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Expression-Based GWAS Reveals Role for Immune Cell Receptor in T2D

NEW YORK (GenomeWeb News) – In a study set to appear online this week in the Proceedings of the National Academy of Sciences, researchers from the US and Japan report that they have linked an immune-cell receptor called CD44 to type 2 diabetes using an expression-based genome-wide association study, or eGWAS, strategy.

The study hinged around a meta-analysis of publicly available gene expression data on almost 600 type 2 diabetes samples and about as many samples from unaffected controls. By including data generated through nearly 1,200 T2D case-control microarray experiments and calculating the likelihood of seeing repeated differential expression for each gene, researchers were able to pinpoint genes that were particularly prone to T2D-associated shifts in expression.

"Our hypothesis is that those genes most repeatedly implicated across a large set of experimental representations of T2D can serve as data-driven causal T2D genes and candidates for validation," corresponding author Atul Butte, a systems medicine researcher at Stanford University, and colleagues wrote.

Using this eGWAS method, the team narrowed in on CD44, a gene that was differentially expressed in around 60 percent of the array experiments assessed. Based on CD44's known functional role — and results from their own follow-up experiments — investigators now suspect that CD44 contributes to insulin resistance by fueling inflammatory processes in fat tissue.

Butte and his colleagues brought together gene expression data for 1,175 samples, including 591 from T2D cases and 584 from unaffected controls. The microarray-based information came from the NCBI's Gene Expression Omnibus, the Diabetes Genome Anatomy Project, and the Nuclear Receptor Signaling Atlas.

By ranking 24,898 genes based on expression patterns in this publicly available data, the researchers were able to put together a list of genes that most frequently showed differential gene expression that could not be explained by chance in samples from T2D cases compared to control samples.

When they looked at the functional categories associated with 127 genes ranked highest in this analysis, investigators saw an over-representation of genes from receptor activity and binding pathways.

And one gene in particular stood out: the chromosome 11 immune cell receptor-coding gene CD44, which was differentially expressed in 78 of 130 experiments assessed and had especially elevated expression in adipose tissues from T2D cases.

Another gene, SPP1, which codes for a cytokine protein that's not only secreted by certain immune cells but also can bind the CD44 receptor, was high on the list of candidate genes as well.

Because that gene had been implicated in fat tissue inflammation-related insulin resistance in past mouse studies of T2D, the team hypothesized that CD44 might also be participating in these obesity-related processes. Indeed, the researchers' subsequent experiments indicated that enhanced CD44 levels coincided with fat tissue inflammation and insulin resistance in both humans and mice, while curbing CD44 protein activity staved off these events.

For instance, mice that became obese and insulin resistant on an especially high fat diet also had an inflammation-related jump in CD44 transcript expression by immune cells in their fat tissue compared with mice fed a typical diet. On the other hand, mice missing CD44 did not exhibit the same sorts of fat tissue inflammation features or insulin resistance when given high-fat food.

Similarly, mice on a high fat diet had lower-than-usual blood sugar levels and fewer immune cells accumulating in their fat tissue when they were treated with a monoclonal antibody targeting the CD44 protein.

In humans, too, researchers found that inflammatory cells in fat tissues from obese individuals were producing the CD44 protein. And individuals with insulin resistance and impaired glucose regulation had correspondingly higher CD44 levels in their circulating blood samples.

More research will be needed to figure out the details of this process and to determine which immune cells spearhead the boost in CD44 expression in fat tissue, the study authors noted. But based on their findings so far, they suggest that the same eGWAS method employed for the current T2D study could also prove useful for uncovering new pathways and players in other complex diseases.

"Although GWAS and other genetic analyses will continue as the method of choice for the next few years," the study's authors concluded, "an eGWAS approach could complement these studies to yield additional pathogenetically important genes for many other complex diseases by using this integrated data-driven approach."

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