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Pathogen Response-Related Variants Tapped for Broader Disease Insights

NEW YORK (GenomeWeb) – Members of a Duke University-led research team have come up with a new catalog of genetic variants influencing host responses to, and interactions with, a range of human pathogens. And that information, in turn, is expected to help in understanding other human diseases.

As part of the Hi-HOST Phenome Project (H2P2), "we have coupled the ability of pathogens to influence human genetic diversity to their use as cellular probes to elucidate mechanisms of disease," corresponding author Dennis Ko, a molecular genetics and microbiology researcher at Duke University, and his colleagues wrote in their Cell Host & Microbe study.

In the project, the researchers relied on high-throughput human in vitro susceptibility testing (Hi-HOST) and other approaches to tease out lymphoblastoid cell line (LCL) responses to a handful of well known human pathogens — from Salmonella enterica to Candida albicans fungi or Toxoplasma gondii — and the genetic variants influencing host responses to one or several pathogens. Those variants overlapped in part with SNPs previously implicated in conditions such as inflammatory bowel disease.

Ko and his team began by exposing 528 different LCLs to seven pathogenic microbes directly and to stimuli from an eighth pathogen, using data at some 15.5 million SNPs to search for potential associations with 79 host-pathogen traits. The search led to variants at 17 loci showing genome-wide significant associations with infection features such as pathogen replication or cytokine production.

"Several of these SNPs demonstrated very different allele frequencies among populations," the authors wrote, noting that this pattern "underscores the need for conducting GWAS in multiple populations for revealing a greater spectrum of genetic differences of functional significance."

The team brought in clinical clues from the eMERGE Network PheWAS pipeline to explore the functional effects of variants identified in the infection association arm of the study. A SNP called rs2869462 that appeared to influence levels of the nearby chemokine CXCL10 during Chlamydia infection, was also linked to inflammatory bowel disease risk.

Another SNP in the transcriptional repressor gene ZBTB20 showed ties to several pathogen-related traits. The researchers found that that variant was not only associated with Chlamydia or Salmonella infection outcomes, for example, but also with viral hepatitis risk. Their RNA sequencing experiments revealed enhanced expression for more than 1,100 genes in cells missing ZBTB20, including genes previously linked to hepatitis C virus activity.

"[G]enetic variation in ZBTB20 has broad pleiotropic effects likely being mediated by suppression of different transcriptional targets," the authors explained, noting that "[t]his example demonstrates that combining H2P2 with PheWAS of clinical traits can lead to a hypothesis that can be quickly tested in the most clinically relevant cell type."

The researchers added that their data "are available on a web portal to facilitate interpreting human genome variation through the lens of cell biology and should serve as a rich resource for the research community."

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