EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS (EDIC)
Principal Investigator: John M. Lachin, Sc.D.
Director of Coordinating Center: Patricia A. Cleary, M.S.
Epidemiology of Diabetes Interventions and Complications (EDIC) is a multi-center, longitudinal, observational study designed to utilize the well- characterized Diabetes Control and Complications Trial DCCT cohort of 1297 patients (EDIC, 2009). Data collection focuses on nephropathy and macrovascular complications. Annual or biennial measurements (using DCCT methods, standardized protocols and central laboratories) of vascular events, albumin excretion, GFR, ECG, ankle-brachial BP index, carotid wall thickness, serum lipids and HbA1c allows the following analyses: 1) continuation of intention-to- treat analyses to determine long-term effects of prior separation of glycemic levels; 2) risk factors for macrovascular outcomes; 3) correlation of progression of micro- and macrovascular outcomes. The current updated version of the EDIC Protocol is available for download.
EDIC began in 1994 and to date has studied more than 90% of the cohort at each annual visit. Numerous manuscripts and presentations have been published, all based on the EDIC data. Numerous manuscripts and presentations have been published, all based on the EDIC data. In addition, EDIC has collaborated with other research groups on grants that look at specific complications of diabetes:
1. "Markers and Mechanisms of Macrovascular Disease in Type 1 Diabetes" (Medical University of South Carolina)
2. "Does Treatment Affect Cognition in Type 1 Diabetes" (Joslin Diabetes Center in Boston)
3. "The DCCT/EDIC Genetics Study" (University of Toronto)
The Biostatistics Center serves as the Data Coordinating Center (DCC) for this epidemiological study. The DCC coordinates the biostatistical and methodological activities of the 28 clinical centers and five laboratories/reading centers. EDIC is designed to continue data collection through 2016. John M. Lachin, Sc.D., is the Principal Investigator and Patricia Cleary, M.S., is the Co-principal Investigator and Director of the Data Coordinating Center.
"Does Treatment Affect Cognition in Type 1 Diabetes" (The EDIC Cognition Study) was an EDIC collaboration with the Joslin Diabetes Center. The goal of this study was to reassess the DCCT/EDIC cohort using the original DCCT neurobehavioral test battery- two decades after the initial testing, augmented by measures that will allow for characterization on several aspects of cognitive function previously found to be affected by the metabolic abnormalities of diabetes. This study was conducted at 28 EDIC clinic sites across the U.S. and Canada, and over eighty percent of active EDIC subjects participated in the study. The EDIC Cognition Study has found that higher HbA1c values were associated with moderate declines in motor speed (p=0.001) and psychomotor efficiency (p<0.0001) 18 years after their initial assessment in the DCCT (Jacobson et al., 2007). In addition, among 249 participants who were 13- to 19-years of age during the DCCT, higher HbA1c values were associated with moderate declines in motor speed and psychomotor efficiency after 18 years (p<0.01) (Musen et al., 2008).
The DCCT/EDIC Genetics Study is another EDIC study. The aims of this study were to a) measure diabetic complications (renal and retinal) from all diabetic full siblings of DCCT/EDIC participants, b) assess the clustering and correlation of diabetic complications in type 1 diabetic full siblings of DCCT/EDIC participants, and c) to determine whether DNA variation at candidate genes is associated with diabetes and its complications using the family-based association design.
There were 217 subjects from the Diabetes Control and Complications Trial (DCCT) and 241 first-degree relatives with IDDM or NIDDM who participated in the study. Among the DCCT subjects, 53% were in the intensive treatment group and 47% were in the conventional group; 44% were from the primary prevention cohort (no retinopathy or microalbuminuria at the DCCT baseline) and 56% were from the secondary intervention cohort (mild-to-moderate nonproliferative retinopathy and <200 mg/24 h albumin excretion rate ÝAER¨ at baseline). Retinopathy and nephropathy were assessed. This study was conducted at 28 EDIC clinic sites across the U.S. and Canada. The Hospital for Sick Children in Toronto, Ontario, Canada functions as the central laboratory for genetics studies, where genetic assays were conducted. The Data Coordinating Center (DCC) at The George Washington University Biostatistics Center coordinated the biostatistical and methodological activities related to this study.
In addition, EDIC plans to collaborate with more studies, including:
1. "The EDIC SCOUT Study" (VeraLight Inc., Albuquerque)
2. "Epigenomic Approaches to Evaluate Metabolic Memory in the EDIC Cohort" (City of Hope Medical Center, Duarte, California)
3. "DCCT/EDIC GWAS" (University of Toronto)
The EDIC SCOUT Study is another new EDIC study. The goal of this study is to assess the risk of diabetes related complications in the DCCT/EDIC cohort by measuring Advanced Glycosylation End-Products (AGEs). In the past, measurements of AGEs required a skin biopsy, which is invasive and is time intensive. Today, we test the usefulness of the SCOUT device, a device which is convenient, non-invasive device, and does not pose any significant risks to patients.
In a recent pilot study "Skin Fluorescence and Type 1 Diabetes Complications: A New Marker of Complication Risk," skin fluorescence was measured in 47 subjects who had participated in the Pittsburgh Epidemiology of Diabetes Complications Study. Subjects were diagnosed with type 1 diabetes before the age 17 and were assessed for AGEs between June - December 2007, when the group was between the ages of 44 - 74. This pilot study found that skin intrinsic fluorescence is associated with renal function, distal symmetrical polyneuropathy, and coronary artery calcification. Thus, non-invasive skin fluorescence shows promise as an effective means to instantaneously assess the risk of diabetes related complications.
It is anticipated that all currently active 1297 EDIC subjects will participate in the EDIC SCOUT Study. This study is being conducted at 28 EDIC clinic sites across the U.S. and Canada. VeraLight, Inc. (of Albuquerque, New Mexico) is the sponsor of the study and will also function in data collection and analysis. The Data Coordinating Center (DCC) at The George Washington University Biostatistics Center will coordinate the biostatistical and methodological activities related to this study.
The goals of the Epigenomic Approaches to Evaluate Metabolic Memory in the EDIC Cohort (The EDIC Epigenetics Study) are to a) evaluate the hypothesis that chromatin changes play significant roles in the etiology of type 1 diabetes (T1D) and its complications, b)evaluate the hypothesis that persistent changes in key chromatin histone methylation markers induced by hyperglycemia are responsible for sustained dysregulated gene expression, c) use new approaches with arrays containing thousands of genes to compare the status of histone modifications in white blood cells between the intensive and conventional DCCT treatment groups, and d) determine the mechanisms involved with metabolic memory.
This proposal is both timely and significant especially since human epigenetics is at the forefront of medical research and very little is yet known in the field of diabetes. Thus, while histone methylation has already been linked to cancers, only a few studies demonstrate the relevance to diabetes. It is anticipated that activity in this area in the upcoming years may decipher the hidden secrets of histone methylation, its variations in diseases such as T1D and correlation with metabolic memory. The completed studies could lead to the development of therapeutic modalities that interfere with these epigenetic mechanisms and thus reduce or prevent debilitating T1D complications.
It is anticipated that 114 of the currently active 1297 EDIC subjects will participate in this study. This study is being conducted at 28 EDIC clinic sites across the U.S. and Canada. The City of Hope in Duarte, California functions as the central laboratory for this study, where epigenetic assays will be conducted and the results of the assays will be stored. The Data Coordinating Center (DCC) at The George Washington University Biostatistics Center will coordinate the biostatistical and methodological activities related to this study.
The DCCT/EDIC Genome Wide Association Study (GWAS) is a new study that has emerged from the earlier DCCT/EDIC Genetics Study. The aim of this study is to identify DNA sequence variations that are associated with renal and retinal complications of type 1 diabetes (T1D). To achieve these goals, genome-wide association analysis, a new and powerful method to detect genetic differences between cases and controls, is being used. In addition, DNA from DCCT/EDIC patients are being compared to DNA from patients from another study called GoKinD. GoKinD was an extreme-case, extreme-control study of nephropathy in patients with T1D. The extensive longitudinal phenotype data collected over the course of DCCT/EDIC is being tested for association with genetic markers from selected genes that capture the majority of common variation to discern the genetic etiology underlying complications of T1D.
Genome-wide association analysis using ~500K SNPs selected based on linkage disequilibrium information from the HapMap project is the primary approach for The DCCT/EDIC GWAS. All 1,419 DCCT/EDIC probands and ~1,800 GoKinD probands had been genotyped with this assay. Single-marker and haplotype based-association analysis were conducted with diabetic complications: nephropathy for DCCT/EDIC and GoKinD, as well as retinopathy, CVD risk factors and neuropathy in DCCT/EDIC probands. Markers showing positive association with outcomes were then genotyped in available relatives of DCCT/EDIC and GoKinD probands and family-based association studies were then performed to confirm that the results are not due to population stratification. The presence of association led to the identification of additional polymorphisms to identify the most likely causal variant. Analysis of multivariate models allowed the understanding of whether the mechanisms by which genes are associated with outcomes occur through covariates that were measured.
The DCCT/EDIC GWAS is both timely and significant especially since in recent years, since there have been many advances in genetics that will allow for testing whether DNA variation in a number of candidate genes is related to susceptibility to diabetes and its complications. Furthermore, genetic linkage and association studies of retinopathy and nephropathy outside the DCCT suggest that genetic differences between individuals contribute to some of the differences between individuals in the development of diabetic complications.
One of the latest findings of The DCCT/EDIC GWAS include the identification of a single nucleotide polymorphism (SNP) associated with hemoglobin A1c levels in patients with type 1 diabetes. "There were three other genetic loci were also related to glycemic control, but none was as 'striking' as SORCS1," said Andrew D. Paterson, MD, of the Hospital for Sick Children in Toronto, at the American Diabetes Association meeting in June 2009. Eventually, the variations may be used to identify patients at risk for poor glycemic control and other diabetic complications. Dr. Paterson and his colleagues said the influence of genetic factors on a patient's ability to control their HbA1c levels will eventually apply to clinical care (Fiore, 2009).
Defining the genes involved in complications through The DCCT/EDIC GWAS has and will continue to provide insight into the molecular pathways involved in complications, eventually leading to better treatments. In the immediate term, identification of susceptibility genes will assist in identification of individuals at increased risk, and allow for therapeutic intervention of targeted individuals.
1. Jacobson A, Ryan CM, Cleary P et al. Long-Term Effect of Diabetes and Its Treatment on Cognitive Function. The New England Journal of Medicine, 2007, 356:1842-1852.
2. Musen G, Jacobson A, Ryan CM, Cleary PA et al. The Impact of Diabetes and its Treatment on Cognitive Function among Adolescents Who Participated in the DCCT. Diabetes Care, 2008, 31:1933-1938.
3. Paterson AD, Waggot D, Boright AP et al. A Genome-Wide Association Study Identifies Variation near SORCS1 as a Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both HbA1c and Glucose. American Diabetes Association 69th Annual Scientific Sessions, Oral Presentation, 2009.
4. Fiore, K. "ADA: Gene Linked to HbA1c in Type 1 Diabetes." MedPage Today, June 6, 2009.)