group. Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies. Aim: To determine whether type 1 diabetes mellitus (T1DM) patients, having parents who immigrated to Sweden, have increased T1DM risk before 18 yr compared with countries of origin. We also determined whether they have different human leukocyte antigen (HLA) genetic markers and islet autoantibodies at diagnosis compared with Swedish patients. Methods: A total of 1988 (53% males) newly diagnosed and confirmed T1DM patients <18 yr registered within the Better Diabetes Diagnosis (BDD) study (May 2005 to September 2008) were included. Participants were classified into three groups: Swedish, non‐Swedish, and Mixed‐origin patients according to country of origin of two generations (parents and grandparents). These groups were compared with respect to T1DM HLA markers and islet autoantibodies [glutamic acid decarboxylase autoantibodies (GAD65Ab), insulin autoantibodies (IAA), and islet antigen‐2 autoantibodies (IA‐2Ab)]. Results: Only 30 (1.5%) patients were born outside Sweden. Swedish patients constituted 66%, non‐Swedish patients 8%, Mixed origins 17%, and 9% were of uncertain origin. Confirmed T1DM in patients within the study was 22 (95% CI: 21–23) patients/10⁵/yr rate for Swedish patients compared with 14 (95% CI: 13–15) among non‐Swedish patients. The HLA‐DQ8 haplotype (p < 0.0001) and DQ2/8 genotype (p < 0.02) predominated among Swedish compared with non‐Swedish patients. In contrast, DQ2 was the most frequent haplotype among non‐Swedish patients [OR = 1.5 (95% CI: 1.0–2.0), p < 0.04]. Multiple (≥2) autoantibodies (p < 0.04) and specifically IA‐2Ab (p < 0.001) were most prevalent among the Swedish patients. Multiple autoantibodies were associated with DQ8 among the Swedish patients only (p < 0.001). Conclusion: Patients born to parents who had immigrated to the high T1DM incidence environment of Sweden have, compared with Swedish patients, more frequent HLA‐DQ2 genetic markers and are diagnosed more often with GAD65Ab.     

HLAs in children with minimal change disease and other types of nephrotic syndrome in the southern part of Turkey

The aim of this study was to investigate the human leukocyte antigen (HLA) profile of children with nephrotic syndrome in the southern part of Turkey. Seventy-eight children with nephrotic syndrome were studied for the frequency of class I and class II human leukocyte antigens. Forty-seven of them were steroid sensitive nephrotic syndrome (minimal change disease-MCD) and 31 were other types of nephrotic syndrome. The results were compared with 133 healthy subjects for HLA groups. HLA B13, Cw5, Cw7, DR4, DR7, DRw10, Drw15(2) and DQ2 in the MCD group and HLA A31, B8, B13, B17, Cw2, Cw6, Cw7, DRw10 and DRw12 in the non-MCD group were found significantly increased when compared to healthy controls. MCD patients with frequent relapses had higher frequencies of both Cw6 and DR1 (p < 0.005) and MCD patients with infrequent relapses had a higher frequency of Cw7 (p < 0.05). In conclusion, HLA groups may help in the early diagnosis of these variants.     

Latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and Celiac disease

Latent autoimmune diabetes mellitus in adults (LADA) is characterized by clinical presentation as type 2 diabetes mellitus after 25 years of age, initial control achieved with oral hypoglycemic agents for at least 6 months, presence of autoantibodies and some immunogenetic features of type 1 diabetes mellitus. An 8.3 year-old girl was referred to our pediatric endocrinology department because of incidental glucosuria. She did not complain of polyuria, polydipsia, or weight loss. Her body mass index (BMI) was at the 80th percentile. Fasting glucose was 126 mg/dl, and OGTT glucose level at 120 min was 307 mg/dl. Although C-peptide levels were normal, her first phase insulin response (FIR) was lower than the 1st percentile. Anti-insulin antibody (AIA), islet cell antibody (ICA), and anti-glutamic acid decarboxylase (antiGAD) were negative. According to the clinical and laboratory findings, she was diagnosed as having type 2 diabetes mellitus. She was started with oral anti-diabetic treatment for a period of 1 year. Insulin had to be initiated for worsening of HbA1c levels. In the fourth year of follow-up, she was admitted to our hospital with diabetic ketoacidosis although she was on an intensive insulin regimen. At this time, C-peptide levels were low, antiGAD and AIA were positive with HLA DR3/DQ2 haplotype. In addition, her thyroid peroxidase antibody and endomysium antibody were found to be high at follow-up. Small intestinal biopsy revealed celiac disease. This patient may represent the first case of latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and celiac disease.     

Coexistent coeliac disease,Graves' disease and diabetes mellitus type 1 in a patient with Down syndrome

A 17-year-old girl with Down syndrome is presented who developed coeliac disease, Graves' disease and diabetes type 1. Her HLA type was A3, A9, B8, B15, DR3, DR5.     

Research of factors for glucose intolerance in mucoviscidosis]

Glucose tolerance has been assessed in cystic fibrosis (CF) children using HbA1C and plasma glucose and insulin determinations during an oral glucose tolerance test (OGTT), along with the determination of HLA-DR and islet-cell (ICA) and anti-insulin (IAA) antibodies. Of 49 patients (25 males, 24 females), aged 2 to 21 years (mean = 10.9 years), 29 had normal glucose tolerance (WHO criteria) during OGTT, 14 had impaired glucose tolerance (IGT) and 6 had an isolated hyperglycemia at 120 min. Fasting plasma glucose and HbA1C were significantly higher in IGT than in normoglycemic patients. However, these two parameters showed poor individual predictive value of disturbance in glucose tolerance. Of 14 patients with abnormal OGTT, 7 were aged below 10 years, with 2 as young as 5 years; 8 patients were females. HLA antigens characteristic of type I diabetes tended to be found less frequently in CF patients than in the general population: 9% were DR3, 7% were DR4 and none was DR3/DR4. There were no HLA differences according to glucose tolerance. ICA and IAA were respectively detected in only one patient. Stimulated plasma insulin was low but did not correlate with glucose tolerance. In conclusion, impaired glucose tolerance is common in cystic fibrosis and can be found early in life. Although insulin secretion is decreased in this population, it does not seem to be the only factor responsible for impaired glucose intolerance. The absence of the genetical and immunological characteristics of type I diabetes confirms that glucose intolerance in cystic fibrosis is due to other pathogenetic mechanisms.