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Epidemiology Shines at Advisory Council Meeting

By Thaddeus Schug
March 2010

Allen Wilcox, M.D., Ph.D.
Wilcox explored the difficulty in "determining whether genetic susceptibilities are causal or whether they are occurring by chance or confounding factors."
(Photo courtesy of Steve McCaw)

Stephanie London, M.D., Dr.P.H.
London looked at more than 500,000 variants across the genome in 492 Mexican children with asthma and their parents to identify genes that may influence asthma (see story(http://www.niehs.nih.gov/news/newsletter/2009/october/science-asthma.cfm)). (Photo courtesy of Steve McCaw)

Gwen Collman, Ph.D.
Acting NIEHS DERT Director Gwen Collman, Ph.D., looked on approvingly as Herbstman compared completing phases of her newly issued K99-R00 grant to learning three new languages at the same time. (Photo courtesy of Steve McCaw)

Julie Herbstman, Ph.D.
"My goal is not to become fluent in bioinformatics, laboratory biology and biostatistics, but to get to the point where I am conversant, so that I can use these skills to collaborate and foster new research projects," said Herbstman. (Photo courtesy of Steve McCaw)

Stephen Baylin, M.D.
Council member Stephen Baylin, M.D., offered Herbstman technical advice regarding methods to quantify DNA methylation. His own research interest is the role of epigenetics in cancer (see story(http://www.niehs.nih.gov/news/newsletter/2008/august/epigenetic-may-be-cancer.cfm)).
(Photo courtesy of Steve McCaw)

A distinctive feature of the February 18-19 meeting of the National Advisory Environmental Health Sciences Council (NAEHSC) was a three-part series of scientific presentations on a wide-range of epidemiological studies supported by NIEHS. Presenting talks were NIEHS Senior Investigator Allen Wilcox, M.D., Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/epi/reproductive/index.cfm), Principal Investigator Stephanie London, M.D., Dr.P.H.(http://www.niehs.nih.gov/research/atniehs/labs/epi/genetics/index.cfm), and grantee (http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7571893) Julie Herbstman, Ph.D.

Testing genetic susceptibility as a cause of disease

Wilcox led off the trio of talks describing his attempt at using genetic susceptibility to discover environmental causes of disease. As Wilcox explained, "People vary genetically in their susceptibility to particular exposures, and if we can identify genetically susceptible subgroups we can find stronger associations between exposure and disease. So the ultimate goal is to use this information so that we can gain insights into biological mechanisms of action."

Wilcox's group examined epidemiology data obtained from a population-based study conducted in Norway, which has one of the highest rates of oral clefts in Europe. The study aimed to determine the roles of prenatal exposures - smoking, alcohol use, and folic acid supplementation - and genetic susceptibility in facial cleft birth defects.

Although his group was not able to link prenatal smoke or folic acid exposure to genetic susceptibility, they found that maternal "binge" alcohol consumption was associated with a two to three times greater likelihood that their babies will be born with oral clefts (see story(http://www.niehs.nih.gov/news/newsletter/2008/september/alcoholbinges.cfm)).

Taking advantage of GWAS to link genes to complex diseases

Next up was Stephanie London, who uses newly developed genome-wide association studies (GWAS) to couple genetic variation with disease state. London, whose primary focus is pulmonary diseases, stated, "We know that asthma is a chronic childhood disease that is influenced by both genetic and environmental factors, but so far, no genes have been definitively shown to influence asthma development. By using new approaches that have emerged in the past two years, such as GWAS, we're able to home in on specific regions that might be involved in the disease process."

Using data from a Mexican population study, London's group has discovered that chromosome 9q21.31 may underlie some of the differences observed in cases of childhood asthma. The variants were located near the TLE4 gene, which codes for a protein involved in cell fate determination and differentiation. London noted that these variations may be due to ethnic backgrounds, and that it will be important to compare different groups to determine disease susceptibility.

Using sibling pairs to study the epigenetic effects of prenatal exposure

Recent NIEHS K99-R00 grantee Julie Herbstman rounded out the series of talks with a discussion of how prenatal exposure to polycyclic aromatic hydrocarbon (PAH) leads to epigenetic gene modifications that likely result in increased susceptibility to disease. She discussed sources of inter-individual epigenetic variation and how this variation limits the ability to detect significant associations in conventional epidemiologic studies of unrelated individuals.

Working at the Columbia Center for Children's Environmental Health (CCCEH) (http://www.cumc.columbia.edu/dept/mailman/ccceh/experts.html)Exit NIEHS at Columbia University, Herbstman is planning to use a sibling-pair study to control some of this variation to better study the relationship between prenatal PAH exposure and DNA methylation (see story(/news/newsletter/2009/april/study-links.cfm)). She is now looking at global DNA methylation and plans to narrow her focus to determine what specific genes undergo epigenetic modifications and how those modifications result in changes in disease susceptibility related to growth and development.

Herbstman concluded her talk by detailing a well mapped-out study design that she hopes will eventually lead to development of strategies designed to help prevent disease among urban infants.

(Thaddeus Schug, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)



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