TXNIP DNA methylation is associated with glycemic control over 28 years in type 1 diabetes: findings from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study.

INTRODUCTION: DNA methylation (DNAme) has been cross-sectionally associated with type 2 diabetes and hemoglobin A1c (HbA1c) in the general population. However, longitudinal data and data in type 1 diabetes are currently very limited. Thus, we performed an epigenome-wide association study (EWAS) in an observational type 1 diabetes cohort to identify loci with DNAme associated with concurrent and future HbA1cs, as well as other clinical risk factors, over 28 years. RESEARCH DESIGN AND METHODS: Whole blood DNAme in 683 597 CpGs was analyzed in the Pittsburgh Epidemiology of Diabetes Complications study of childhood onset (<17 years) type 1 diabetes (n=411). An EWAS of DNAme beta values and concurrent HbA1c was performed using linear models adjusted for diabetes duration, sex, pack years of smoking, estimated cell type composition variables, and technical/batch covariates. A longitudinal EWAS of subsequent repeated HbA1c measures was performed using mixed models. We further identified methylation quantitative trait loci (meQTLs) for significant CpGs and conducted a Mendelian randomization. RESULTS: DNAme at cg19693031 (Chr 1, Thioredoxin-Interacting Protein (TXNIP)) and cg21534330 (Chr 17, Casein Kinase 1 Isoform Delta) was significantly inversely associated with concurrent HbA1c. In longitudinal analyses, hypomethylation of cg19693031 was associated with consistently higher HbA1c over 28 years, and with higher triglycerides, pulse rate, and albumin:creatinine ratio (ACR) independently of HbA1c. We further identified 34 meQTLs in SLC2A1/SLC2A1-AS1 significantly associated with cg19693031 DNAme. CONCLUSIONS: Our results extend prior findings that TXNIP hypomethylation relates to worse glycemic control in type 1 diabetes by demonstrating the association persists over the long term. Additionally, the associations with triglycerides, pulse rate, and ACR suggest TXNIP DNAme could play a role in vascular damage independent of HbA1c. These findings strengthen potential for interventions targeting TXNIP to improve glycemic control in type 1 diabetes through its role in SLC2A1/glucose transporter 1-mediated glucose regulation.

Risk of longer-term neurological conditions in the Deepwater Horizon Oil Spill Coast Guard Cohort Study - Five years of follow-up.

BACKGROUND: Long-term neurological health risks associated with oil spill cleanup exposures are largely unknown. We aimed to investigate risks of longer-term neurological conditions among U.S. Coast Guard (USCG) responders to the 2010 Deepwater Horizon (DWH) oil spill. METHODS: We used data from active duty members of the DWH Oil Spill Coast Guard Cohort Study (N=45224). Self-reported oil spill exposures were ascertained from post-deployment surveys. Incident neurological outcomes were classified using International Classification of Diseases, 9th Revision, codes from military health encounter records up to 5.5 years post-DWH. We used Cox Proportional Hazards regression to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for various incident neurological diagnoses (2010-2015). Oil spill responder (n=5964) vs. non-responder (n= 39260) comparisons were adjusted for age, sex, and race, while within-responder comparisons were additionally adjusted for smoking. RESULTS: Compared to those not responding to the spill, spill responders had reduced risks for headache (aHR=0.84, 95% CI: 0.74-0.96), syncope and collapse (aHR=0.74, 95% CI: 0.56-0.97), and disturbance of skin sensation (aHR=0.81, 95% CI: 0.68-0.96). Responders reporting ever (n=1068) vs. never (n=2424) crude oil inhalation exposure were at increased risk for several individual and grouped outcomes related to headaches and migraines (aHR range: 1.39-1.83). Crude oil inhalation exposure was also associated with elevated risks for an inflammatory nerve condition, mononeuritis of upper limb and mononeuritis multiplex (aHR=1.71, 95% CI: 1.04-2.83), and tinnitus (aHR=1.91, 95% CI: 1.23-2.96), a condition defined by ringing in one or both ears. Risk estimates for those neurological conditions were higher in magnitude among responders reporting exposure to both crude oil and oil dispersants than among those reporting crude oil only. CONCLUSION: In this large study of active duty USCG responders to the DWH disaster, self-reported spill cleanup exposures were associated with elevated risks for longer-term neurological conditions.

The Impact of a Yearlong Diabetes Prevention Program-Based Lifestyle Intervention on Cardiovascular Health Metrics.

INTRODUCTION: The American Heart Association created "Life's Simple Seven" metrics to estimate progress toward improving US cardiovascular health in a standardized manner. Given the widespread use of federally funded Diabetes Prevention Program (DPP)-based lifestyle interventions such as the Group Lifestyle Balance (DPP-GLB), evaluation of change in health metrics within such a program is of national interest. This study examined change in cardiovascular health metric scores during the course of a yearlong DPP-GLB intervention. METHODS: Data were combined from 2 similar randomized trials offering a community based DPP-GLB lifestyle intervention to overweight/obese individuals with prediabetes and/or metabolic syndrome. Pre/post lifestyle intervention participation changes in 5 of the 7 cardiovascular health metrics were examined at 6 and 12 months (BMI, blood pressure, total cholesterol, fasting plasma glucose, physical activity). Smoking was rare and diet was not measured. RESULTS: Among 305 participants with complete data (81.8% of 373 eligible adults), significant improvements were demonstrated in all 5 risk factors measured continuously at 6 and 12 months. There were significant positive shifts in the "ideal" and "total" metric scores at both time points. Also noted were beneficial shifts in the proportion of participants across categories for BMI, activity, and blood pressure. CONCLUSION: AHA-metrics could have clinical utility in estimating an individual's cardiovascular health status and in capturing improvement in cardiometabolic/behavioral risk factors resulting from participation in a community-based translation of the DPP lifestyle intervention.

Predictors of the age at which natural menopause occurs in women with type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study.

OBJECTIVE: Women with type 1 diabetes (T1D) are thought to experience menopause earlier than women without diabetes, although not all studies agree. We assessed metabolic predictors of the age at which natural menopause occurs among women with T1D participating in the Epidemiology of Diabetes Complications study. METHODS: Women with childhood-onset (<17 y) of T1D who underwent natural menopause without use of hormone therapy during their menopausal transition were included in the analysis (n = 105; mean baseline age, 29.5 and diabetes duration, 20.2 y). Self-reported reproductive history and the Women's Ischemia Syndrome Evaluation hormonal algorithms were used to determine menopause status. Linear regression was used to ascertain whether time-weighted metabolic factors (eg, BMI, lipids, HbA1c, insulin dose, albumin excretion rate [AER]) were associated with age at natural menopause. RESULTS: Univariately, only insulin dose (ß = -4.87, P = 0.04) and log (AER) (ß = -0.62, P = 0.02) were associated (negatively) with age at natural menopause. Adjusting for BMI, smoking status, lipids, HbA1c, number of pregnancies, and oral contraceptive use, each 0.1 unit increase in the daily dose of insulin per kilogram body weight was associated with 0.64 years younger age at natural menopause (P = 0.01), while for every 30% increase in AER, age at natural menopause decreased by 0.18 years (P = 0.03). CONCLUSION: Higher average levels of insulin dose and AER over time were significantly associated with a younger age at which natural menopause occurred among women with T1D. The biologic mechanisms underlying the observed associations between exogenous insulin dose and AER on reproductive health should be investigated among women with T1D.

Cardiovascular health in early adulthood predicts the development of coronary heart disease in individuals with type 1 diabetes: 25 year follow-up from the Pittsburgh Epidemiology of Diabetes Complications study.

AIMS/HYPOTHESIS: Type 1 diabetes increases CHD risk. We examined the use of the American Heart Association's cardiovascular health metrics (blood pressure, total cholesterol, glucose/HbA1c, BMI, physical activity, diet, smoking) to predict incidence of CHD among individuals with type 1 diabetes, with the hypothesis that a better American Heart Association health metric profile would be associated with lower incident CHD. METHODS: Prevalence of the seven cardiovascular health metrics was determined using first and second visits from adult participants (mean age 28.6 years) in the Epidemiology of Diabetes Complications prospective cohort study of childhood-onset type 1 diabetes. An ideal metric score (0-7) was defined as the sum of all metrics within the ideal range, and a total metric score (0-14) was calculated based on poor, intermediate and ideal categories for each metric. Incident CHD development (medical record-confirmed CHD death, myocardial infarction, revascularisation, ischaemic electrocardiogram changes or Epidemiology of Diabetes Complications physician-determined angina) over 25 years of follow-up was examined by metric scores. RESULTS: Among 435 participants, BMI, blood pressure, total cholesterol and smoking demonstrated the highest prevalence within the ideal range, while diet and HbA1c demonstrated the lowest. During 25 years of follow-up, 177 participants developed CHD. In Cox models, each additional metric within the ideal range was associated with a 19% lower risk (p = 0.01), and each unit increase in total metric score was associated with a 17% lower risk (p < 0.01) of CHD, adjusting for diabetes duration, estimated glomerular filtration rate, albumin excretion rate, triacylglycerols, depression and white blood cell count. CONCLUSIONS/INTERPRETATION: Among individuals with type 1 diabetes, higher cardiovascular health metric scores were associated with lower risk of incident CHD. The American Heart Association-defined cardiovascular health metrics provide straightforward goals for health promotion that may reduce CHD risk in the type 1 diabetes population. Graphical abstract.

Periodontal disease, smoking, cardiovascular complications and mortality in type 1 diabetes.

AIM: To assess the role of periodontal disease (PD) as a predictor of coronary artery disease (CAD) and mortality in a prospective type 1 diabetes (T1D) cohort and to evaluate the role of smoking in this relationship. METHODS: Data were based on 320 participants of the Pittsburgh Epidemiology of Diabetes Complications study of T1D who, during 1992-94, received a partial mouth periodontal exam, and who were followed for up to 19 years to ascertain complication incidence. PD was defined as clinical attachment loss of ≥4 mm for at least 10% of the examined sites. Predictors of all-cause mortality; Hard CAD (CAD death, myocardial infarction or revascularization), and Total CAD (Hard CAD, angina, ischemic ECG) were assessed using Cox models. RESULTS: During 19 years of follow-up, 33.7% (97/288) developed CAD, 27.3% (83/304) developed Hard CAD, and 16.9% (54/320) died. Among current smokers, 46.4% (26/56) developed CAD, 42.7% (24/56) developed Hard CAD and 29.5% (18/61) died. PD was not associated with all-cause mortality, although it was a significant predictor of both CAD (HR = 1.12, CI = 1.01-1.23) and Hard CAD (HR = 1.30, CI = 1.11-1.51). As smoking modified the PD-CAD and PD-Hard CAD associations, analyses were stratified by smoking status. PD was associated with an increased risk of CAD (HR = 1.25, CI = 1.03-1.50) and Hard CAD (HR = 1.85, CI = 1.17-2.93) only among smokers. CONCLUSION: PD was a significant predictor of CAD and Hard CAD among current smokers with T1D.

Risk Factor Modeling for Cardiovascular Disease in Type 1 Diabetes in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study: A Comparison With the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC).

In a recent Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study report, mean HbA1c was the strongest predictor of cardiovascular disease (CVD) after age. In DCCT/EDIC, mean diabetes duration was 6 years (median 4) at baseline and those with high blood pressure or cholesterol were excluded. We now replicate these analyses in the Pittsburgh Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset (at <17 years of age) type 1 diabetes, with similar age (mean 27 years in both studies) but longer diabetes duration (mean 19 years and median 18 years) and no CVD risk factor exclusion at baseline. CVD incidence (CVD death, myocardial infarction (MI), stroke, revascularization, angina, or ischemic electrocardiogram) was associated with diabetes duration, most recent albumin excretion rate (AER), updated mean triglycerides, baseline hypertension, baseline LDL cholesterol, and most recent HbA1c Major atherosclerotic cardiovascular events (CVD death, MI, or stroke) were associated with diabetes duration, most recent AER, baseline systolic blood pressure, baseline smoking, and updated mean HbA1c Compared with findings in DCCT/EDIC, traditional risk factors similarly predicted CVD; however AER predominates in EDC and HbA1c in DCCT/EDIC. Thus, the relative impact of HbA1c and kidney disease in type 1 diabetes varies according to diabetes duration.

Greater progression of coronary artery calcification is associated with clinically relevant cognitive impairment in type 1 diabetes.

BACKGROUND AND AIMS: We assessed the predictive role of coronary artery calcification (CAC) in clinically relevant cognitive impairment in 148 middle-aged individuals with childhood-onset type 1 diabetes (T1D) from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. METHODS: Baseline CAC was measured in 1996-98 and repeated 4-8 years later. Per extensive neuropsychological testing in 2010-15, 28% (41/148) of participants met the study definition of clinically relevant cognitive impairment (two or more of 7 select test scores ≥1.5SD worse than demographically appropriate published norms). Logistic regression models with backward selection were constructed for statistical analysis. RESULTS: Mean age and T1D duration at first CAC measure were 37 and 29 years, respectively. A greater burden of initial CAC was associated with cognitive impairment determined 14 years later. Compared to Agatston score = 0, odds ratio (OR) and 95% confidence intervals (CI) of 0<-100, 100<-300 and >300 were 1.4 (0.6, 3.6), 2.3 (0.6, 9.7), and 7.9 (1.6, 38.5), respectively. With both initial and progression of CAC in the multivariable model, backward selection retained only CAC progression, showing it was significantly associated with cognitive impairment (OR [95% CI]: 1.7 [1.1, 2.9]). In those with an initial CAC>0, CAC density was marginally, inversely, associated with cognitive impairment when controlling for CAC volume (OR [95%CI]: 0.3 (0.1, 1.2), p value = 0.078). CONCLUSIONS: Greater CAC burden was associated with clinically relevant cognitive impairment in middle-aged adults with childhood-onset T1D. CAC progression appears to be a more powerful predictor than initial calcification.

White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes.

OBJECTIVE: Although microvascular complications are common in type 1 diabetes mellitus (T1DM), few studies have quantified the severity, risk factors, and implications of cerebral microvascular damage in these patients. As life expectancy in patients with T1DM increases, patients are exposed to age- and disease-related factors that may contribute to cerebral microvascular disease. METHODS: Severity and volume of white matter hyperintensities (WMH) and infarcts were quantified in 97 middle-aged patients with childhood-onset T1DM (mean age and duration: 50 and 41 years, respectively) and 81 non-T1DM adults (mean age: 48 years), concurrent with cognitive and health-related measures. RESULTS: Compared with non-T1DM participants, patients had more severe WMH (Fazekas scores 2 and 3 compared with Fazekas score 1, p < 0.0001) and slower information processing (digit symbol substitution, number correct: 65.7 ± 10.9 and 54.9 ± 13.6; pegboard, seconds: 66.0 ± 9.9 and 88.5 ± 34.2; both p < 0.0001) independent of age, education, or other factors. WMH were associated with slower information processing; adjusting for WMH attenuated the group differences in processing speed (13% for digit symbol, 11% for pegboard, both p ≤ 0.05). Among patients, prevalent neuropathies and smoking tripled the odds of high WMH burden, independent of age or disease duration. Associations between measures of blood pressure or hyperglycemia and WMH were not significant. CONCLUSIONS: Clinically relevant WMH are evident earlier among middle-aged patients with childhood-onset T1DM and are related to the slower information processing frequently observed in T1DM. Brain imaging in patients with T1DM who have cognitive difficulties, especially those with neuropathies, may help uncover cerebral microvascular damage. Longitudinal studies are warranted to fully characterize WMH development, risk factors, and long-term effects on cognition.

Evaluation of non-invasive screening measures to identify individuals with prediabetes.

AIMS: Because blood-based screening to identify those with prediabetes to take part in Diabetes Prevention Program (DPP) translation efforts can be costly and time-consuming, non-invasive methods are needed. The aims of this paper are to evaluate the ability of the American Diabetes Association (ADA) risk test in identifying individuals with prediabetes, as well as the use of body composition measures for this purpose. In addition the utility of these alternate methods to ascertain the presence of the metabolic syndrome was assessed. METHODS: Potential participants were recruited from a worksite and three community centers to take part in a DPP translation study. Participants completed onsite screening where anthropometric measures, fasting lipids and glucose, and hemoglobin A1c were assessed. Those with a BMI ≥24 kg/m(2) and prediabetes and/or the metabolic syndrome were eligible to participate. Non-invasive screening methods were evaluated for their ability to identify those with prediabetes and the metabolic syndrome based on clinically measured values. RESULTS: All non-invasive methods were highly sensitive (68.9% to 98.5%) in the detection of prediabetes, but specificity was low (6.7% to 44.5%). None of the alternatives evaluated achieved acceptable discrimination levels in ROC analysis. Similar results were noted in identifying the metabolic syndrome. CONCLUSIONS: The non-invasive methods evaluated in this study effectively identify participants with prediabetes, but would also allow for enrollment of a large number of individuals who do not have prediabetes. Deciding whether to use these alternatives, blood-based measures, or a combination of both will ultimately depend on the purpose of the program and the level of flexibility regarding participant eligibility.

Changing impact of modifiable risk factors on the incidence of major outcomes of type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications Study.

OBJECTIVE: The incidence of type 1 diabetes complications appears to be decreasing, but relative contributions of risk factors are unclear. We thus estimated the effect of modifiable risk factors on the incidence of a composite end point, major outcomes of diabetes (MOD). RESEARCH DESIGN AND METHODS: The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study was used to derive two cohorts based on diabetes diagnosis year (1960-1969 and 1970-1980). Baseline exam data in the current analysis for the 1960s group were collected in 1986-1988 and for the 1970s in 1996-1998. Each group was followed for 8 years for MOD incidence (diabetes-related death, myocardial infarction, revascularization procedure/blockage ≥50%, stroke, end-stage renal disease, blindness, and amputation). Assessed risk factors include the following: HbA1c, hypertension, microalbuminuria, BMI, hypercholesterolemia, and smoking. Accelerated failure time models were used to estimate the acceleration factor. RESULTS: MOD incidence decreased in the 1970s cohort (15.8% [95% CI 11.6-21.4]) compared with the 1960s (22.6% [17.0-29.1]) over the 8-year follow-up (P = 0.06). Hypertension and microalbuminuria were associated with significantly accelerated MOD incidence in both cohorts (P < 0.01 for both). High HbA1c (P = 0.0005), hypercholesterolemia (P = 0.01), and current smoking (P = 0.003) significantly accelerated the incidence of MOD in the 1960s but not 1970s cohort. BMI was not associated with MOD in either cohort. CONCLUSIONS: These results suggest that hypertension and microalbuminuria remain important predictors of complications that are not being adequately addressed.

Type A behavior and risk of all-cause mortality, CAD, and CAD-related mortality in a type 1 diabetic population: 22 years of follow-up in the Pittsburgh Epidemiology of Diabetes Complications Study.

OBJECTIVE: To determine whether type A behavior predicts all-cause mortality and incident coronary artery disease (CAD) in a type 1 diabetic population. RESEARCH DESIGN AND METHODS: Follow-up data (22 years) from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset type 1 diabetes were analyzed for the 506 participants who completed the Bortner Rating Scale (measuring type A behavior) and Beck Depression Inventory (BDI) at baseline (1986-1988). CAD comprised myocardial infarction as determined by hospital records/Q waves on electrocardiogram (ECG), CAD death (determined by a mortality classification committee), angiographic stenosis, ischemic ECG, and angina. RESULTS: There were 128 deaths (25.3%) during follow-up. Univariate analysis showed an inverse relationship between Bortner scores and all-cause mortality (P=0.01), which remained significant after allowing for age, sex, duration, HbA1c, education, smoking, BMI, and physical activity (P=0.03). However, the addition of BDI scores attenuated the relationship (P=0.11) with a significant interaction (P=0.03) such that any protective effect against mortality was limited among individuals with lower BDI scores (bottom three quintiles) (P=0.07), whereas no effect was seen in those with higher BDI scores (P=0.97). Bortner scores showed only a borderline association with incident CAD (P=0.09). CONCLUSIONS: Those with higher type A behavior have lower all-cause mortality in our type 1 diabetic population, an effect that interacts with depressive symptomatology such that it is only operative in those with low BDI scores. Further research should focus on understanding this interaction.

Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.

Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resolution. We show that diabetic mice have increased numbers of circulating neutrophils and Ly6-C(hi) monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil production of S100A8/S100A9, and its subsequent interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions, and promotes regression. In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes.

Test characteristics of the ankle-brachial index and ankle-brachial difference for medial arterial calcification on X-ray in type 1 diabetes.

OBJECTIVE: Medial arterial calcification (MAC) is common in diabetes, has a characteristic appearance on X-ray imaging, and has been linked with peripheral arterial stiffness and cardiovascular disease. However, few studies have measured X-ray MAC. It has been suggested that an ankle-brachial index (ABI) >1.30 or an ankle-brachial difference (ABD) >75 mm Hg may identify X-ray MAC, but test characteristics are unknown. We hypothesized that an ABI >1.30 and ABD >75 mm Hg would have high specificity but low sensitivity for MAC on X-ray imaging. METHODS: This was a cross-sectional study of 185 community-living individuals with type 1 diabetes. The ABI and the ABD were assessed. The outcome was linear "tram-track" calcifications in the lower limbs characteristic of MAC. RESULTS: Mean age was 32 ± 6 years, and mean diabetes duration was 23 ± 7 years. X-ray MAC was noted in 97 individuals (57%), 15 (8%) had ABI >1.30, and 14 (8%) had ABD >75 mm Hg. As assessed by the ABI, the area under the receiver operating characteristic curve for MAC was modest (0.65) and was slightly higher for the ABD (0.75). An ABI >1.30 had high specificity (99%) and positive predictive value (93%) but poor sensitivity (14%) and an overall accuracy of 55% for MAC. An ABD >50 mm Hg remained highly specific (98%) but had higher sensitivity (30%) and overall accuracy (62%). CONCLUSIONS: Individuals with type 1 diabetes and an ABI >1.30 or ABD >50 mm Hg are very likely to have MAC on X-ray imaging, yet many with MAC will not have an ABI or ABD above these thresholds. Given the high specificity, evaluating high ABI or ABD may be useful to understand correlates of MAC but may underestimate MAC prevalence.

Variants of the adenosine A(2A) receptor gene are protective against proliferative diabetic retinopathy in patients with type 1 diabetes.

AIMS: The adenosine A(2A) receptor (ADORA(2A)) may ameliorate deleterious physiologic effects associated with tissue injury in individuals with diabetes. We explored associations between variants of the ADORA(2A) gene and proliferative diabetic retinopathy (PDR) in a cohort of patients with type 1 diabetes (T1D). METHODS: The participants were from the Pittsburgh Epidemiology of Diabetes Complications prospective study of childhood-onset T1D. Stereoscopic photographs of the retinal fundus taken at baseline, then biennially, for 10 years were used to define PDR according to the modified Airlie House system. Two tagging single nucleotide polymorphisms (tSNPs; rs2236624-C/T and rs4822489-G/T) in the ADORA(2A) gene were selected using the HapMap (haplotype map) reference database. RESULTS: A significant association was observed between SNP rs2236624 and PDR in the recessive genetic model. Participants homozygous for the T allele displayed a decreased risk of developing prevalent PDR (odds ratio, OR = 0.36; p = 0.04) and incident PDR (hazard ratio = 0.156; p = 0.009), and for all cases of PDR combined (OR = 0.23; p = 0.001). The protective effect of T allele homozygosity remained after adjusting for covariates. Similarly, for SNP rs4822489, an association between PDR and T allele homozygosity was observed following covariate adjustment (OR = 0.55; 95% CI: 0.31-0.92; p = 0.04). CONCLUSION: Genetic variants of ADORA(2A) offer statistically significant protection against PDR development in patients with T1D.

Retinal vessel diameter and the incidence of coronary artery disease in type 1 diabetes.

PURPOSE: To examine the relationship between retinal vessel diameter and coronary artery disease (CAD) incidence in type 1 diabetes (T1D) using data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. DESIGN: Prospective cohort study of childhood-onset T1D. METHODS: Data are from 448 participants who had retinal photographs taken at baseline examination (May 1986 to November 1988) and no history of laser photocoagulation. Computer-assisted grading was used to measure retinal arteriolar and venular caliber. CAD incidence (CAD death, myocardial infarction, revascularization/stenosis > or =50%, ischemic electrocardiogram, or physician-diagnosed angina) was ascertained over a median follow-up time of 18 years (range, 2 months to 20.5 years). RESULTS: Mean baseline arteriolar and venular caliber were 180.0 microm (standard deviation [SD], 15.2 microm) and 273.3 microm (SD, 28.0 microm), respectively; 80 (17.9%) CAD events occurred during follow-up. After covariate adjustment for T1D duration, gender, hypertension, serum lipids, and smoking status, smaller arteriolar caliber was significantly associated with CAD (hazard ratio [HR], 1.42; P = .03), but larger venular caliber was not. A vessel diameter-gender interaction term was significant for arteriolar caliber (P = .006). Stratified by gender, smaller arteriolar caliber was significantly associated with the incidence of CAD in women (HR, 1.92; P = .004), but not men. Venular caliber was not associated with CAD in either gender. CONCLUSION: Smaller arteriolar caliber may indicate an increased risk of CAD in women, but not men, with T1D. Additional studies are needed to further examine the role of microvascular disease in the pathogenesis of CAD in women with T1D.

Double-edged relationship between adiposity and coronary artery calcification in type 1 diabetes.

Coronary artery disease (CAD), a leading cause of death in type 1 diabetes (T1D), often occurs two or more decades earlier in this population compared to the population without diabetes. Although CAD generally increases with adiposity, this association is unclear in T1D. In this study, we examined associations of adiposity with coronary artery calcium (CAC) in 315 individuals with T1D. Mean age and diabetes duration were 42 and 34 years, respectively, at study entry. CAC, visceral adiposity (VAT) and subcutaneous adiposity (SAT) were determined by electron beam tomography; and BMI and waist circumference (WC) were determined. The presence of CAC was positively associated with VAT, SAT and BMI in men (p<0.05) and with all four adiposity measures in women (p<0.05) after adjustment for age and other traditional cardiovascular risk factors. However, after adjustment, the degree of CAC was not associated with any of the four adiposity measures, with the exception of SAT in women. Women in the lowest tertile of SAT had more CAC than those in the second tertile (p<0.016). Adiposity was positively associated with the presence of CAC, but the relationship with its severity was either inverse or non-existent. This double-edged association emphasises the complex relationship between adiposity and cardiovascular risk in diabetes.