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In it Together

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Toiling away in their labs, researchers the world over have been doing their own genome-wide association studies of disease, and occasionally corroborating their data with others' to see whether they've found anything different. That was the scenario for asthma researchers in the US until about two and a half years ago when, at the encouragement of a National Heart, Lung, and Blood Institute program officer, various researchers in the field came together to form a consortium called Eve. The point was to "make better use of the data we've all collected over many years," says Carole Ober, a professor at the University of Chicago, who leads the consortium.

"We as a community came together with the notion that ... our individual genetic studies — while important — were relatively underpowered; the sample sizes were not large enough to really be able to detect the bulk of the genetic variation that causes asthma," adds Harvard Medical School's Benjamin Raby. "By pooling our resources together, we would be able to increase our sample size, maximize our resources, and hopefully find new genes."

A similar effort was already underway in Europe. There, the Gabriel consortium — named after the protective archangel as the group was studying protective factors — brought 35 labs together to search for genetic and environmental causes of asthma. In naming the new American group, the researchers kept with the biblical theme. "[We] went with Eve, who was the mother of all mankind, because asthma has a strong maternal effect," Ober says. "Our study also is the largest ethnically diverse study of asthma, so we thought that was appropriate."

The Eve Consortium, which comprises nine labs at institutions across the US, aims to "discover asthma susceptibility genes in ethnically diverse populations," Ober says. To do so, the group has two projects underway, both being funded by grants from the American Recovery and Reinvestment Act. One is a meta-analysis of the members' prior work, and the other aims to build a new biorepository of asthma cell lines and metadata for the patients from which they are derived.

So far, Ober and Raby both say the consortium has been working well. "I think we were all very skeptical when we came together. … Everyone had the typical concerns about pooling data, but it's really been fantastic," Ober says. "Everybody's worked together well and we are all very excited about the results. It turned out to be a really good collaboration."

Back over the data

By pooling the GWAS data its members had amassed separately, the Eve Consortium now has data from more than 12,000 participants to draw upon for their meta-analyses. This data set encompasses three ethnic groups: African-Americans and African-Caribbeans, European-Americans, and Latino-Americans.

For its initial study, the consortium looked at asthma as the primary phenotype. "That turned out to be very successful," Ober says, adding that the group has submitted a manuscript. In that first meta-analysis, the researchers found five genes with strong signals that they highlight in their paper. One is specific to people of African descent, while the other four are present in all of the groups they studied. Of those four, Ober points out, one had already been found by their European counterpart. In September, the Gabriel Consortium published a paper in the New England Journal of Medicine linking a region of chromosome 17 that contains the ORMDL3 locus to childhood-onset of asthma. "We had a very strong signal at that locus," Ober says, which provides additional support for the region's role in asthma.
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Ober adds that for the Eve Consortium's paper, the group replicated the top 11 most significant associations they found, and has nearly completed a more extensive replication study of the top thousand or so SNPs. "We had over a million in the GWAS. We used a pretty liberal threshold for replication," she says. In addition to the replication study, the consortium is also exploring other phenotypes related to asthma, such as serum IgE, disease severity, and gene-environment interactions.

To the people

The other large effort undertaken by Eve involves the development and maintenance of an asthma-specific biorepository. Funded by a separate multi-center ARRA grant from NHLBI, the Asthma BioRepository for Integrative Genomic Research, or Asthma BRIDGE, will include immortalized cell lines and complementary data sets.

To stock the repository, the researchers are turning to the original GWAS project participants. The team is asking the participants to provide blood samples — in order to make immortalized cell lines — and additional samples, such as lymphocytes, bronchial epithelium, airway macrophages, or even lung biopsies — to enable genetic expression studies and molecular characterization. They aim to collect samples from a subset of about 10 percent of their original GWAS participants.

The idea is to interrogate gene expression levels from the new samples and compare them with the patient's genetic and phenotypic information collected in the original studies. From there, the team will "try and triangulate which signals are influencing susceptibility to disease," says Raby, who is leading this project along with Scott Weiss, also at Harvard.

Finding the people who had participated in the original GWAS studies has not been too difficult, Ober says, as her group has been able to re-recruit 40 patients so far. Overall, Raby notes, they are about halfway to their goal of 1,500 participants — and halfway through their grant. He adds that some of the ease in finding people is because some of the GWAS are still ongoing and that other researchers have been checking back in with participants on a yearly basis. At some point, Ober says she expects the flow to slow down. "Of the subjects we could find, a lot of them wanted to come back and participate," she says.

Currently, Raby says, the team has established cell lines — which are "growing nicely" — for all 750 available participants, the expression analysis work has begun at the Channing Laboratory at Harvard, and methylation work is underway at the University of Southern California.

When all is said and done, the repository will be made publicly available — the participants are renewing their informed consent for the broad distribution of their data, Raby adds. The cell lines will be available — along with a database of their genotype, phenotype, expression, and genome-wide methylation data — through NIH. "[Researchers] can access specific cells from individuals of a particular genetic background," he adds.
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It will be some time before the data the Eve Consortium is churning through makes its way to the clinic, but the expectation is that it will help change how asthma is treated by giving researchers the tools to understand the underlying genetics and pathways. "Our hope is that in very short term after that we'll be able to do more prospective, validative studies looking at the predictive value of these variants that we identified in diagnosis and in projecting the natural history of disease or the response to treatment," Raby says.

Ober adds that there may eventually be tailored therapies for asthma. "The ultimate goal of these studies is to improve treatment for patients by figuring out the molecular pathology of disease and treating that directly rather than just treating the symptoms as we do now," she says. "It's possible that this will also lead to personalized treatments where we'll be able to determine which pathways and which genes are disrupted in each patient, and then tailor the treatment directly to those [genes] individually, but that is still way down the line."

The Breakdown

Members: Researchers at the University of Chicago, Harvard University, Johns Hopkins University, Henry Ford, NHLBI, Wake Forest University, NIEHS, the University of Southern California, the University
of California, San Francisco, and the University of Arizona.

Funding:
$1,728,807 for the Eve Asthma Genetics Consortium, PI: Carole Ober; $4,236,197 for the Asthma BioRepository for Integrative Genomics Research, PIs: Benjamin Raby and Scott Weiss

Timeframe: Both grants began September 30, 2009. The consortium's grant runs through August 31, 2011, while the repository grant lasts through September 29, 2011.

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