Dose-dependent effect of smoking on risk of coronary heart disease,heart failure and stroke in individuals with type 1 diabetes

Aims/hypothesis

The aim of this study was to assess the potential dose-dependent effects of smoking on the risk of CHD, heart failure and stroke in individuals with type 1 diabetes.

Methods

The study included 4506 individuals with type 1 diabetes who were participating in the Finnish Diabetic Nephropathy (FinnDiane) study. Intensity of smoking was estimated by packs per day and cumulative smoking by pack-years. Cox regression analyses were used to estimate the risk of incident CHD, heart failure or stroke during follow-up.

Results

One pack per day significantly increased the risk of incident CHD in current smokers compared with never smokers (HR 1.45 [95% CI 1.15, 1.84]), after adjustment for age, sex, HbA_1c, hypertension, duration of diabetes and BMI. The risk of CHD in former smokers was similar to the risk in never smokers. The risk of incident heart failure was 1.43 (95% CI 1.03, 1.97) in current smokers per one pack per day and 1.37 (95% CI 1.05, 1.77) in former smokers, while the risk of incident stroke was 1.70 (95% CI 1.26, 2.29) and 1.49 (95% CI 1.14, 1.93), respectively. After further adjustments for lipids, however, the difference in the risk of heart failure in current and former smokers was no longer significant. Cumulative smoking data were similar to smoking intensity data.

Conclusions/interpretation

There is a dose-dependent association between smoking and cardiovascular disease in individuals with type 1 diabetes. In men in particular, the risk of incident stroke remains high even after smoking cessation and is increased in current and former smokers independently of other risk factors.

     

Early mortality in EURODIAB population-based cohorts of type 1 diabetes diagnosed in childhood since 1989

AIMS/HYPOTHESIS: The aims of this study were to provide a contemporary picture of mortality and causes of death in Europe following a diagnosis of type 1 diabetes made before the 15th birthday, and to examine excess mortality by country for possible links to incidence level or national prosperity. METHODS: Thirteen population-based EURODIAB registers in 12 countries followed-up 28,887 children diagnosed since 1989, either by record linkage to population registers or through contact with doctors providing care. RESULTS: There were 141 deaths in the cohort during 219,061 person-years of follow-up compared with 69.1 deaths expected from national mortality rates, a standardised mortality ratio (SMR) of 2.0 (95% CI 1.7-2.4). The SMR varied from 0 to 4.7 between countries, but showed little relationship with the country's incidence rate or gross domestic product (US$ per capita). The SMR did not change significantly with attained age, calendar period or time since diagnosis. The female SMR (2.7; 95% CI 2.0-3.5) was greater than the male SMR (1.8; 95% CI 1.4-2.2), although absolute numbers of excess deaths were similar in the two sexes. One-third of deaths were classified as directly attributable to diabetes (many with mention of ketoacidosis) and half were unrelated to diabetes. There was a non-significant excess of accidental/violent deaths (48 observed vs 40.7 expected; SMR 1.2; 95% CI 0.9-1.6) but little excess in suicides (11 observed, 10.2 expected; SMR 1.1; 95% CI 0.5-1.9). CONCLUSIONS/INTERPRETATION: Before the onset of late complications, significant excess mortality existed following the diagnosis of type 1 diabetes in childhood, even in recent years. Variation between countries in this excess could not be explained.     

Age at Onset of Type 1 Diabetes in Parents and Recurrence Risk in Offspring

OBJECTIVE

Our aim was to study the recurrence risk of type 1 diabetes in the offspring of parents with adult-onset (15–39 years) type 1 diabetes and to evaluate the transmission of diabetes within a continuum of parental age at onset of diabetes from childhood to adulthood.

RESEARCH DESIGN AND METHODS

Diabetes status of all offspring (n = 9,636) in two Finnish cohorts of parents with type 1 diabetes was defined until the end of year 2007. Cumulative incidences of type 1 diabetes among the offspring were estimated, and several factors contributing to the risk were assessed.

RESULTS

During 137,455 person-years, a total of 413 offspring were diagnosed with type 1 diabetes. The cumulative incidence by 20 years was 4.0% (95% CI 3.1–4.8) for the offspring of parents with adult-onset diabetes. The risk was equal according to the sex of the parents. The cumulative incidence decreased in parallel with the increase in age at onset of diabetes in the fathers. In the offspring of diabetic mothers, the risk was equal regardless of the age at onset of diabetes. However, the reduced risk in the maternal offspring was most pronounced in the daughters of the mothers with a diagnosis age <10 years.

CONCLUSIONS

Type 1 diabetes transmission ratio distortion is strongly related to the sex and age at onset of diabetes in the diabetic parents.Type 1 diabetes can occur at any age, although it is predominantly seen in children and young adults. Therefore, the majority of studies have been conducted in children aged <15 years. The recurrence risk in the offspring ranges from 3 to 6% depending on the study design, follow-up time, and the population where the study was conducted (1–3). Little is known about the recurrence risk in first-degree relatives of subjects diagnosed with type 1 diabetes, aged >15 years. The incidence of type 1 diabetes is much lower in young adults than in children (4–6). Consequently, the risk of family members may also be different among the diabetic subjects affected after childhood.Sex-related factors seem to be involved in the transmission of diabetes from one generation to the next (7). By 20 years of age, 5–8% of the offspring of diabetic men and only 2–5% of the offspring of diabetic women have been found to be affected (1–3,8). We have previously shown that the recurrence risk of diabetes in the offspring of parents diagnosed between 0–17 years of age was higher the younger the father was when diagnosed with type 1 diabetes. This pattern was not present in the offspring of the mothers (8). However, it is not known whether the sex-related factors play a role in the transmission of diabetes in adult-onset type 1 diabetes. We have now enlarged our study to also include the offspring of parents diagnosed with diabetes between 15 and 39 years of age. This gives us an opportunity to determine the risk in the offspring of parents with a broad age span at diagnosis and to elucidate whether there are differences in the risk between the offspring of diabetic mothers and fathers.     

Physical therapists who claimed workers' compensation: a qualitative study

BACKGROUND AND PURPOSE: Although most physical therapists experience work-related musculoskeletal disorders (WMSDs) at some time, only a small minority claim workers' compensation. This article describes the experiences of a group of therapists with WMSDs who made compensation claims. METHODS: Interviews were used to document the experiences of physical therapists who reported that they had changed their career because of WMSDs. RESULTS AND DISCUSSION: Therapists described their experiences in negative terms and found dealing with the workers' compensation system frustrating and unpleasant. They encountered attitudes that labeled them as malingerers and felt their credibility was questioned. CONCLUSIONS: Physical therapists' experiences of the workers' compensation system were negative, and they were keen to become independent of it. Those who claimed workers' compensation perceived that a compensable claim could limit their employment opportunities, making confidentiality an important issue when treating other health care professionals.     

Serum 25-hydroxyvitamin D level during early pregnancy and type 1 diabetes risk in the offspring

Aims/hypothesis  

Vitamin D deficiency during the fetal period or infancy is one of the suggested environmental factors for type 1 diabetes and for its increasing incidence. To test this hypothesis we compared serum 25-hydroxyvitamin D (25(OH)D) levels during early pregnancy in mothers of children who subsequently developed type 1 diabetes (case mothers) with mothers of non-diabetic healthy children (control mothers) of the same age.     

Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

Aims/hypothesis

Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD.

Methods

We exploited a novel algorithm, ‘Bag of Naive Bayes’, whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK–Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US).

Results

Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case–control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p?<?0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno.

Conclusions/interpretation

This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.     

Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes

Aims/hypothesis

An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes.

Methods

The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10^?4 were followed up in 3,750 additional patients with type 1 diabetes from seven studies.

Results

The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p?<?5?×?10^?8). In the replication group, a nominally significant association (p?=?0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p?=?0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.

Conclusions/interpretation

This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.