Frederic Winnock

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

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.

Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes

The autoimmune attack in type 1 diabetes is not only targeted to β cells. We assessed the prevalence of thyroid peroxidase (aTPO), parietal cell (PCA), antiadrenal (AAA) and endomysial antibodies (EmA‐IgA), and of overt autoimmune disease in type 1 diabetes, in relation to gender, age, duration of disease, age at onset, β‐cell antibody status (ICA, GADA, IA2A) and HLA‐DQ type. Sera from 399 type 1 diabetic patients (M/F: 188/211; mean age: 26 ± 16 years; duration: 9 ± 8 years) were tested for ICA, PCA, AAA and EmA‐IgA by indirect immunofluorescence, and for IA2A (tyrosine phosphatase antibodies), GADA (glutamic acid decarboxylase‐65 antibodies) and aTPO by radiobinding assays. The prevalence rates were: GADA 70%; IA2A, 44%; ICA, 39%; aTPO, 22%; PCA, 18%; EmA‐IgA, 2%; and AAA, 1%. aTPO status was determined by female gender (β = − 1·15, P = 0·002), age (β = 0·02, P = 0·01) and GADA + (β = 1·06, P = 0·02), but not by HLA‐DQ type or IA2A status. Dysthyroidism (P < 0·0001) was more frequent in aTPO + subjects. PCA status was determined by age (β = 0·03, P = 0·002). We also observed an association between PCA + and GADA + (OR = 1·9, P = 0·049), aTPO + (OR = 1·9, P = 0·04) and HLA DQA1*0501‐DQB1*0301 status (OR = 2·4, P = 0·045). Iron deficiency anaemia (OR = 3·0, P = 0·003) and pernicious anaemia (OR = 40, P < 0·0001) were more frequent in PCA + subjects. EmA‐IgA + was linked to HLA DQA1*0501‐DQB1*0201 + (OR = 7·5, P = 0·039), and coeliac disease was found in three patients. No patient had Addisons disease. In conclusion, GADA but not IA2A indicate the presence of thyrogastric autoimmunity in type 1 diabetes. aTPO have a female preponderance, PCA are weakly associated with HLA DQA1*0501‐DQB1*0301 and EmA‐IgA + with HLA DQA1*0501‐DQB1*0201.

Gastric parietal cell antibodies are associated with glutamic acid decarboxylase-65 antibodies and the HLA DQA1*0501-DQB1*0301 haplotype in Type 1 diabetes mellitus

SUMMARY

Increased Prevalence of Abnormal Immunoglobulin M, G, and A Concentrations at Clinical Onset of Insulin-Dependent Diabetes Mellitus : A Registry-Based Study

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.