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.

Aims/hypothesis. Although ischaemic heart disease is the predominant cause of mortality in older people with diabetes, age-specific mortality rates have not been published for patients with Type 1 diabetes. The Diabetes UK cohort, essentially one of patients with Type 1 diabetes, now has sufficient follow-up to report all heart disease, and specifically ischaemic heart disease, mortality rates by age. Methods. A cohort of 23,751 patients with insulintreated diabetes, diagnosed under the age of 30 years and from throughout the United Kingdom, was identified during the period 1972 to 1993 and followed for mortality until December 2000. Age-and sex-specific heart disease mortality rates and standardised mortality ratios were calculated. Results. There were 1437 deaths during the follow-up, 536 from cardiovascular disease, and of those, 369 from ischaemic heart disease. At all ages the ischaemic heart disease mortality rates in the cohort were higher than in the general population. Mortality rates within the cohort were similar for men and women under the age of 40. The standardised mortality ratios were higher in women than men at all ages, and in women were 44.8 (95%CI 20.5-85.0) at ages 20-29 and 41.6 (26.7-61.9) at ages 30-39. Conclusions/interpretation. The risk of mortality from ischaemic heart disease is exceptionally high in young adult women with Type 1 diabetes, with rates similar to those in men with Type 1 diabetes under the age of 40. These observations emphasise the need to identify and treat coronary risk factors in these young patients. [Diabetologia (2003) 46:760-765]

Aims/hypothesis The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998) and second (1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008) halves of the period. Methods All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology.Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied. Results Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase -012-2571-8 were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half. Conclusions/interpretation The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.Diabetologia (2012) 55:2142-2147 DOI 10.1007/s00125

Aims/hypothesis Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years. Methods Age/sex-standardised incidence rates for the 0-to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25 years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends. Results Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0-to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5-to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10-to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4 year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012. Conclusions/interpretation Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4 year periodicity, no plausible explanation for this can be given.

The aims of the first proficiency evaluation of the Diabetes Antibody Standardization Program (DASP) were to assess general implementation of assay methods and to evaluate the new World Health Organization (WHO) reference reagent for autoantibodies to GAD and IA-2. Forty-six laboratories in 13 countries received coded sera from 50 patients with newly diagnosed type 1 diabetes and 50 blood donor control subjects, together with the WHO reference reagent and diluent serum. Results were analyzed using receiver operator characteristic (ROC) curves. Sensitivity was adjusted to 90% specificity in workshop controls. The median adjusted sensitivity for GADA (45 laboratories) was 84% (range 62-96%), for IA-2A (43 laboratories) was 58% (50 -74%), and for insulin autoantibody (IAA; 23 laboratories) was 36% (13-66%). ROC curve analysis showed all GADA and IA-2A assays, and 18/23 IAA assays found significant differences between patients and control subjects. There was good concordance between laboratories in ranking of samples by GADA and IA-2A levels or if results were expressed in relation to the WHO reference reagent. Assays that achieved the highest sensitivity for IAA were also concordant in ranking samples, but overall concordance for IAA was poor. Differences in assay protocols between laboratories must be addressed so that all centers and kit manufacturers can perform to the same high standard. Diabetes