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North American Group IDs Loci Influencing Cystic Fibrosis Lung Disease Severity

By Andrea Anderson

NEW YORK (GenomeWeb News) – Researchers reported in Nature Genetics online yesterday that they have found new genetic loci modifying lung disease severity in individuals with cystic fibrosis.

Using a combination of genome-wide association and family-based linkage approaches in nearly 3,500 individuals from three cohorts, researchers involved in the North American Cystic Fibrosis Gene Modifier Consortium tracked down apparent modifiers of cystic fibrosis lung disease risk in regions on chromosomes 11 and 20.

"This is one of the ways in which individualized medicine is going to come around," co-corresponding author Garry Cutting, a genetic medicine and pediatrics researcher at Johns Hopkins University School of Medicine, told GenomeWeb Daily News.

"It's not just deciding all individuals have [cystic fibrosis] … It's now recognizing the reasons that people with [cystic fibrosis] differ," he added. "That hopefully will also lead to the recognition that [a given] therapy will work for this person but not that person because of the modifiers they have."

Although it's known that cystic fibrosis is caused by mutations in the so-called cystic fibrosis transmembrane conductance regulator gene CFTR, Cutting and his co-authors explained, questions remain about the environmental and genetic factors mediating lung disease severity in individuals with the recessive condition.

"Candidate gene studies have produced conflicting results, with only a few large-scale replications accounting for a small proportion of heritable variation in cystic fibrosis lung function," they wrote. "Identification of other genetic modifiers could identify potential mechanisms for variation in lung function in cystic fibrosis, as well as for common diseases such as chronic obstructive pulmonary disease, and suggest new targets for intervention."

In an effort to track down genetic factors influencing the extent of cystic fibrosis-related lung disease, members of the North American Cystic Fibrosis Gene Modifier Consortium looked at individuals enrolled through three studies: the Genetic Modifier Study, the Canadian Consortium for Genetic Studies and the cystic fibrosis Twin and Sibling study.

The team used a genome-wide association approach to evaluate individuals from the Genetic Modifier Study, which included individuals from the extremes of the lung function spectrum, and the Canadian Consortium for Genetic Studies, which included individuals with pancreatic insufficiency.

Because the Twin and Sibling study included families with two or more cystic fibrosis-affected children, the researchers were able to do both GWAS and linkage analyses in that cohort.

In general, the team classified lung disease severity using a quantitative lung disease measure based on each individual's forced expiratory volume data over several years — an approach that allowed them to take into account lung disease progression in individuals with cystic fibrosis.

In general, the established lung disease predictor measures the volume of air that can be forced out of the lungs in one second. For the current study, researchers used this data to come up with a percentile scale relating lung function across the spectrum of cystic fibrosis patients and incorporating information on survival characteristics.

"What we could do, because we know the disease very, very well is do a really in depth phenotyping, so that we could agree upon a really good, robust measure of the severity of lung disease across a whole series of ages in these patients," Cutting said.

Using the Illumina 610-Quad array, researchers genotyped 3,467 individuals with cystic fibrosis from the three cohorts. They then analyzed data for individuals from the Genetic Modifier Study and Canadian Consortium for Genetic Studies as a whole and based on CFTR mutation genotype.

For the 1,978 individuals with the most common CFTR mutation — a homozygous deletion affecting three base pairs of the gene — the researchers detected a SNP called rs12793173 on chromosome 11 showing a genome-wide significant association with lung disease severity. The association was even more pronounced when the team did analyses incorporating information on other factors such as sex and weight.

The chromosome 11 SNP was also linked to lung disease severity in the 557 individuals in the Twin and Sibling group who had the same homozygous CFTR mutation. Linkage analyses of individuals from that study, meanwhile, pointed to a region on chromosome 20 that was tied to lung disease severity in that cohort.

Both of the newly identified regions contain promising leads, Cutting explained. For instance, the chromosome 11 site lies between APIP and EHF, genes suspected of modifying lung function in other diseases.

The chromosome 20 association falls in a region that houses regulatory signatures, he noted, and there are clues that it might influence a cluster of genes involved in epithelial cell function, including apoptosis and cell turnover in tissues lining the lungs and airway.

On the other hand, the chromosome 20 locus contains several genes that could conceivably contribute to cystic fibrosis-related lung disease, Cutting explained. Among them is a melanocortin receptor 3 gene called MC3R, which has been implicated in both inflammation and energy balance — processes that seem to be important in cystic fibrosis.

"There [are] two potential new pathways that come out of just thinking about that gene, which sits very close to the height of that peak," Cutting said. For example, he noted, he and his collaborators are currently using mouse models to look in more detail at the role of energy balance in cystic fibrosis.

Along with follow-up studies looking at the most suspicious genes in the chromosome 11 and 20 regions, the team plans to work within an international consortium to do additional association and linkage studies involving another 3,000 or so cystic fibrosis patients from France and North America, Cutting said.

In the process, they hope to not only find additional genetic variants contributing to lung disease severity in cystic fibrosis, but also to confirm or refute some suggestive associations and linkage peaks from the current study, he said. In the long term, Cutting explained, researchers hope that identifying protective modifier genes may open the door for new therapeutic targets.

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