Thyroid hormone resistance from newborns to adults: a Spanish experience.

OBJECTIVE: Thyroid hormone resistance (RTH ß) is a rare genetic disorder characterized by an altered response of target tissue to the action of thyroid hormone. Few studies on RTH ß have been carried out in southern European populations. We aimed to describe the clinical and genetic characteristics at the time of diagnosis in a Spanish cohort of patients with genetically confirmed RTH ß, with ages ranging from newborns to adults. METHODS: Retrospective multicenter study of 28 patients who were genetically confirmed as RTH ß. Clinical and biochemical data were collected from the reference centers, and the studied variables included age, sex, anthropometric data, clinical characteristics and biochemical results. In the Basque country, a simultaneous analysis of TSH and T4 is carried out in the program for the screening of inborn errors of metabolism. A molecular analysis of the thyroid hormone beta (THRB) gene was performed. RESULTS: The total cohort included 20 adults and eight pediatric patients (six newborns). Of the total, 5 (17.8%) were diagnosed by clinical characteristics (goiter, hypertension or tachycardia), 13 (46.4%) were analyzed in the context of a family study and 10 (35.7%) were diagnosed after obtaining an altered fT4 and/or TSH level in a biochemical analysis performed due to clinical symptoms unrelated to RTH ß. Four of the newborns included in the series were diagnosed by the result of neonatal screening, which allows us to estimate a minimum local incidence of RTH ß of 1/18,750 live newborns. The genetic analysis showed the presence of 12 different heterozygous mutations in the THRB gene. CONCLUSIONS: We report the clinical and genetic characteristics of a Spanish RTH ß cohort, from neonates to adults. We also describe one novel mutation in the THRB gene as the cause of the disease. The simultaneous analysis of TSH and T4 carried out in the program for the screening of inborn errors of metabolism facilitates the early diagnosis of RTH ß in newborns and has allowed us to estimate a minimum local incidence of RTH of 1/18,750 live newborns.

[Consensus on the detection and management of prediabetes. Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society]. / Consenso sobre la detección y el manejo de la prediabetes. Grupo de Trabajo de Consensos y Guías Clínicas de la Sociedad Española de Diabetes.

In Spain, according to the Di@bet.es study, 13.8% of the adult population suffers from diabetes and 14.8% from some form of prediabetes (impaired glucose tolerance, impaired fasting glucose or both). Since early detection of prediabetes can facilitate the implementation of therapeutic measures to prevent its progression to diabetes, we believe that preventive strategies in primary care and specialized clinical settings should be agreed. Screening for diabetes and prediabetes using a specific questionnaire (FINDRISC) and/or the measurement of fasting plasma glucose in high risk patients leads to detecting patients at risk of developing diabetes and it is necessary to consider how they should be managed. The intervention in lifestyle can reduce the progression to diabetes and reverse a prediabetic state to normal and is a cost-effective intervention. Some drugs, such as metformin, have also been shown effective in reducing the progression to diabetes but are not superior to non-pharmacological interventions. Finally, an improvement in some cardiovascular risk factors has been observed although there is no strong evidence supporting the effectiveness of screening in terms of morbility and mortality. The Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society has issued some recommendations that have been agreed by the Sociedad Española de Endocrinología y Nutrición, Sociedad Española de Endocrinología Pediátrica, Sociedad Española de Farmacia Comunitaria, Sociedad Española de Medicina Familiar y Comunitaria, Sociedad Española de Médicos Generales, Sociedad Española de Médicos de Atención Primaria, Sociedad Española de Medicina Interna, Asociación de Enfermería Comunitaria and Red de Grupos de Estudio de la Diabetes en Atención Primaria.

Is routine endocrine evaluation necessary after paediatric traumatic brain injury?

BACKGROUND: Traumatic brain injury (TBI) is a common event in childhood. It is a recognised cause of hypopituitarism both in adult and paediatric patients. Routine endocrine evaluation has been proposed for adult TBI-survivors; nevertheless, incongruous data have been reported in children. AIM: The goal of this study was to describe the prevalence of pituitary dysfunction after TBI in a cohort of children. MATERIAL/SUBJECTS AND METHODS: This is a cross-sectional study comprising retrospective medical record review and prospective testing. Children with brain injury discharged from the Paediatric Intensive Care Unit from year 2004 to 2009 were recruited. Height and weight were recorded, systemic examination was performed and baseline pituitary function tests were undertaken. Provocative tests were performed only if abnormal basal levels were detected. RESULTS: Thirty-six patients were collected; the mean age at assessment was 7.2 years and the mean interval since injury 3.3 years. All patients had skull fracture or intracranial haemorrhage; 36.6 % of them had moderate to severe TBI. No abnormalities were found on examination. Low serum IGF 1 levels were detected in four patients and two patients had low serum cortisol levels with inappropriately normal plasma ACTH concentrations. No evidence of pituitary dysfunction was observed in these patients after clinical follow-up, repeated baseline hormone levels or dynamic function tests. CONCLUSIONS: No endocrine sequelae have been detected in this population. The routine endocrine evaluation in children with mild to moderate TBI might not be justified, according to our findings.

Exploring the diabetogenicity of the HLA-B18-DR3 CEH: independent association with T1D genetic risk close to HLA-DOA.

The objective of this study was to identify additional diabetes susceptibility markers in the MHC that could be responsible for the differential diabetogenicity of different HLA-DR3 CEHs. High-resolution SNP genotyping of the MHC was carried out in 15 type 1 diabetes (T1D) patients and 39 non-diabetic controls, homozygous for DR3-DQ2 and with one copy of the A(*)30-B(*)18-MICA(*)4-F1C30-DRB1(*)0301-DQB1(*)0201-DPB1(*)0202 HLA haplotype. Significantly associated SNPs were replicated in an independent sample of 554 T1D patients and 841 controls without HLA matching. Electrophoretic mobility shift assay was used to show a functional effect of an associated SNP. Seven SNPs showed evidence of association in the initial discovery experiment. Upon replication, only rs419434 (upstream HLA-DOA gene) remained significant. A functional variant (rs432375) in complete LD with rs419434 was shown to affect USF-1 binding and could be responsible for the association signal in the region. We have identified a new susceptibility locus within the MHC with a modest contribution to T1D (OR=1.93; CI: 1.52-2.44; P=10(-8)) that is independent of HLA-DRB1 locus.

Panhypopituitarism: genetic versus acquired etiological factors.

OBJECTIVE: Mutations in the genes encoding pituitary transcription factors (mainly PROP1, POUF1 and HESX1) are responsible for familial combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD) while only a low percentage of mutations are the cause of sporadic forms. Indeed, it has been suggested that environmental rather than genetic factors could be important in the pathogenesis of CPHD. PATIENTS AND METHODS: Thirty-six sporadic patients diagnosed with CPHD or SOD were included in the study. All coding exons and intron-exon boundary regions of PROP1, POUF1 and HESX1 were amplified by PCR and subsequently sequenced. RESULTS: Two novel missense mutations in the HESX1 gene (Q117P, K176T) were identified in two patients. Polymorphisms in PIT1 and PROP1 were also detected. A higher percentage of breech delivery in male patients with CPHD versus females was observed. CONCLUSIONS: The low percentage of mutations found in the most common transcription factors involved in CPHD show that a better characterization of hormonal and morphological phenotypes is necessary for patients with CPHD included in genetic studies, and other genetic or non-genetic factors have to be taken into account.

Clinical and genetic characterization of congenital hyperinsulinism in Spain.

CONTEXT: Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic ß-cells. OBJECTIVE: To characterize clinically and genetically CHI patients in Spain. DESIGN AND METHODS: We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype. RESULTS: We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in KATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the KATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis. CONCLUSIONS: Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the KATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.

Consensus on the detection and management of prediabetes. Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society. / Consenso sobre la detección y el manejo de la prediabetes. Grupo de Trabajo de Consensos y Guías Clínicas de la Sociedad Española de Diabetes.

In Spain, according to the Di@bet.es study, 13.8% of the adult population suffers from diabetes and 14.8% from some form of prediabetes (impaired glucose tolerance, impaired fasting glucose or both). Since early detection of prediabetes can facilitate the implementation of therapeutic measures to prevent its progression to diabetes, we believe that preventive strategies in primary care and specialized clinical settings should be agreed. Screening for diabetes and prediabetes using a specific questionnaire (FINDRISC) and/or the measurement of fasting plasma glucose in high risk patients leads to detecting patients at risk of developing diabetes and it is necessary to consider how they should be managed. The intervention in lifestyle can reduce the progression to diabetes and reverse a prediabetic state to normal and is a cost-effective intervention. Some drugs, such as metformin, have also been shown effective in reducing the progression to diabetes but are not superior to non-pharmacological interventions. Finally, an improvement in some cardiovascular risk factors has been observed although there is no strong evidence supporting the effectiveness of screening in terms of morbility and mortality. The Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society has issued some recommendations that have been agreed by the Sociedad Española de Endocrinología y Nutrición, Sociedad Española de Endocrinología Pediátrica, Sociedad Española de Farmacia Comunitaria, Sociedad Española de Medicina Familiar y Comunitaria, Sociedad Española de Médicos Generales, Sociedad Española de Médicos de Atención Primaria, Sociedad Española de Medicina Interna, Asociación de Enfermería Comunitaria and Red de Grupos de Estudio de la Diabetes en Atención Primaria.

[Consensus on the detection and management of prediabetes. Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society]. / Consenso sobre la detección y el manejo de la prediabetes. Grupo de Trabajo de Consensos y Guías Clínicas de la Sociedad Española de Diabetes.

In Spain, according to the Di@bet.es study, 13.8% of the adult population suffers from diabetes and 14.8% from some form of prediabetes (impaired glucose tolerance, impaired fasting glucose or both). Since early detection of prediabetes can facilitate the implementation of therapeutic measures to prevent its progression to diabetes, we believe that preventive strategies in primary care and specialized clinical settings should be agreed. Screening for diabetes and prediabetes using a specific questionnaire (FINDRISC) and/or the measurement of fasting plasma glucose in high risk patients leads to detecting patients at risk of developing diabetes and it is necessary to consider how they should be managed. The intervention in lifestyle can reduce the progression to diabetes and reverse a prediabetic state to normal and is a cost-effective intervention. Some drugs, such as metformin, have also been shown effective in reducing the progression to diabetes but are not superior to non-pharmacological interventions. Finally, an improvement in some cardiovascular risk factors has been observed although there is no strong evidence supporting the effectiveness of screening in terms of morbility and mortality. The Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society has issued some recommendations that have been agreed by the Sociedad Española de Endocrinología y Nutrición, Sociedad Española de Endocrinología Pediátrica, Sociedad Española de Farmacia Comunitaria, Sociedad Española de Medicina Familiar y Comunitaria, Sociedad Española de Médicos Generales, Sociedad Española de Médicos de Atención Primaria, Sociedad Española de Medicina Interna, Asociación de Enfermería Comunitaria and Red de Grupos de Estudio de la Diabetes en Atención Primaria.

[Consensus on the detection and management of prediabetes. Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society]. / Consenso sobre la detección y el manejo de la prediabetes. Grupo de Trabajo de Consensos y Guías Clínicas de la Sociedad Española de Diabetes.

In Spain, according to the Di@bet.es study, 13.8% of the adult population suffers from diabetes and 14.8% from some form of prediabetes (impaired glucose tolerance, impaired fasting glucose or both). Since early detection of prediabetes can facilitate the implementation of therapeutic measures to prevent its progression to diabetes, we believe that preventive strategies in primary care and specialized clinical settings should be agreed. Screening for diabetes and prediabetes using a specific questionnaire (FINDRISC) and/or the measurement of fasting plasma glucose in high risk patients leads to detecting patients at risk of developing diabetes and it is necessary to consider how they should be managed. The intervention in lifestyle can reduce the progression to diabetes and reverse a prediabetic state to normal and is a cost-effective intervention. Some drugs, such as metformin, have also been shown effective in reducing the progression to diabetes but are not superior to non-pharmacological interventions. Finally, an improvement in some cardiovascular risk factors has been observed although there is no strong evidence supporting the effectiveness of screening in terms of morbility and mortality. The Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society has issued some recommendations that have been agreed by the Sociedad Española de Endocrinología y Nutrición, Sociedad Española de Endocrinología Pediátrica, Sociedad Española de Farmacia Comunitaria, Sociedad Española de Medicina Familiar y Comunitaria, Sociedad Española de Médicos Generales, Sociedad Española de Médicos de Atención Primaria, Sociedad Española de Medicina Interna, Asociación de Enfermería Comunitaria and Red de Grupos de Estudio de la Diabetes en Atención Primaria.

Oral dexamethasone administration: new pharmacological test for the assessment of growth hormone secretion.

Acute intravenous (i.v.) dexamethasone administration has been described recently as a new test for the diagnosis of growth hormone (GH) deficiency. In the present study, a new protocol of dexamethasone administration was evaluated. Twelve normal adults and 18 normal prepubertal children were studied. The dexamethasone i.v. test was performed in six adults at a dose of 4 mg and 12 children at a dose of 2 mg/m2. Blood samples were collected 15 min before, at time zero and every 15 or 30 min during 5 h, resulting in a total of 16 samples. In the remaining six adults and six children, 8 and 4 mg, respectively, of dexamethasone were administered orally at the subject's home, and blood sampling started 90 min later when they arrived at the hospital. Plasma GH was measured by radioimmunoassay. The dexamethasone-induced GH response (mean +/- SEM, micrograms/l) to the i.v. or oral protocol did not differ in either the adults (i.v. 8.2 +/- 2.1; oral 8.0 +/- 1.6) or the children (i.v. 14.9 +/- 1.3; oral 13.6 +/- 1.8). It is concluded that the simpler protocol of acute oral dexamethasone administration hereby presented can be a safe and suitable test of GH secretion.

On the confidence interval of the equivalence point in linear titrations.

As the point of intersection in linear-branch titration curves results from two optimized linear regressions, calculated by least-squares from n(1) and n(2) pairs of values of the signal y as a function of the added volume of titrant upsilon, the value of the equivalence volume V(e) has the character of an estimated average V (e) hence a confidence interval is associated with it. If the point of intersection V (e) belongs concomitantly to both regressions then the same value of y (e) should correspond to the two extreme values V'(e) and V'(e) of the confidence interval as to V (e) itself. Consequently, the two segments of the confidence interval are obtained by averaging each of the two unequal segments of the separate confidence intervals. Alternatively, considering that multiple estimates of V (e) can be obtained, the confidence interval can be calculated from the normally distributed random variables Deltaa' and Deltab' of the two linear regressions.

Dual growth hormone (GH) response to repeated GH releasing hormone stimulus in children and adults.

Several authors have demonstrated that plasma growth hormone (GH) levels as response to acute GH releasing hormone (GHRH) stimulation in adults are decreased by a previous GHRH injection whereas they are maintained in children. Probably the most accepted hypothesis for this finding is the increase in the somatostatinergic tone. The aim of the present study was to evaluate the dual GH response to repeated GHRH stimuli to clarify the possible influence of somatostatinergic activity in the type of response. Eighteen healthy prepubertal children, mean age 9.2 years (range: 6.0-12.9 years) and 19 healthy adult volunteers, mean age 25.5 years (range: 17-35 years) were studied with the GHRH test. An additional group of 10 normal adults with similar characteristics (mean age 31 years, range 25-35 years) were also recruited as a control group for somatostatinergic assessment. The GH response to the first GHRH bolus was similar in both children and adults. However, while children showed a preserved response to the second stimulus, it was diminished in adults. As expected, thyroid stimulating hormone (TSH) was within the normal range in all subjects. When the evolution of TSH was compared between the group of non-responders and the control group, no significant differences were found either at basal time or at 120 min, showing a similar decreasing trend for serum TSH level. The variation of TSH levels were also expressed as the proportion of TSH response after 2 hours compared to the basal level (TSH-120/TSH-0) but no significant differences were found (GHRH non-responders group mean: 73.6%, range: 51.3-93.7; control group mean: 70.7%, range: 62.9-92.5). In conclusion, the results confirm that in adults but not in children, the somatotrope responsiveness to GHRH is inhibited by a previous bolus of GHRH. The finding that the plasma TSH level diminishes in a similar manner in both non-responders and the control group is in agreement with the rejection of the hypothesis of the influence of somatostatin.

Molecular analysis of hereditary hyperferritinemia-cataract syndrome in a large Basque family.

Hereditary hyperferritinemia-cataract syndrome is a genetic condition characterized by constitutively increased serum ferritin values in the absence of iron overload and by bilateral cataract. It has been demonstrated that mutations in the stem loop structure of the iron regulatory element (IRE) located in the 5'-untranslated region of the ferritin L-subunit gene (19q13.1) are responsible for the anomalous expression of this protein. Although not clearly explained, cataract formation seems secondary to the increased levels of ferritin in the lens. We analyzed a large Basque family in order to identify possible germline alterations of the iron regulatory element of the ferritin-L gene in affected individuals and first-degree relatives. All members of the family presented hyperferritinemia and cataract except a young child who had hyperferritinemia but did not present cataract. Sequence analysis permitted the identification of an A40-->G mutation in all members, including this child. This could demonstrate that cataract formation is a consequence of ferritin accumulation in the lens.

Molecular analysis of Frasier syndrome: mutation in the WT1 gene in a girl with gonadal dysgenesis and nephronophthisis.

The Wilms' tumor gene (WT1) encodes a protein that is believed to exert transcriptional and tumor-suppressor activities. Mutations in this gene have occasionally been associated with Wilms' tumor (<15% patients) and, more consistently, with three syndromes characterized by urogenital abnormalities (WAGR, Denys-Drash and Frasier syndromes). We report 17 years follow-up of a 29 year-old phenotypic female with 46,XY karyotype, gonadal dysgenesis and nephronophthisis in order to identify possible germline alterations of the WT1 gene. Frasier syndrome was suspected and confirmed by genetic analysis. Sequence analysis permitted the identification of an A40-->G mutation in position +5 in the donor splice site of intron 9. During surgery for streak gonads extirpation, a microscopic gonadoblastoma was found, a typical complication of Frasier syndrome.

The outcome of patients with lupus nephritis and the impact of cardiovascular risk factors.

BACKGROUND: Systemic lupus erythematosus (SLE) is the prototype of autoimmune connective tissue diseases. Renal disease is a frequent manifestation of SLE that influences the outcome of the patients. The aim of the current study was to determine and analyze the clinical features and subsequent outcome of 70 patients with LN, followed in our department over the past 5 years, focusing on the impact of cardiovascular risk factors in the renal outcome and mortality. PATIENTS AND METHODS: Our prospective study included 70 patients with SLE and LN and 70 patients with SLE without signs of renal involvement, all patients fulfilled the revised ACR (American College of Rheumatology) criteria for the classification of SLE. Demographical data, risk factors and comorbidities were recorded. RESULTS: Patients with lupus nephritis had a mean age of 37 years (range 15-65, SD 1.8). During the study, we had a rate of drop off of 15 patients with lupus nephritis (21%) and 19 patients without nephritis (26%). Patients with LN had a higher prevalence of positive anti-dsDNA antibodies (85.4% vs 49%, p<0.001, RR=2.2) and a lower percent of rheumatoid factor (FR) positive (5.45% vs 15.68%, p=0.03, RR=0.34) compared with the controls, a higher prevalence of corticosteroid treatment (65.45% vs 7.83%, p<0.001, RR=2.1) and immunosuppressive treatment (AZA 27.27% vs 3.92%, p=0.01, RR=1.71, CFM 34.54% vs 0%, p<0.001, RR=2.16), a higher frequency of hypertension (47.27% vs 9.8%, p<0.001, RR=2.4), hyperlipidaemia (49.09% vs 1.96%, p<0.001, RR=1.81) and anti-PL antibodies (49.09% vs 20%, p=0.001, RR=2.70),and a higher mortality (16% vs 2%, p=0.02, RR=1.76). 20 patients (36.36%) from the survival group (55 patients), evoluated to renal failure, 9.09% of these with end -stage renal failure, results that are similar with the ones in other studies. CONCLUSIONS: The study reveals the fact that cardiovascular risk factors such as hypertension, hyperlipidaemia and antiphospholipid syndrome are associated with a higer rate of mortality and an evolution to end-stage renal disease.

The majority of cases of neonatal diabetes in Spain can be explained by known genetic abnormalities.

BACKGROUND: Neonatal diabetes is a rare disease characterized by hyperglycaemia within the first 3 months of life and requiring insulin treatment; it can either be transient (TNDM) or permanent (PNDM). Alterations at band 6q24 and heterozygous activating mutations in KCNJ11, the gene encoding the pore-forming subunit of the KATP channel, can cause neonatal diabetes. Aims We screened the 6q24 region, KCNJ11, GCK, FOXP3 and IPF1 genes for mutations in families with PNDM or TNDM to establish a phenotype-genotype correlation. METHODS: Twenty-two patients with neonatal diabetes were recruited. Inclusion criteria were insulin-treated diabetes diagnosed within the first 3 months and insulin treatment for at least 15 days. Clinical data were recorded in a questionnaire. RESULTS: We identified 17 genetic alterations in our patients: six alterations at the 6q24 band associated with TNDM and nine mutations in KCNJ11, five of which were novel. The analysis for a phenotype-genotype correlation showed that patients with 6q24 alterations had a lower birth weight and were diagnosed earlier than patients with KCNJ11 mutations. At follow-up of the TNDM patients with genetic alterations, 43% developed diabetes or impaired glucose tolerance in later life (one with 6q24 duplication and two with N48D and E227K mutations at KCNJ11 gene). Furthermore, half the first-degree relatives who carried a genetic alteration but who had not suffered from neonatal diabetes were diagnosed with diabetes or impaired glucose tolerance before the age of 30 years. CONCLUSIONS: KCNJ11 mutations are common in both TNDM and PNDM and are associated with a higher birth weight compared with patients with 6q24 abnormalities. Patients with TNDM should be screened for abnormalities in glucose metabolism in adult life.

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease.

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo- and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D- and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (P<10(-5)) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.

Influence of sex and age at onset on autoantibodies against insulin, GAD65 and IA2 in recent onset type 1 diabetic patients.

METHODS: Autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and tyrosine phosphatase IA2 (IA2A) were measured in sera from 448 recent onset patients with type 1 diabetes mellitus (DM) subdivided according to sex (194 female and 254 male) and age at onset (134 patients diagnosed before 10 years, 187 between 10 and 20 years, 66 between 20 and 30 years and 61 over 30 years. RESULTS: Autoantibodies were more frequent in female DM patients (93.8 vs. 86.6%, p = 0.013) due to an increased prevalence of both GADA (86.1 vs. 70.1%) and IA2A (59.3 vs. 49.2%), with GADA levels also significantly higher in women (0.24 vs. 0.18 U, p = 0.0003). When age groups were compared, there was a reduction in prevalence in patients over 20 years for both IAA (70% for patients diagnosed under 20 and 36% for older patients) and IA2A (65 and 25%, respectively). These differences also affected IAA levels, with the highest antibody titres in the youngest group (1,214.1 nU/ml in children under 10 compared to 546.9, 345.6 and 341.1 nU/ml in the subsequent groups; p < 10(-4)). GADA prevalence did not differ significantly between age groups but, nevertheless, autoantibody levels were highest among the oldest type 1 DM patients (0.327 U compared to 0.216, 0.197 and 0.176 U in the decreasing age groups; p < 10(-4)). CONCLUSION: There are sex- and age-related differences affecting the presence and/or titres of beta cell autoantibodies. We speculate that these differences could reflect the severity and specificity of the autoimmune attack against the endocrine pancreas and might influence the rate of progression to type 1 DM or the risk of developing other autoimmune diseases.