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Biomedical subjects

Edwin A M Gale

Publications and source records attributed to Edwin A M Gale.

At least 19 recordsLinked to original sources
PubMed2006

Dying of diabetes.

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Africa South of the Sahara↗
PubMed2006

Islet autoimmunity in children with Down's syndrome.

There is an unexplained excess of type 1 diabetes and other organ-specific autoimmune diseases in children with Down's syndrome, but the immunogenetic characteristics of diabetes in Down's syndrome have not been investigated. We studied the frequency of islet autoantibodies in 106 children with Down's syndrome and no history of autoimmunity and analyzed HLA class II genotypes in 222 children with Down's syndrome, 40 children with Down's syndrome and type 1 diabetes, 120 age- and sex-matched children with type 1 diabetes, and 621 healthy control subjects. Co-occurrence of at least two islet autoantibody markers was observed in 6 of 106 nondiabetic children with Down's syndrome compared with 13 of 2,860 healthy age-matched children (P < 0.001). There was an excess of diabetes-associated HLA class II genotypes in children with Down's syndrome and type 1 diabetes compared with age- and sex-matched healthy control subjects (P < 0.001). Down's syndrome children with type 1 diabetes were, however, less likely to carry the highest risk genotype DR4-DQ8/DR3-DQ2 than children with type 1 diabetes from the general population (P = 0.01) but more likely to carry low-risk genotypes (P < 0.0001). The frequency of subclinical islet autoimmunity is increased in Down's syndrome, and susceptibility to type 1 diabetes in Down's syndrome is partially HLA mediated. Other factors, possibly including genes on chromosome 21, may increase the penetrance of type 1 diabetes in Down's syndrome.

Adolescent↗
PubMed2005

Survival of the fittest? Natural selection in islet transplantation.

The full potential of cadaveric islet transplantation will only be realized by avoiding both pretransplant insults programming islets for subsequent death and posttransplant triggers for apoptosis and necrosis. The immediate blood mediated inflammatory response causes significant islet loss in the immediate posttransplant period. However, if we focus on this alone we will miss many opportunities to improve transplanted islet survival. Even when single donor islet transplants become the norm, there will still be more patients who might benefit from islet transplants than grafts available. Input from "transplanters" and diabetologists is essential in order to select appropriate patients for islet transplantation.

Graft Survival↗
PubMed2005

Is puberty an accelerator of type 1 diabetes in IL6-174CC females?

The pubertal peak in onset of type 1 diabetes occurs earlier in girls than boys. We postulated that this sex difference might be mediated in part by estrogen or by genes regulated by estrogen, such as the interleukin-6 (IL6) gene. Previous studies concerning the role of an estrogen-sensitive single nucleotide polymorphism (SNP) in the IL6 promoter in type 1 diabetes have proved contradictory. We therefore selected a large, genetically homogenous population-based cohort, analyzed by age at onset and sex, to test the hypothesis that the IL6-174G>C SNP affects age at onset of type 1 diabetes in females but not in males. We found that the IL6-174CC genotype was significantly less frequent in females diagnosed after than in those diagnosed before the age of 10 years (19 vs. 13%, P = 0.016). No genotype difference was observed in males stratified for age at onset. Among children diagnosed after age 10, the median age of onset was 11.9 years (intraquartile range 10.7-14.6) in 34 girls homozygous for IL6-174C compared with 13.2 years (11.6-15.4) in 229 girls with other genotypes and 13.5 years (12.0-15.6) in 339 males with any IL6-174 genotype (P = 0.012). These data support the hypothesis that pubertal changes may contribute to accelerated onset of type 1 diabetes in genetically susceptible females. This phenomenon may be orchestrated by the action of estrogen on the IL6 promoter.

Adolescent↗
PubMed2004

Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom.

The autoimmune disease process leading to childhood-onset type 1 diabetes appears to start in infancy, and decisions on treatment to prevent initiation of autoimmunity will need to be based on genetic susceptibility alone. We set out to quantify the absolute risk associated with human leukocyte antigen (HLA) DRB1-DQA1-DQB1 class II genotypes and to develop strategies for recruitment into primary prevention trials. HLA class II haplotype- and genotype-specific risks were derived from 753 United Kingdom families from the Bart's-Oxford population-based study of type 1 diabetes and combined with incidence data from the region to calculate the absolute risk of development of diabetes. A hierarchy of susceptibility was established for both HLA class II haplotypes and genotypes, and the sensitivity and specificity of each genotype was established relative to age at disease onset. Highest risk was conferred by the genotype DRB1*03-DQA1*0501-DQB1*0201/DRB1*0401-DQA1*0301-DQB1*0302 (5% absolute risk of diabetes by age 15 yr), although sensitivity was only 22.6%. Combining the six highest risk genotypes conferred similar risk but increased sensitivity to 36.6% and was most sensitive for diagnosis of diabetes before age 5 yr (48.4%), whereas inclusion of 11 genotypes achieved the same sensitivity for diagnosis for ages 10-14 yr. Analysis of genotype-specific risk should form the basis for design of future primary prevention trials in the general population.

Age of Onset↗
PubMed2004

Activating mutations in the KCNJ11 gene encoding the ATP-sensitive K+ channel subunit Kir6.2 are rare in clinically defined type 1 diabetes diagnosed before 2 years.

We have recently shown that permanent neonatal diabetes can be caused by activating mutations in KCNJ11 that encode the Kir6.2 subunit of the beta-cell ATP-sensitive K(+) channel. Some of these patients were diagnosed after 3 months of age and presented with ketoacidosis and marked hyperglycemia, which could have been diagnosed as type 1 diabetes. We hypothesized that KCNJ11 mutations could present clinically as type 1 diabetes. We screened the KCNJ11 gene for mutations in 77 U.K. type 1 diabetic subjects diagnosed under the age of 2 years. One patient was found to be heterozygous for the missense mutation R201C. She had low birth weight, was diagnosed at 5 weeks, and did not have a high risk predisposing HLA genotype. A novel variant, R176C, was identified in one diabetic subject but did not cosegregate with diabetes within the family. In conclusion, we have shown that heterozygous activating mutations in the KCNJ11 gene are a rare cause of clinically defined type 1 diabetes diagnosed before 2 years. Although activating KCNJ11 mutations are rare in patients diagnosed with type 1 diabetes, the identification of a KCNJ11 mutation may have important treatment implications.

Diabetes Mellitus, Type 1↗
PubMed2003

Association of intercellular adhesion molecule-1 gene with type 1 diabetes.

Intercellular adhesion molecule-1 (ICAM-1) functions via its ligands, the leucocyte integrins, in adhesion of immune cells to endothelial cells and in T cell activation. The third immunoglobulin-like extracellular domain binds integrin Mac-1 and contains a common non-conservative aminoacid polymorphism, G241R. Phenotypically, ICAM-1 has been associated with type 1 diabetes, a T-cell-mediated autoimmune disease. We assessed two independent datasets, and noted that R241 was associated with lower risk of type 1 diabetes than is G241 (3695 families, relative risk 0.91, p=0.03; 446 families, 0.60, p=0.006). Our data indicate an aetiological role for ICAM-1 in type 1 diabetes, which needs to be confirmed in future genetic and functional experiments.

Diabetes Mellitus, Type 1↗
PubMed2003

Mortality from cerebrovascular disease in a cohort of 23 000 patients with insulin-treated diabetes.

BACKGROUND AND PURPOSE: Disease of the cardiovascular system is the main cause of long-term complications and mortality in patients with type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. Cerebrovascular mortality rates have been shown to be raised in patients with type II diabetes but have not previously been reported by age and sex in patients with type I diabetes. METHODS: A cohort of 23 751 patients with insulin-treated diabetes, diagnosed under the age of 30 years from throughout the United Kingdom, was identified during 1972 to 1993 and followed up for mortality until the end of December 2000. Age- and sex-specific mortality rates and standardized mortality ratios (SMRs) were calculated. RESULTS: There were 1437 deaths during the follow-up, 80 due to cerebrovascular disease. Overall, the cerebrovascular mortality rates in the cohort were higher than the corresponding rates in the general population, and the SMRs were 3.1 (95% CI, 2.2 to 4.3) for men and 4.4 (95% CI, 3.1 to 6.0) for women. When stratified by age, the SMRs were highest in the 20- to 39-year age group. After subdivision of cause of death into hemorrhagic and nonhemorrhagic origins, there remained a significant increase in mortality from stroke of nonhemorrhagic origin. CONCLUSIONS: Analyses of mortality from this cohort, essentially one of patients with type I diabetes, has shown for the first time that cerebrovascular mortality is raised at all ages in these patients. Type I diabetes is at least as great a risk factor for cerebrovascular mortality as type II diabetes.

Adolescent↗
PubMed2002

High familial risk and genetic susceptibility in early onset childhood diabetes.

Early onset type 1 diabetes is associated with rapid beta-cell failure and high levels of HLA-mediated genetic susceptibility. We examined familial risk of disease in relation to age at onset in 1,299 families participating in the Bart's Oxford population-based family study of type 1 diabetes. Risk of diabetes was estimated by survival analysis in 1,430 siblings and 2,419 parents and related to age at onset in the proband. Unaffected relatives at high risk were identified by measurement of islet autoantibodies, and HLA class II genotyping was performed in probands where DNA was available (573 children). The cumulative risk of diabetes by age 20 years was 11.7% in siblings of probands diagnosed before age 5 years, compared with 3.6% for ages 5-9 years and 2.3% for ages 10-14 years (P < 0.0001). In parents, the cumulative risk by age 40 years was 5.9% if the proband was diagnosed before age 5 years, compared with 3.7% for ages 5-9 years and 3.7% for ages 10-14 years (P = 0.04). Of 1,169 unaffected siblings tested at study entry, 7.3% had two or more autoantibody markers if the proband was diagnosed before age 5 years, compared with 2.2 and 2.4%, respectively, for ages 5-9 and 10-14 years (P = 0.002). The frequency of the highest risk genotype decreased with increasing age at onset. Of children diagnosed before age 5 years, 52% were heterozygous for HLA DRB1*03-DQA1*0501-DQB1*02/DRB1*04-DQA1*0301-DQB1*0302 compared with 32% and 33%, respectively, for children diagnosed at ages 5-9 and 10-14 years (P < 0.001). Diabetes with onset before age 5 years is therefore a marker of high familial risk.

Adolescent↗