Iceland

AGE-Related Epigenetic Changes - Environmental Causes and Disease Consequences
(Grant: # R01ES015211 )  Publications
Fallin, Margaret Daniele (dfallin@jhsph.edu ) - Johns Hopkins University
Abstract: Epigenetic mechanisms such as methylation may be very important in human disease, especially for diseases of older ages. Yet studies documenting epigenetic changes over the human lifespan, the vulnerability of epigenetic marks to environmental exposures, and the subsequent effects on human disease have been limited due to the absence of technical and biosample resources. A team has been assembled with the technology and resources to measure changes in methylation over time in the same individual for the purpose of examining a relationship between exposure and such changes, and assess the relationship between methylation and disease, by combining the epigenetic and epidemiologic expertise at Johns Hopkins with the resources of colleagues at the Icelandic Heart Association (IHA). The IHA has followed over 18K participants of the Reykjavik Heart Study since 1967 and has recently collected extensive cardiovascular and functional measures on 5758 of the surviving cohort as part of the AGES-Reykjavik study. Of these, 638 participants have DNA samples available for epigenetic measurement from two visits spanning 15 years, allowing for measurement of epigenetic changes over time in the same individual, which must occur if environment can influence epigenetic marks, but has never been directly observed in a human population. In addition, diet and smoking data and serum samples are available since 1967 as well as recent phenotype measures and disease outcomes for all 5758 AGES participants (2004-2005). The specific aims include assessing the: (1) Impact of environmental factors including dietary fish intake, serum folate levels, and smoking on inter-individual changes in whole-genome and candidate-gene specific methylation spanning 15 years; (2) Relationship between 15-year changes in methylation and subsequent disease-related quantitative measurements such as blood pressure, BMI, central adiposity, and coronary calcification; (3) Cross-sectional relationship between urinary cadmium (Cd) and candidate gene methylation; and (4) Cross-sectional relationship between candidate gene methylation and disease outcomes including CVD and cancer. This unique resource and team allows the first opportunity for longitudinal epigenetic measurement over 15 years in the same people, and connection of these epigenetic measurements to dietary and smoking exposures, as well as to cancer and cardiovascular disease consequences.

Emory Collaborative Center: Pd Environmental Research
(Grant: # U54ES012068 )  Publications
Delong, Mahlon R (medmrd@emory.edu ) - Emory University
Abstract: The purpose of the Emory CCPDER is to perform cutting-edge collaborative research on PD pathogenesis, with a focus on gene-environment interactions. The CCPDER brings together 3 established investigators - Drs. Greenamyre, Levey and Miller - who are each individually interested in the pathogenesis of PD and the roles that gene-environment interactions play in this disorder. Drs. Greenamyre and Levey bring both clinical and basic research perspectives to the Center. Dr. Miller brings an environmental toxicologist's point of view to the group. The proposed research will take place under the auspices of the new Center for Neurodegenerative Diseases (CND) in the recently completed Whitehead Research Building, where the investigators will share contiguous lab space and core equipment and facilities. The Emory CCPDER will capitalize on the expertise of each individual project leader in a truly collaborative, multidisciplinary endeavor in which the investigators will literally interact on a daily basis. The CCPDER consists of 3 integrative research projects supported by a Research Development Core. There are no Scientific Cores because the CND was conceived as a facility that would contain most necessary core facilities within its walls, with free access to all facilities by all CND investigators. Project 1 expands the rotenone model of PD into mice and organotypic slice cultures in order to examine geneenvironment interactions in this model. It will also screen other similar pesticides for their ability to cause PD, and it will screen neuroprotective strategies. Project 2 examines the vesicular monoamine transporter (VMAT2) as a target of environmental toxicants, such as organochlorines. Genetic approaches will be used to manipulate VMAT2 and examine its interactions with genes important in PD pathogenesis, such as alpha-synuclein. Project 3 is a genetic and pathological study of a new genetic linkage to PD, PARK10, which has been associated with increased risk of 'sporadic' PD in Iceland. Sporadic PD patients will be evaluated at Emory and high-density genome scans will be performed. Candidate genes have been identified and antibodies raised to the gene products. These will be assessed in human postmortem brain specimens and in experimental models of PD. The projects and administrative core involve molecular neurobiology, human genetics, clinical research, education, and collaboration with a PD epidemiologist. Common themes of the interactive projects include pesticides, gene-environment interactions, the ubiquitin/proteasome system, and dopamine. Each of the projects capitalizes on one or more existing funded projects. This fact, together with the core facilities of the CND allows us to leverage the requested funds for maximal effect.