Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk.

The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.

IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.

In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.

SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients.

SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.

Characterisation of novel missense mutations in the GH receptor gene causing severe growth retardation.

Two Swedish brothers, 2.5 and 4 years of age, were found to fulfil all the clinical and laboratory characteristics of Laron's syndrome. They were shown to have unique missense mutations in the GH receptor gene. Both of their parents were of normal height, but they both separately carried one of the identified gene alterations. A molecular model of the first receptor alteration suggests that a collapse in three-dimensional receptor structure most likely contributed to the GH insensitivity in these patients.

Eating disorders in adolescent girls with insulin-dependent diabetes mellitus: a population-based case-control study.

In this study the prevalence of eating disorders in a population-based cohort of 89 female patients with type 1 diabetes, 14-18 y of age, was compared with that in age-matched healthy controls. Of all diabetic girls in the study area, 92% participated in the study. The majority were treated with multiple insulin injections and the mean HbA1c of the participants was 8.4%. On average, diabetic girls were 6.8 kg heavier than the controls. A two-stage design was used. The first consisted of a validated self-report questionnaire, the Eating Disorder Inventory (EDI). Girls who had high scores were then interviewed about eating habits and mental health using a semistructured interview, the BAB-T (Assessment of Anorexia-Bulimia - Teenager version). No cases of anorexia or bulimia nervosa were found, but 15 diabetic patients (16.9%) compared with 2 control girls (2.2%), p<0.01, had disturbed eating behaviour according to the questionnaire. In 6 of these 15 diabetic girls an eating disorder was confirmed at the interview, mainly binge eating and self-induced vomiting. None of the control girls showed an eating disorder. Overweight diabetic girls scored higher on EDI than non-overweight diabetic girls (chi2 = 4.9; p = 0.038). No relationships were found between EDI scores and metabolic control (HbA1c), dose of insulin, frequency of hypoglycaemia or diabetic ketoacidosis.

Urinary growth hormone excretion in post-menarcheal adolescent girls with type 1 diabetes.

The aim of the present study was to compare measurements of urinary growth hormone (GH), serum insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP3) between two groups of post-menarcheal girls, 13-18 y of age, one comprising 64 type 1 diabetic patients and the other 64 healthy girls matched for age and stage of puberty. GH was determined on two occasions in nocturnal urine samples by using a modification of an immunoradiometric method for serum. Significantly higher urinary GH concentrations but lower IGF-I and IGFBP3 levels were found in diabetic girls than in controls (p < 0.001). A significant correlation was found between urinary GH concentrations and the daily dose of insulin (U kg[-1]) (r = 0.426, p = 0.003). Urinary GH concentrations were also significantly related to HbA1c (r = 0.380, p = 0.003). In conclusion, disturbances of the GH-IGF-I axis may be evaluated by the use of non-invasive urinary GH measurements, which is a simple alternative to frequent sampling of serum GH. Increased GH secretion seems to be related to a great need for insulin and poor metabolic control. More knowledge about underlying causal factors in the disturbed GH-IGF-I axis is required.

Homozygous protein C deficiency in two siblings.

Homozygous protein C (PC) deficiency is reported in two siblings (girl and boy) who received their proper diagnoses at the ages of 7 4/12 and 1 3/12 years respectively. The girl had perinatal asphyxia without bleeding. At 1 year of age she developed purpura fulminans. Treatment with heparin and plasma was successful. At 7 4/12 years she developed tender, bluish nonnecrotic skin changes after an orthopedic operation. The PC level was 0.08 U/ml. The boy had had a large intraventricular hemorrhage neonatally and developed severe brain damage. At 1 3/12 years he manifested the same skin changes as his sister and was treated similarly. The PC level was 0.05 U/ml. Both children now receive warfarin continuously and are essentially free of symptoms. The cases represent homozygous phenotypes in a family with a recessive trait of PC deficiency without thrombotic disease. The cases also show that severe PC deficiency may be compatible with life beyond infancy without any specific therapy.

Case of Legionnaires' disease with deep venous thrombosis.

During the last three years many cases of Legionnaires' disease have been reported. Several cases reported had underlying disorders such as immunity deficiencies, or were undergoing immunosuppressive therapy. In this report we describe a previously healthy young man who acquired Legionnaires' disease and recovered after ampicillin-gentamicin treatment. During recovery he developed a lower leg thrombosis followed by pulmonary embolism.