Seed CDC Funding for Public Health Genomics Research Fiscal Year 2008

CDC’s Office of Public Health Genomics (OPHG) announced the availability of seed funding for innovative, high-impact CDC projects that help build CDC’s infrastructure to conduct genomics research and integrate genomics into public health research and programs. There were 19 proposals received, of which five were selected, with priority given to those with potential to demonstrate health impact within a 2-year period. The following list provides information about 2008 seed funding recipients.

Effects of Preconceptional Folic Acid Supplementation on Epigenetic Patterns of DNA Methylation

Principal Investigators: Krista Crider, PhD (CCHP/NCBDDD), Craig Hooper, PhD (CCHP/NCBDDD)
In 1992, the U.S. Public Health Service recommended that women of childbearing age consume 400 μg/day of folic acid. Subsequently, fortification of the grain supply in the United States was mandated in 1998. Concern has been raised about possible unintended consequences (both positive and negative) of folic acid fortification and supplementation, as the pleiotropic effects of the folate pathway are yet to be fully elucidated. The goal of this project is to increase our understanding of normal DNA methylation levels and patterns, their genotype dependence, and to characterize changes associated with pregnancy and folic acid supplementation in order to help inform policy makers and to optimize folic acid supplementation and fortification recommendations.

Autism Spectrum Disorder: High-throughput Screening for Potential Candidate Genes and Etiologic Hazardous Agents of Environmental Origin

Principal Investigators: Eugene Demchuk, PhD (ATSDR/DTEM/OD), Michael Schwartz, MD, MS (CCEHIP/NCEH/OTPER), Patricia Ruiz, PhD (ATSDR/DTEM/OD), and Hugh Hansen, PhD (ATSDR/DTEM/OD)
Autism Spectrum Disorder (ASD) is an increasingly common developmental disability in industrial nations. ASD is thought to result from gene-environment interactions. Despite research progress in identifying candidate genes associated with ASD, no clear etiology or causative marker has been found. If and when a genetic predisposition is identified, the next research question will be — What environmental trigger is responsible for the development or manifestation of the clinical phenotype? To address this question we propose to develop a rapid-screening computational toxicology methodology which can be applied to large numbers of environmental pollutants (ligands) and a known or suspected biological target for autism. Starting with a model database of hypothesized chemical triggers and a set of critical-pathway genes, we will screen the chemicals against known genetic variants using state-of-the-art molecular docking techniques. Top scored gene/chemical combinations are expected to offer an educated choice for further in-depth analysis of gene-environment interactions in the future.

Evaluation of the Modifying Effect of Apolipoprotein E (APOE) Genotype on the Association of Prenatal Blood Lead Levels and Auditory Brainstem Response Among Infants Born in Two New York City Hospitals

Principal Investigators: Timothy A. Dignam, MPH (CCEHIP/NCEH)
Hearing loss is one of the most common major abnormalities present among infants. Two to four infants per 1,000 are born in the United States with severe-to-profound newborn hearing loss. Undetected, hearing loss delays speech, language, and cognitive development. Numerous studies have shown that prenatal lead exposure is associated with a variety of neurobehavioral and electrophysiologic abnormalities. However, knowledge about the effects of maternal lead exposure at current United States levels (i.e., blood lead levels < 10 μg/dL), on the neonatal auditory system function is limited. This study will focus on the APOE genotype as a genetic effect modifier. Apolipoprotein E (ApoE) is an intracellular protein that transports cholesterol and fatty acids and plays an important role in the structure of cell membranes and myelin. Cholesterol and ApoE are important in the neurodevelopment of the fetus (cholesterol is used in neuronal metabolism) and may serve as modifiers of the response to maternal nutrient intake or maternal exposure to neurotoxins. Thus, genetic variants may make a shift in the dose-response relationship to environmental toxins such as lead. The goal of this study is to examine the gene-environment interactions between prenatal blood lead exposure and APOE genotype while examining the infant auditory brainstem response pattern.

Genetic Modulation of Worker Susceptibility to Noise-induced Hearing Loss

Principal Investigator: Rickie R. Davis, PhD (NIOSH/DART) and Mary Ann Butler, PhD (NIOSH/DART)
NIOSH estimates that 4 million American workers are exposed to potentially hazardous noise every day. Noise-induced hearing loss (NIHL) is the number one self-reported work-related injury in the U.S. In spite of 30 years of occupational hearing conservation programs, worker hearing continues to be damaged by noise. It has been shown in both animal models and human cohorts that the presence of certain genes increases susceptibility to NIHL. The ultimate goal of this research is to reduce the incidence of NIHL by integrating genetic tests into worker safety programs. Cadherin and connexin will be examined because of their vital role in hearing. Connexin variation is a common basis of congenital deafness. Two genes will be examined because of their association with hearing (CDH23 [cadherin 23] and GJB2 [connexin 26]), two genes because of their antioxidant roles (SOD2 [superoxide dismutase] and PON2 [paraoxynase]), and three genes because they have previously been identified as contributing to NIHL susceptibility (HSPA6 [heat shock protein], KCNQ4 [potassium recycling] and CAT [catalase]).

Integrative Genomic Approach in Prediction of Chronic Beryllium Disease (CBD)

Principal Investigator: Erin McCanlies, PhD (NIOSH/HELD), Petia Simeonova, MD, PhD (NIOSH/HELD/TMBB) and Berran Yucesoy, PhD (NIOSH/HELD/TMBB)
Chronic beryllium disease (CBD) is a serious granulomatous lung disease resulting from a type IV hypersensitivity response to beryllium (Be) exposure in the workplace. It is estimated that over one million workers have been exposed to Be. CBD continues to occur in industries where Be is manufactured and processed such as aerospace, nuclear, automotive and electronics. Although some individuals with CBD remain stable for years, others quickly progress to end-stage fibrotic lung disease. The treatment of disease requires extensive clinical evaluation and palliative medication which can ameliorate symptoms, but not cure the disease. For this reason, further understanding of the pathophysiological mechanisms of BeS and CBD is important for early detection, potential treatment modalities, and disease prevention. A number of studies have demonstrated the importance of Human Leukocyte Antigen (HLA) class II molecules in the development of BeS and CBD. HLA molecules may be involved in both the Be antigen presentation and control of the expression of a subset of genes involved in disease progression. To date, most studies have examined BeS and CBD by evaluating single nucleotide polymorphisms (SNPs) or small groups of candidate genes. The currently proposed project will define genes and genetic variations involved in BeS and CBD using a novel approach based on recently developed technologies, namely HLA array and global gene expression analyses. This study will allow us to correlate genetic characteristics with gene expression data in a clinically well-defined Be-exposed population, which has not been previously done. This unique study will provide a better understanding of the progression from BeS to CBD, a prerequisite for developing new prevention or treatment strategies.

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