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Variants Impacting Gene Expression of Immune Cell Types Emerge From Study

NEW YORK (GenomeWeb) – A team led by investigators at the La Jolla Institute for Allergy and Immunology and the University of California, San Diego has described genetic interactions with gene expression in more than a dozen immune cell types for the ongoing "Database of Immune Cell Expression, Expression Quantitative Trait Locus (eQTL), and Epigenomics" (DICE) project.

"[T]he DICE project provides a reference of transcriptomic and eQTL data for the human immune system, which is likely to facilitate mechanistic and functional investigations into the role of disease risk variants in relevant cell types," corresponding author Pandurangan Vijayanand, a researcher affiliated with the La Jolla Institute for Allergy and Immunology, UCSD, and the University of Southampton, and his colleagues wrote.

As they reported online today in Cell, the researchers performed array-based genotyping on 91 healthy participants, along with RNA sequencing for 13 immune cell types and two activated cell types, to narrow in on cis-eQTLs influencing the activity of nearly 12,300 genes. More than 40 percent of those genes had ties to genotypes in just one of the cell types considered, they reported, while biological sex also showed pronounced effects on cell type-specific expression.

The DICE project "was established to define the transcriptional and epigenomics landscape of many human immune cell types in relation to genetic variation," the authors explained, "thereby identifying both the cell type restriction and potential function of human disease-associated SNPs."

To that end, the researchers performed RNA sequencing on 1,544 samples — representing three innate immune cell types, four naïve adaptive immune cell types, and six CD4+ T memory cell types isolated by fluorescence activated cell sorting — in parallel with Illumina Infinium multi-ethnic array-based SNP genotyping on the 91 participants. They also considered two activated cell states and obtained longitudinal samples from 15 of the individuals.

The team's analyses revealed thousands of transcripts with differential expression in specific immune cell types and highlighted cis-eQTLs corresponding with the expression of 12,254 genes in one or more of the cell types. A significant proportion of those were active in just one of the cell types profiled.

Certain cell types appeared especially prone to having differentially expressed genes linked to SNPs identified in past genome-wide association studies, the researchers reported. For example, they found that expression of a gene called NAB1 that has been implicated in the rare autoimmune liver disease primary biliary cholangitis was influenced by its genotype in natural killer cells in the innate arm of the immune system.

The researchers also saw sex-biased expression of nearly 1,900 genes, and once again, many of those expression differences turned up in just one immune cell type. They proposed that these and other sex-related differences "will spur interest in understanding the biological consequences of such changes."

"The next phases of the DICE project will further enrich this dataset with descriptions from additional rare immune cell types," the authors concluded, "and the inclusion of cell-specific epigenomic profiles that can allow pinpointing functional disease risk variants."