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Genomic Study Points to Immune Cell eQTLs as Potential Contributors to TB Susceptibility

NEW YORK (GenomeWeb News) – In a study published today in the Proceedings of the National Academy of Sciences, an international research team described the strategy they used to uncover genetic variants that appear to affect individuals' immune response to infection by the tuberculosis-causing bacterium Mycobacterium tuberculosis.

By bringing together gene expression and genotyping information on human primary dendritic cells before and after the cells were exposed to M. tuberculosis, the researchers narrowed in on nearly 200 expression quantitative trait loci that appear to contribute to the expression of immune genes prior to M. tuberculosis infection or during infection.

At least some of the proposed tuberculosis-response eQTLs overlapped with variants that were nominally associated with pulmonary tuberculosis in a previous genome-wide association study of the disease, the group reported, hinting that some of the same loci mediating the expression of immune genes may also contribute to tuberculosis susceptibility.

"Taken together, our results indicate that response eQTL are likely enriched for susceptibility alleles for [tuberculosis]," senior author Yoav Gilad, a human genetics researcher at the University of Chicago, and co-authors wrote.

"In particular, our data strongly support the notion that dual-specificity phosphatase 14 (DUSP14) is a new susceptibility gene for [tuberculosis]," they added.

Although tuberculosis is an infectious disease, past studies have shown that environmental factors are not the only components in disease risk. Instead, certain individuals seem to be more prone to tuberculosis infection owing to inherited genetic factors.

For their part, Gilad and colleagues speculated that the heritable side of tuberculosis susceptibility might be related to differences in immune response to M. tuberculosis.

"In the context of an infectious disease such as [tuberculosis], the most important molecular networks affecting disease susceptibility are probably those involved in mechanisms of immune defense," they wrote. "We thus reasoned that genetic variants that are associated with variation in immune response to [M. tuberculosis] infection would be highly promising genetic candidates for susceptibility to [tuberculosis]."

To explore that possibility in more detail, the researchers focused their attention on dendritic cells, which contribute to both innate and adaptive arms of the human immune system.

Using the Illumina HumanHT-12 version 4 BeadChip, they first assessed gene expression patterns across the genomes of dendritic cells derived from white blood cell samples collected from 65 healthy individuals of European ancestry.

Comparisons of gene expression patterns in the dendritic cells before and after exposure to M. tuberculosis pointed to nearly 3,000 genes that seemed to be more highly expressed in cells infected by the bug — including several known immune response genes.

On the other hand, more than 4,000 genes showed muted expression following infection, with metabolic genes over-represented amongst these down-regulated genes.

In an attempt to find eQTLs related to these expression shifts, the team used Illumina Omni1-Quad BeadChip arrays to genotype samples from each participating individual — a search that unearthed 756 potential cis-regulatory variants in uninfected dendritic cells and 720 such variants in M. tuberculosis-infected cells.

Of these, researchers verified 198 suspected eQTLs in their subsequent statistical analyses, including 102 eQTLs in the uninfected cells and 96 in the cells exposed to the tuberculosis-causing bug.

Their follow-up experiments did not uncover loci influencing the levels of cytokine and other immune-related proteins secreted by infected cells, though researchers did find clues that the expression of certain proteins corresponded to the genotypes identified in their eQTL analysis.

The proposed response eQTLs were also over-represented among SNPs previously shown to be nominally associated with pulmonary tuberculosis in a GWAS by members of the African TB Genetics Consortium and the Wellcome Trust Case Control Consortium, the researchers reported, consistent with the notion that variants affecting immune response might also influence M. tuberculosis infection susceptibility.

Among the new candidate eQTLs identified, a variant in the gene DUSP14 stuck out due to its apparently strong influence on DUSP14 expression as well as its potential association with pulmonary tuberculosis.

Even so, the team noted that additional research is needed to determine whether this and other apparent response eQTLs are specifically involved in tuberculosis response or whether they have broader roles in infectious disease in general.

"We expect that our findings will stimulate future work aimed at characterizing response eQTLs associated with other infectious diseases," the authors concluded, "and that such work will allow us to further classify specific [M. tuberculosis]-response eQTLs on the one hand and genetic variation that is associated with more general variation in the response to infectious agents on the other hand."

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