RESUMO
Type 1 diabetes is an autoimmune heterogeneous disease that is determined by environmental and genetic factors. A possible retroviral etiology has been inferred from the observation that human endogenous retrovirus (HERV)-K18 encoding a superantigen (SAg) has a polymorphism associated with this disease. Type 1 diabetes families from Germany and Belgium were genotyped for the novel HERV-8914 (303 families) and for the known HERV-8594 (284 families) polymorphisms within the SAg-coding region on the HERV-K18. Case-control analysis was performed for the HERV-8914 polymorphism (506 patients) and for the HERV-8594 polymorphism (370 patients) and compared with 350 German controls. Haplotypes were constructed. Additionally, a microsatellite within the CD48 gene was analyzed in German type 1 diabetes families (n=125) as well as in patients (n=375) and in healthy controls (n=350). No association was found for HERV-K18 polymorphisms or the CA repeat within the CD48 gene with type 1 diabetes mellitus either in families or by comparing patients and controls. In conclusion, we cannot confirm a role of HERV-K18 polymorphisms -HERV-8914 and HERV-8594- or of the CD48 CA repeat for type 1 diabetes susceptibility.
Assuntos
Antígenos CD/genética , Diabetes Mellitus Tipo 1/genética , Retrovirus Endógenos/genética , Proteínas de Membrana/genética , Superantígenos/genética , Antígeno CD48 , Estudos de Casos e Controles , Criança , Pré-Escolar , Repetições de Dinucleotídeos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Íntrons/genética , Desequilíbrio de Ligação , Masculino , Polimorfismo Genético , SoftwareRESUMO
AIMS/HYPOTHESIS: Type I (insulin-dependent) diabetes mellitus results from an immune-mediated destruction of pancreatic beta cells for which HLA haplotypes DR3-DQ2 and DR4-DQ8 represent the strongest genetic risk markers. Mothers of patients with rheumatoid arthritis carry more frequently the HLA DR4-DQ8 haplotype as non-transmitted haplotype than mothers of healthy control subjects. As maternal cells have been shown to persist in their offspring up to 30 years after birth, we investigated whether the association of HLA DR3-DQ2 and DR4-DQ8 with Type I diabetes is purely a genetic effect acting through inheritance or whether it can also act as an environmental factor, for example through foetal exposure in utero to maternal circulating cells. METHODS: We analysed the non-transmitted parental HLA DQ alleles of 464 families (1367 subjects) with a Type I diabetic offspring. HLA DQ alleles were assessed using sequence-specific primers and allele-specific oligonucleotides hybridisation. A chi-square test was done to compare allele and transmission frequencies in the respective subsets of families. RESULTS: The non-transmitted HLA DR3-DQ2 and DR4-DQ8 were more frequent in mothers than in fathers of all non- DQ2/DQ8 heterozygous diabetic offspring ( p=0.0001) as well as in offspring not carrying any HLA high-risk allele ( p=0.0243). In patients with either risk allele alone, more maternal than paternal non-transmitted risk alleles complemented the constellation to DQ2/DQ8 ( p<0.0099). CONCLUSION/INTERPRETATION: HLA high risk alleles were more frequent among maternal non-inherited (but possibly exposed) alleles than among paternal non-inherited alleles. These results indicate that HLA DR-DQ is an environmental risk factor for Type I diabetes.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Impressão Genômica/genética , Antígenos HLA-DQ/genética , Alelos , Diabetes Mellitus Tipo 1/epidemiologia , Pai , Feminino , Humanos , Masculino , Mães , Núcleo Familiar , Linhagem , Caracteres SexuaisRESUMO
The autoimmune attack in type 1 diabetes is not only targeted to beta 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, beta-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 (beta = - 1.15, P = 0.002), age (beta = 0.02, P = 0.01) and GADA + (beta = 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 (beta = 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 Addison's 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.
Assuntos
Autoimunidade , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DQ/genética , Adolescente , Glândulas Suprarrenais/imunologia , Adulto , Autoanticorpos/sangue , Doença Celíaca/imunologia , Criança , Feminino , Ligação Genética , Glutamato Descarboxilase/imunologia , Humanos , Iodeto Peroxidase/imunologia , Masculino , Especificidade de Órgãos , Células Parietais Gástricas/imunologiaRESUMO
A quarter of type 1 diabetic patients have thyrogastric autoantibodies (thyroid peroxidase and gastric parietal cell antibodies). Clinical, immune, and genetic risk factors help predict antibody status. First degree relatives of these patients may also frequently exhibit these antibodies. We assessed the prevalence of thyrogastric antibodies and dysfunction in first degree relatives in relation to age, gender, human leukocyte antigen-DQ type, beta-cell antibody (islet cell, glutamic acid decarboxylase-65, and tyrosine phosphatase antibodies), and proband thyrogastric antibody status. Sera from 272 type 1 diabetic patients (116 men and 156 women; mean age, 27 +/- 18 yr; duration, 10 +/- 9 y), 397 first degree relatives (192 men and 205 women; parents/siblings/offspring, 48/222/127; age, 22 +/- 10 yr), and 100 healthy controls were tested for islet cell antibodies and gastric parietal cell antibodies by indirect immunofluorescence and for tyrosine phosphatase, glutamic acid decarboxylase-65, and thyroid peroxidase antibodies by radiobinding assays. Glutamic acid decarboxylase-65 antibodies were present in 68% and 5%, islet cell antibodies were present in 36% and 2.5%, tyrosine phosphatase antibodies were present in 45% and 0.5%, thyroid peroxidase antibodies were present in 21% and 4.5%, and gastric parietal cell antibodies were present in 18% and 11% of diabetic patients and relatives, respectively. The presence of thyroid peroxidase antibodies in relatives was determined by age (beta = 0.22; P = 0.0001) and proband thyroid peroxidase antibodies status (beta = -2.6; P = 0.002; odds ratio = 11.1). Gastric parietal cell antibody positivity in relatives was associated with age (beta = 0.04; P = 0.026). Gastric parietal cell antibody-positive compared with gastric parietal cell antibody-negative relatives were more likely to have gastric parietal cell antibody-positive probands (P = 0.01; odds ratio = 3.0). beta-Cell antibody status and human leukocyte antigen-DQ type did not influence thyrogastric antibody status in relatives. (Sub)clinical dysthyroidism was found in 3%, iron deficiency anemia was present in 12% (26% gastric parietal cell antibody-positive and 9% gastric parietal cell antibody-negative subjects; P = 0.009), and pernicious anemia was found in 0.5% (5% gastric parietal cell antibody-positive and 0% gastric parietal cell antibody-negative subjects; P = 0.012) of relatives. They had less thyroid dysfunction (P < 0.0001) and pernicious anemia (P = 0.018) than diabetic probands. In conclusion, thyrogastric antibodies and dysfunction are more prevalent in type 1 diabetic patients than in first degree relatives. The presence of these antibodies in relatives is associated with age and proband antibody status, but not with beta-cell antibodies or human leukocyte antigen-DQ type.
Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Estômago/imunologia , Glândula Tireoide/imunologia , Adulto , Envelhecimento/metabolismo , Feminino , Imunofluorescência , Glutamato Descarboxilase/imunologia , Antígenos HLA-DQ/metabolismo , Humanos , Iodeto Peroxidase/imunologia , Masculino , Células Parietais Gástricas/imunologia , Caracteres SexuaisRESUMO
UNLABELLED: AIMS/HYPOTHESIS. We investigated whether the reported HLA-DQ/DR restricted male-to-female (M:F) excess in Type I (insulin-dependent) diabetes mellitus also exists in Belgian patients, is specific for immune-mediated diabetes, remains genotype-restricted after adjustment for age at diagnosis, and is associated with sex-dependent environmental factors. METHODS: Autoantibodies, HLA-DQ and 5'INS (5'insulin gene) polymorphisms were assessed in 2,532 diabetic patients (all phenotypes) diagnosed under 40 years of age. Autoantibodies and body mass index (expressed as a standard deviation score by comparison to age-matched and sex-matched control subjects; SDS-BMI) were measured in 1986 siblings or offspring of Type I diabetes patients (0-39 years). RESULTS: In patients aged 15-39 years at diagnosis, the male-to-female ratio was 1.5 or more regardless of their antibody status and significantly higher (p < 0.001) than that in the age-matched Belgian general population. There was no sex bias in patients under 15 years of age. Overall, the male-to-female ratio was significantly higher in patients without HLADQA1*0301-DQB1*0302 (p < or = 0.003) but stratification in age groups and multivariate analysis identified age as the major determinant of male-to-female ratio. The SDS-BMI increased (p < 0.01) in male antibodypositive relatives (n = 103) but not in female antibody-positive (n = 92) or in antibody-negative relatives (n = 1,791). This phenomenon tended to be restricted to male relatives who were positive only for glutamate decarboxylase antibodies (n = 44). CONCLUSIONS/INTERPRETATION: The male-to-female excess in Belgian diabetic patients diagnosed in early adulthood is not specific for immune-mediated Type I diabetes and not HLA-DQ or 5'INS restricted. Our data suggest that, similar to Type II (non-insulin-dependent) diabetes mellitus, the metabolic burden of obesity and insulin resistance could preferentially precipitate postpubertal clinical onset in male subjects with slowly progressive subclinical (immune-mediated) diabetes.