Atopy, home environment and the risk of childhood-onset type 1 diabetes: a population-based case-control study.

BACKGROUND: The marked increases in the incidence of type 1 diabetes in recent decades strongly suggest the role of environmental influences. These environmental influences remain largely unknown. OBJECTIVE: To investigate atopy and home environment (such as children living at home, sharing a bedroom and house moves) as potential risk factors for type 1 diabetes. SUBJECTS AND METHOD: In Northern Ireland, 175 children with type 1 diabetes and 4859 control children completed a questionnaire on atopy experience, family composition and home environment. Control children from two age groups (6-8 yr old and 13-14 yr old) were identified from randomly selected primary and secondary schools across Northern Ireland. Cases were identified from a population-based type 1 diabetes register. RESULTS: There was little evidence of a difference in the proportion of participants with a history of atopy in the cases compared with controls. There was a significant reduction in the risk of diabetes in children who lived with more siblings {odds ratio (OR) = 0.58 [95% confidence interval (95% CI) 0.39-0.85] in children who lived with three or more siblings compared with one or none} and in children who moved house more often [OR = 0.59 (95% CI 0.40-0.88) in children who moved house twice or more compared with never]. CONCLUSION: The reduced risk of type 1 diabetes in children living with siblings, sharing a bedroom and moving house more often could reflect the protection afforded by exposure to infections in early life and consequently may provide support for the hygiene hypothesis.

Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects.

Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.

Reduced prevalence of limited joint mobility in type 1 diabetes in a U.K. clinic population over a 20-year period.

OBJECTIVE: Limited joint mobility (LJM), one of the earliest clinically apparent long-term complications of type 1 diabetes, is a risk marker for subsequent microvascular complications. We hypothesize that the prevalence of LJM may have decreased during the past two decades due to improved standards of glycemic control. RESEARCH DESIGN AND METHODS: A single observer performed a survey in 204 consecutive patients with type 1 diabetes (106 men and 98 women, age 27 +/- 1 years, HbA(1c) 8.3 +/- 0.1%, duration of diabetes 14.5 +/- 0.8 years, insulin dose 63 +/- 2 units/day). We used the same examination method and criteria for assessment of LJM as used by us in an earlier study in 1981-1982. RESULTS: The prevalence of LJM has fallen from 43 to 23% between the 1980s and 2002 (P < 0.0001). The relative risk for LJM in 2002 compared with the 1981-1982 cohort was 0.53 (0.40 < RR < 0.72, P < 0.0001). The prevalence of LJM was increased with longer duration of diabetes (<10 years, 13%; 10-20 years, 19%; 20-29 years, 30%; >30 years, 65%; P < 0.001). The relative risk for those with a mean HbA(1c) <7% in 2002 was 0.3 (0.1 < RR < 1.2, P = 0.05) when compared with those with mean HbA(1c) >7%. CONCLUSIONS: The present study confirms the hypothesis that the prevalence of LJM is lower than 20 years ago and that improved standards of glycemic control and diabetes care may have contributed to this occurrence. Joint limitation in type 1 diabetes is strongly associated with duration of diabetes. The presence of LJM remains a common and important clinical marker for subsequent microvascular disease and can be a useful clinical tool for identification of patients at increased risk.

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.

A meta-analysis of the association between childhood type 1 diabetes and atopic disease.

OBJECTIVE: To review the published literature and perform a meta-analysis summarizing the evidence in support of an inverse association between type 1 diabetes and the atopic disorders: asthma, eczema, and allergic rhinitis in children. RESEARCH DESIGN AND METHODS: MEDLINE, Web of Science, and PubMed were searched to identify relevant studies. These were assessed on quality criteria, and odds ratios (ORs) and 95% CIs were calculated for each study from the reported prevalences of atopy in children with diabetes and in control children. Meta-analysis was then used to derive a combined OR and test for heterogeneity in findings between studies. RESULTS: Twenty-five studies were identified. Heterogeneity in the findings from different studies was evident but was considerably reduced when the asthma and rhinitis analyses were restricted to those studies judged to be of adequate design. The meta-analysis revealed an inverse association between asthma and type 1 diabetes, but the finding only attained significance when analysis was restricted to the studies of adequate design (OR 0.82, 95% CI 0.68-0.99). In this subset an association of similar magnitude was observed between eczema and type 1 diabetes (0.82, 0.62-1.10) although this failed to attain statistical significance, and heterogeneity between studies was still present. There was little evidence of an association between rhinitis and type 1 diabetes (0.97, 0.82-1.16) in this subset of studies. CONCLUSIONS: Our analysis suggests that there is a small but significant reduction in the prevalence of asthma in children with type 1 diabetes, but the findings for the other atopic diseases are less conclusive.

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.