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Biomedical subjects

F K Gorus

Publications and source records attributed to F K Gorus.

At least 37 records · Page 2Linked to original sources
PubMed1998

Implantation of standardized beta-cell grafts in a liver segment of IDDM patients: graft and recipients characteristics in two cases of insulin-independence under maintenance immunosuppression for prior kidney graft.

Islet allografts in insulin-dependent diabetic (IDDM) patients exhibit variable survival lengths and low rates of insulin-independence despite treatment with anti-T-cell antibodies and maintenance immunosuppression. Use of poorly characterized freshly isolated preparations makes it difficult to determine whether failures are caused by variations in donor tissue. This study assesses survival of standardized beta-cell allografts in C-peptide negative IDDM patients on maintenance immunosuppression following kidney transplantation and without receiving anti-T-cell antibodies or additional immunosuppression. Human islets were isolated from pancreatic segments after maximal 20 h cold-preservation. During culture, preparations were selected according to quality control tests and combined with grafts with standardized cell composition (> or = 50% beta cells), viability (> or = 90%), total beta-cell number (1 to 2 x 10(6)/kg body weight) and insulin-producing capacity (2 to 4 nmol x graft(-1) x h(-1)). Grafts were injected in a liver segment through the repermeabilized umbilical vein. After 2 weeks C-peptide positivity, four out of seven recipients became C-peptide negative; two of them were initially GAD65-antibody positive and exhibited a rise in titre during graft destruction. The other three patients remained C-peptide positive for more than 1 year, two of them becoming insulin-independent with near-normal fasting glycaemia and HbA1c; they remained GAD65- and islet cell antibody negative. The three patients with surviving grafts presented a history of anti-thymocyte globulin therapy at kidney transplantation. Long-term surviving grafts increased C-peptide release following intravenous glucagon or oral glucose but not following intravenous glucose. Thus, cultured human beta-cells can survive for more than 1 year in IDDM patients on maintenance anti-rejection therapy for a prior kidney graft and without the need for an increased immunosuppression at the time of implantation. The use of functionally standardized beta-cell grafts helps to identify recipient and graft factors which influence their survival and metabolic effects. Insulin-independence can be achieved by injection of 1.5 million beta-cells per kg body weight in a liver segment. These beta-cell implants respond well to adenylcyclase activators but poorly to glucose.

Adolescent↗
PubMed1998

Dancing eye syndrome and hyperphosphatasemia.

An 11-month-old boy with a relapsing dancing eye syndrome associated with elevation of serum alkaline phosphatase, lactate dehydrogenase, and aminotransferase activities is reported. During two clinical episodes the serum alkaline phosphatase activity increased up to four times the upper reference limit, remained elevated for a few weeks and normalized gradually in parallel with clinical improvement under steroid therapy. We found no evidence of liver or bone pathology nor of a neural crest tumor. The association between dancing eye syndrome and hyperphosphatasemia has not yet been described. The beneficial effect of the steroid therapy strengthens the hypothesis of an autoimmune origin.

Alanine Transaminase↗
PubMed1998

Increased prevalence of abnormal immunoglobulin M, G, and A concentrations at clinical onset of insulin-dependent diabetes mellitus: a registry-based study. The Belgian Diabetes Registry.

In view of the reported association of insulin-dependent diabetes mellitus (IDDM) with viral infections, (non-) islet-specific immune changes, and partial immunodeficiencies, we used immunonephelometry to measure circulating levels of IgM, IgG, and IgA in a registry-based group of IDDM patients under age 40 years at clinical onset (n = 397) and in age-matched nondiabetic siblings (n = 316) and control subjects (n = 322). Overall, IgM and IgA concentrations were higher, and IgG concentrations lower, in patients than in control subjects or siblings (P < 0.001). In siblings, IgM concentrations were higher than in control subjects (P < 0.001). Using age-adjusted reference intervals, abnormal Ig concentrations were noted in 27% of the patients at onset versus only 10% of the siblings and 7% of the control subjects (P < 0.001). For onset between 20 and 40 years (n = 220), 30% of the patients presented either increased IgM levels (21%) or decreased IgG levels (11%). Both independent phenomena occurred regardless of diabetes-associated immune and genetic markers. In patients and siblings, IgM levels were positively correlated with pancreatic lipase activity. In diabetic children (0-9 years; n = 65), a subgroup presented increased IgA levels (15%) in association with the highest HLA DQ-linked genetic risk and elevated IgM levels. The changes in total Ig concentrations at onset were largely reversed under insulin therapy. They may reflect exposure to environmental triggers, such as viral infections, or to (relative) insulinopenia prior to clinical disease onset. Whatever their cause, different serum Ig levels exist in different age groups of recent-onset IDDM patients.

Adolescent↗
PubMed1997

IA-2-autoantibodies complement GAD65-autoantibodies in new-onset IDDM patients and help predict impending diabetes in their siblings. The Belgian Diabetes Registry.

IA-2 has been identified as an autoantigen that is recognized by immunoglobulins from insulin-dependent diabetic (IDDM) patients. Using a liquid phase radiobinding assay, we performed an IA-2-autoantibody (IA-2-Ab) assay in 474 IDDM patients and 482 non-diabetic control subjects aged 0-3 years. IA-2-Ab were detected in 58% of the patients and 0.8% of control subjects. Their prevalence in patients was lower than that of islet cell autoantibodies (ICA; 73%) or glutamic acid decarboxylase (M(r) 65 kDa)-autoantibodies (GAD65-Ab; 82%) but higher than that of insulin autoantibodies (IAA; 42%). IA-2-Ab were more frequent in patients under age 20 years (70%) than between 20 and 40 years (45%; p < 0.001). In the whole IDDM group, 92% of patients were positive for at least one of the three molecular assays, which is higher than the positivity for the ICA assay (73%). Only 1% was negative in the molecular assays and positive in the ICA assay. IA-2-Ab levels were positively correlated with ICA titres (p < 0.001) and HLA DQ A1*0301-DQ B1*0.02 (p < 0.003) by multivariate analysis. In a group of 481 non-diabetic siblings (age 0-39 years) of IDDM patients only 7 were IA-2-Ab positive (1.5%). All seven were under age 20 years and positive for at least two other autoantibodies and for DQ A1*0301-DQB1*0302. Four of these seven developed IDDM during the 6-70-month follow-up period. The positive predictive value of IA-2-Ab (57%) was higher than that of ICA, GAD65-Ab or IAA alone, or in combination (< or = 20%) but these calculations are restricted by the relatively short observation period and the small number of cases. The only IA-2-Ab-negative case of pre-diabetes was also negative for IAA and GAD65-Ab, while it was strongly positive for ICA. In conclusion, IA-2-Ab show a high diagnostic specificity for IDDM and are predictive markers of impending diabetes in siblings of patients. In combination with other molecular antibody assays they may replace ICA testing in future. Our data also indicate that other autoantibodies than IA-2-Ab, GAD65-Ab and IAA contribute to ICA.

Adolescent↗
PubMed1997

CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry.

Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5' region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients <40 years old we investigated the possible interactions of a CTLA-4 gene A-to-G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA-DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients. G-allele-containing CTLA-4 genotypes (relative risk (RR)= 1.5; 95% confidence interval (CI) = 1.2-2.0; P < 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA-DR3 or DR4 alleles; HLA-DQA1*0301-DQB1*0302 and/or DQA1*0501-DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA-2-Ab, GAD65-Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti-thyroid peroxidase, anti-thyroid-stimulating hormone (TSH) receptor, anti-parietal cell, anti-intrinsic factor) were determined, but association between CTLA-4 risk genotypes and markers of polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA- or INS-linked risk. In conclusion, the presence of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.

Abatacept↗
PubMed1997

21-hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison's disease. Belgian Diabetes Registry.

The diagnostic specificity of recombinant 21-hydroxylase autoantibodies (21OH-Ab) for Addison's disease was tested in adult patients with either Graves' disease (GD), insulin-dependent diabetes mellitus (IDDM), or polyendocrinopathy, as well as in healthy controls. Using a radiobinding assay with in vitro translated recombinant human 21-hydroxylase, we found 21OH-Ab in 24/28 (86%) idiopathic Addison patients, and using an immunofluorescence assay we found adrenal cortex autoantibodies (ACA) in 12/28 (43%) patients (P = 0.002). All the 12 ACA-positive sera were also positive for 21OH-Ab and ACA were found in 11/15 (73%) patients with less than 15 years and in 1/13 (8%) patients with 15-38 years of disease duration (P = 0.002). 21OH-Ab were present in 3/92 (3%) patients with GD, in 1/180 (0.6%) with IDDM and in 0/106 healthy subjects. The 21OH-Ab-positive GD and IDDM patients were also positive for ACA. None of 17 patients with polyendocrinopathy, but without Addison's disease, had 21OH-Ab. None of the 180 Belgian IDDM patients had Addison' s disease or developed an adrenal insufficiency at follow up. In two out of three Graves patients, the presence of 21OH-Ab was associated with clinical and biochemical signs of adrenal insufficiency. Of the 89 21OH-Ab-negative patients with GD none had Addison's disease at the time of blood sampling, and 79 were followed up for 5.6-7.5 years and none developed clinical signs of adrenal insufficiency. We conclude that the presence of 21OH-Ab in patients with endocrine autoimmune diseases is highly specific for Addison's disease.

Addison Disease↗
PubMed1997

Associations of GAD65- and IA-2- autoantibodies with genetic risk markers in new-onset IDDM patients and their siblings. The Belgian Diabetes Registry.

OBJECTIVE: To investigate the association of GAD (65-kDa) autoantibodies (GAD65-Abs) and IA-2 autoantibodies (IA-2-Abs) with human leukocyte antigen (HLA)-DQ and insulin gene (INS) risk markers in patients with recent-onset IDDM and their siblings. RESEARCH DESIGN AND METHODS: Blood was sampled from 608 recent-onset IDDM patients and 480 siblings, aged 0-39 years and consecutively recruited by the Belgian Diabetes Registry, to determine GAD65- and IA-2-Ab (radiobinding assay), HLA-DQ- (allele-specific oligonucleotyping), and INS-genotypes (restriction fragment length polymorphism analysis; siblings, n = 439). RESULTS: At the onset of IDDM, GAD65-Abs were preferentially associated with two populations at genetic risk but only in the 20- to 39-year age-group: 1) their prevalence was higher in carriers of DQA1*0301-DQB1*0302 (88 vs. 73% in non[DQA1*0301-DQB1*0302], P = 0.001), and 2) an association was found in patients lacking this haplotype but carrying DQA1*0501-DQB1*0201, together with INS I/I (87 vs. 54% vs. non[INS I/I], P = 0.003). Siblings of IDDM patients also presented the association of GAD65-Abs with DQA1*0301-DQB1*0302 (13 vs. 2% non[DQA1*0301-DQB1*0302], P < 0.001), while associations with the second genetic risk group could not yet be assessed. At the onset of IDDM, IA-2-Ab prevalence was higher in carriers of DQA1*0301-DQB1*0302 (69 vs. 39% non[DQA1*0301-DQB1*0302], P < 0.001) but not of DQA1*0501-DQB1*0201 or INS I/I. This association was present in both the 0- to 19- and the 20- to 39-year age-groups. It was also found in siblings of IDDM patients (4 vs. 0% non[DQA1*0301-DQB1*0302], P < 0.001). CONCLUSIONS: Both GAD65- and IA-2-Abs exhibit higher prevalences in presence of HLA-DQ- and/or INS-genetic risk markers. Their respective associations differ with age at clinical onset, suggesting a possible usefulness in the identification of subgroups in this heterogeneous disease.

Adolescent↗
PubMed1997

Epidemiology, clinical aspects, and biology of IDDM patients under age 40 years. Comparison of data from Antwerp with complete ascertainment with data from Belgium with 40% ascertainment. The Belgian Diabetes Registry.

OBJECTIVE: To compare the incidence rate of IDDM in the age-groups 0-14 and 15-39 years in Antwerp, Belgium, and to compare demographic, clinical, and biological data from Antwerp IDDM patients with 92% ascertainment with those from a larger Belgian patient group with 40% ascertainment. RESEARCH DESIGN AND METHODS: Incident cases of IDDM were reported by physicians of the Belgian Diabetes Registry and in Antwerp by several other sources. In Antwerp, completeness of ascertainment was calculated by the capture-recapture method. Demographic and clinical data were collected by questionnaire. Blood was sampled for HLA-DQ genotyping and, in new-inset patients, for autoantibodies. RESULTS: In Antwerp, the age- and sex-standardized IDDM incidence rates were similar in both age-groups (0-14 years: 11.8/100,000; 15-39 years: 8.9/100,000). The incidence rate decreased in girls above age 15 years (6.9/100,000; P = 0.003) but not in boys (11.0/100,000). Both in Antwerp and Belgium, IDDM was diagnosed more frequently in the 15-39 years age-group (60% of all cases) than under age 15 years, with a lower prevalence of acute symptoms, ketonuria, high-risk HLA-DQ genotype, and autoantibodies against insulin, islet cells, and IA-2, but with a higher prevalence of GAD65 autoantibodies. CONCLUSIONS: In Antwerp, the incidence rate of IDDM under age 15 years is intermediately high compared with the rates in other European regions. It is similar in the 15-39 years age-group, but with a marked male predominance. Demographic, clinical, and biological data show the same age-dependent heterogeneity as the data collected nationwide, with 40% ascertainment indicating the representativeness of the latter.

Adolescent↗
PubMed1996

The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry.

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell-mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ-specific autoimmune disease.

Abatacept↗
PubMed1996

Abnormal circulating pancreatic enzyme activities in more than twenty-five percent of recent-onset insulin-dependent diabetic patients: association of hyperlipasemia with high-titer islet cell antibodies. Belgian Diabetes Registry.

Pancreatic amylase and lipase activities were measured in sera of 307 Caucasian insulin-dependent diabetes mellitus patients (IDDM) at clinical onset, 303 nondiabetic siblings of registered patients, and 207 control subjects under age 40 years. In all subject groups lipasemia and pancreatic (but not salivary) amylasemia increased with age and were significantly correlated. Using age-dependent reference ranges, reduced pancreatic enzyme levels were measured in 18% of patients, 6% of siblings, and only 2% of control subjects (p < 0.001). Increased lipase levels were noted in 10% of patients and in only 3% of siblings and 2% of control subjects (p < 0.001). Using both univariate and multivariate statistical analysis, elevated lipase activities at clinical onset were associated with higher titers of autoantibodies against islet cell cytoplasmic antigens and glucagon, but not against insulin or the 65-kDa isoform of glutamic acid decarboxylase (GAD65-Ab), or with markers of genetic predisposition or metabolic dysregulation. These findings indicate the presence of modest, but statistically significant, variations in circulating pancreatic enzyme levels in 28% of IDDM patients at clinical onset (p < 0.001 vs. 5% in control subjects). Increased lipase levels may express a form or a stage of the disease with exocrine cell damage; their association with higher titers of islet cell and glucagon autoantibodies is not yet explained. Lower lipase and isoamylase levels are thought to result from the reduced acinar cell function in the vicinity of insulin-depleted islets. It must be tested whether pancreatic enzyme activities in serum can also be altered during the preclinical stage and can thus be considered as an additional marker for the disease process in the pancreas.

Adolescent↗
PubMed1996

Evaluation of an immunoturbidimetric assay for haemoglobin A1c on a Cobas Mira S analyser.

We evaluated a homogenous immunoturbidimetric assay for haemoglobin A1c (Tina-quant Haemog bin A1c, Boehringer Mannheim, GmbH, Mannheim, Germany) adapted to a Cobas Mira S analyser (F. Hoffmann-La Roche & Co., Basel, Switzerland) and not requiring sample pretreatment. Between-day CV's determined over a 6 week period were 5.9% and 5.3% for mean haemoglobin A1c values of 5.4% and 17.0% of total haemoglobin respectively. The imprecision was higher than with an in-house ion-exchange high performance liquid chromatographic method. Bilirubin, triacylglycerols and the labile fraction of haemoglobin A1c did not interfere with the assay of haemoglobin A1c. Fetal haemoglobin is not recognized by the antibodies used. Results correlated well with those obtained by high performance liquid chromatography. In conclusion, the Tina-quant assay is not prone to common interferences and allows the rapid and automated determination of haemoglobin A1c on open photometric analysers.

Blood Chemical Analysis↗
PubMed1996

The importance of diabetes registries and clinical biology for the study and treatment of type 1 (insulin-dependent) diabetes mellitus.

The Belgian Diabetes Registry (BDR) has studied the epidemiology of Type 1 diabetes with clinical onset before age 40 years in the Antwerp district. Both in the age categories 0-14 years and 15-39 years, the incidence approximates 10 new cases per 100,000 inhabitants per years. Most patients are adults. Juvenile-onset diabetic patients who were so far more intensively studied must therefore not be considered as "prototypes" for the disease, but rather represent "atypical" cases with rapid evolution. Participation in international programs (EURODIAB ACE, DIAMOND) has characterized the incidence of Type 1 diabetes in Belgium as being intermediate between values in low-incidence regions (5 to 10 cases/100,000 inhabitants/yr such as in parts of Southern or Eastern Europe) and values in high-incidence regions 30 to 40 cases/100,000 inhabitants/yr such as in Finland and Sardinia). Type 1 diabetes is a heterogenous disease in terms of clinical presentation, etiological factors and biological markers. Clinical and fundamental research on Type 1 diabetes needs to study patient groups which faithfully reflect this heterogeneity. This is best achieved by recruiting patients through diabetes registries. In Belgium, the BDR presently registers about 40% of all new cases of Type 1 diabetes with onset before age 40 years. Until now, more than 1700 patients and about 1100 first degree relatives are registered. This group is representative of the Belgian population of Type 1 diabetic patients with onset before age 40 years. High quality-assays for immune and genetic markers of Type 1 diabetes were designed and validated through repeated participation in international quality control programs. By systematically performing these assays on the representative non-selected samples of BDR-patients, it became possible to further clarify the clinical biology of Type 1 diabetes and to demonstrate hitherto unrecognized associations among disease markers. Certain of these markers (insulin auto-antibodies, IAA; islet cell antibodies, ICA; HLA DQA1*0301-DQB1*0302 risk haplotype) are more frequent for clinical onset before age 10 years and appear associated in that age category. Other markers (glutamate decarboxylase antibodies; GAD-Ab) occur more frequently at onset between age 10 and 40 years, where they are preferentially associated with increased genetic risk. Yet another genetic marker (1/1 susceptibility genotype in the 5' polymorphic region of the insulin gene) occurs regardless of age and presence of auto-antibodies, preferentially in patients without the highest HLA-linked genetic risk. Age-dependent differences in marker frequency and -associations possibly reflect age-dependent differences in etiological factors, in order of appearance of biological markers, or in progression rate of the disease. Presently, more than 90% of the patients under age 40 years carry at least one diabetes-associated immune or genetic marker, which opens perspectives for a better classification of the disease, especially in adults. Preliminary follow-up studies in first-degree relatives of registered patients confirm the diabetes-predictive value of the markers studied. A group of subjects at high risk for the disease could thus be identified. These subjects qualify for participation in preventive intervention trials. In this respect BDR officially represents Belgium in several international programs: EURODI-AB ACE for marker-studies, ICARUS for diabetes prediction, ENDIT for diabetes-prevention and GETREM for optimal diabetes treatment. This collaboration will focus in the near future on neonatal screening and follow-up, objective classification criteria for diabetes in adults, refined diabetes-prediction and preventive intervention studies. BDR may also serve as a tool for systematic research on the complications, innovative treatments and socio-economical aspects of diabetes.

Adolescent↗
PubMed1995

High diagnostic sensitivity of glutamate decarboxylase autoantibodies in insulin-dependent diabetes mellitus with clinical onset between age 20 and 40 years. The Belgian Diabetes Registry.

Patients with adult-onset Type 1 (insulin-dependent) diabetes mellitus (IDDM) are more difficult to identify than young patients, as their clinical onset is often less acute with a questionable state of insulin dependency. Classification may be facilitated by the detection of autoantibodies that are associated with IDDM. The prevalence of islet cell autoantibodies (ICA) and insulin autoantibodies (IAA) is, however, markedly lower in adult than in young patients. The present study assesses the usefulness of antibodies against glutamate decarboxylase (GAD), as a complementary marker. Sera from 312 recent-onset IDDM patients under age 40 and 163 age-matched controls were assayed for IAA, ICA, and antibodies against recombinant GAD65 (M(r) 65,000) or GAD67 (M(r) 67,000). IAA or ICA occurred in over 90% of patients diagnosed under age 20 but only in 65% of patients between age 20 and 40. Determination of GAD65-Ab did not increase the percent antibody positive patients under age 10, but did so at older ages: from 92-98% in the 10-19 years age group, and from 65-85% in the 20-39 years age group. The determination of GAD67-Ab did not add to the information provided by the GAD65-Ab assay. Our results indicate that, alone or in combination with ICA, the GAD65-Ab assay identified more patients with an IDDM marker in the age group 20-39 years than in the group under age 20.

Adolescent↗
PubMed1995

Genetic susceptibility for insulin-dependent diabetes mellitus in Caucasians revisited: the importance of diabetes registries in disclosing interactions between HLA-DQ- and insulin gene-linked risk. Belgian Diabetes Registry.

Whether genetic susceptibility for insulin-dependent diabetes mellitus (IDDM) at the 5' insulin gene polymorphic region (5' INS) interacts with human leukocyte antigen (HLA)-DQ-linked disease risk and whether it is associated with autoantibody formation is presently controversial. Diabetes registries allow more systematic reassessment of these questions. Two hundred and ninety-six Caucasian IDDM patients were recruited by the Belgian Diabetes Registry and sampled at disease onset, together with 195 ethnically matched control subjects. 5'INS genotypes were determined by Southern blotting, HLA-DQ by allele-specific oligotyping, and autoantibodies by validated immunoassays. The 5' INS 1/1 genotype was more prevalent in patients than in controls [relative risk (RR) = 2.3; P < 10(-4)]. Regardless of age at onset, the 5' INS 1/1 genotype occurred less frequently in patients with the high-risk genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 than in patients without it (P < 0.04). The RR associated with this high-risk HLA-DQ genotype (24.9; P < 10(-6)) was not affected by the presence or absence of the 5' INS 1/1 genotype. Combined positivity for the 5' INS 1/1 genotype and for one of three other HLA-DQ genotypes associated with an intermediate risk for IDDM conferred an age-independent RR of 12.1 (P < 10(-4)). In the absence of the 5' INS 1/1 genotype, intermediate-risk HLA-DQ genotypes no longer conferred a significant risk (2.9; not significantly different from 1). In subjects carrying neutral, protective, or infrequent HLA-DQ genotypes, the overall RR for IDDM was significantly lower than 1 (0.2; P < 10(-6)) in the absence of the 5' INS 1/1 genotype but not in its presence (0.8; not significantly different from 1). The 5' INS 1/1 genotype was not preferentially associated with immune markers for IDDM. In conclusion, regardless of age at onset and the presence of autoantibodies, 5' INS polymorphisms contribute preferentially to IDDM susceptibility in subjects without the highest HLA-DQ-associated risk.

Adolescent↗
PubMed1994

Influence of age on the associations among insulin autoantibodies, islet cell antibodies, and HLA DAQ1*0301-DQB1*0302 in siblings of patients with type 1 (insulin-dependent) diabetes mellitus. Belgian Diabetes Registry.

In recent-onset type 1 (insulin-dependent) diabetes mellitus (IDDM), insulin autoantibodies (IAA) and islet cell antibodies (ICA) occur preferentially in young (< 10 yr) patients with the HLA DQA1*0301-DQB1*0302 risk haplotype. We investigated whether this association also exists in siblings of IDDM patients. In our group of 310 siblings, aged 0-39 yr, 6% were positive for IAA, 7% for ICA 12 Juvenile Diabetes Foundation units (JDFU) or more, 5% for ICA 20 JDFU or more, and 2% for high titer ICA (> or = 80 JDFU). The occurrence of IAA and ICA (> or = 20 JDFU) was significantly associated, with a preferential relationship to the HLA DQA1*0301-DQB1*0302 susceptibility haplotype. In the present group of siblings, IAA and DQA1*0301-DQB1*0302 were significantly associated under age 10 yr (26% positivity for IAA vs. 4% in relatives without this haplotype). In this age group, IAA were more prevalent than (high titer) ICA (6%) in the presence of the haplotype. The association between (high titer) ICA and DQA1*0301-DQB1*0302 was not restricted to subjects under age 10 yr. High titer ICA (n = 5) occurred exclusively in homozygotes for the latter haplotype and in carriers of the heterozygous DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 high risk genotype, mostly under age 20 yr (four of five). The preferential occurrence of IAA in DQA1*0301-DQB1*0302-positive siblings under age 10 yr was caused by their high prevalence (47%) in subjects with the heterozygous high risk genotype in this age group. As in patients at onset, IAA and high titer ICA are preferentially associated with the DQA1*0301-DQB1*0302 haplotype in siblings of IDDM patients, but, unlike at onset, these associations are observed with specific genotypes only and are more pronounced in subjects under age 10 yr for IAA only. Longitudinal analysis in first degree relatives and other normal controls carrying the DQA1*0301-DQB1*0302 haplotype should assess the hypothesis that IAA qualify as earlier predictive markers for IDDM than high titer ICA.

Adolescent↗
PubMed1993

Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. The Belgian Diabetes Registry.

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 20 years (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 DQA1*0301-DQB1*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 DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 was more prevalent than all other DQA1-DQB1 genotypes taken together, leading to a higher prevalence of the DQA1*0301-DQB1*0302 haplotype in this age group (75%) than in the 10-39 years age group (54%). Under age 10 years, the presence of DQA1*0301-DQB1*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 10-39 years, the DQA1*0301-DQB1*0302 haplotype presented a lower association with insulin autoantibodies (approximately 40%) and islet cell autoantibodies (50 to 65% high titre), prevalences which no longer differed from those in subjects lacking this haplotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Type 1 (insulin-dependent) diabetes mellitus: an autoimmune, predictable and preventable disease? Lessons from national registries and new challenges to clinical biology.

Type 1 (insulin-dependent) diabetes mellitus is a frequent chronic disease that affects children as well as adults. The disease keeps a life-long burden on patients, their environment and society. Although still incompletely understood, its pathogenesis becomes progressively unravelled. Autoimmune phenomena play an important role, be it as underlying cause or as consequence or innocent bystanders of another primary event. Much of the present knowledge on environmental and genetic triggers for the slow islet beta-cell destruction culminating in clinically overt disease has been acquired through national diabetes registries. The latter represent confidential data- and blood sample banks that collect epidemiological, clinical and biological information from as many new cases as possible within a given area. These registries operate along international guidelines and offer a worldwide framework for optimizing prediction of clinically overt disease in individuals at risk by means of specialized clinical biological tests, carried out in reference laboratories under international quality control surveillance. Better understanding of pathogenesis and predictability of Type 1 diabetes also creates perspectives for disease prevention. Collaborative efforts of national registries provide the methodology of choice to assess the effectiveness of proposed pharmacological or immunological interventions. Several international trials are being contemplated for the near future. Clinical biology will play an important role for selection of the subjects and their further monitoring.

Adolescent↗