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Autoimmune Disease Risk Tied to Genetic Variation in Transcription Factor Binding

NEW YORK — Genetic variants that affect the ability of a particular transcription factor to bind DNA within neutrophils could influence susceptibility to autoimmune diseases, a new study has found.

Neutrophils make up most of the white blood cell population and are both inflammatory and highly cytotoxic cells. As a side effect of their role in the immune system, they are thought to contribute to inflammatory and autoimmune disorders.

In a new study appearing in Nature Communications, an international team of researchers combined functional analyses of neutrophils with previously collected genome-wide association study data. They found that genetic changes that affect the ability of the master transcription factor PU.1 to bind DNA may influence autoimmune disease risk and uncovered more than a dozen genes that may be involved.

"It is crucial to understand the mechanisms in the cell if we are to fully understand the impact of [gene variation] on disease," co-senior author Biola-Maria Javierre, a group leader at Josep Carreras Leukemia Research Institute in Barcelona, said in a statement. "In this case, how the genetic variants affect the ability of PU.1 binding, which goes on to modulate gene expression in neutrophils, could be vital in understanding the role that neutrophils play in certain autoimmune diseases."

Using ChIP-seq data from the BLUEPRINT project cohort — a study that examined variation in blood cells and whether it affected risk of complex diseases like heart disease and autoimmune diseases like rheumatoid arthritis and asthma — the researchers generated an atlas of PU.1 binding. PU.1 is known to affect myeloid development and binds a number of enhancer elements in myeloid cells, and its loss in mouse neutrophils leads to a hyperinflammatory phenotype following infection.

Based on the common genetic variation within that cohort of nearly 100 individuals, the researchers began to home in on genetic influences of PU.1 binding by identifying quantitative trait loci.

These PU.1 tfQTLs were associated with local chromatin state, the researchers noted. They added that variants affecting PU.1 binding and active H3K4me histone marks tended to be in the same direction, while they were generally in the opposite direction for PU.1 and the repressive M3K27me3 marks, which is consistent with the activating role of PU.1. Occasionally, though, PU.1 and the repressive M3K27me3 marks had similar effects, suggesting it may also act as a repressor.

At the same time, using data from the UK Biobank and other studies, the researchers noted that the PU.1 tfQTLs were enriched for associations with myeloid traits like cell count as well as autoimmune and inflammatory diseases like hay fever, asthma, rheumatoid arthritis, and ulcerative colitis.

By further combining promoter capture Hi-C and eQTL data in neutrophils, the researchers searched for potential target genes behind these PU.1-disease associations. Through this, they identified 27 high-confidence target genes. For instance, they zeroed in on the RNASET2 gene, which has previously been linked to IBD, as well as the PLCL1 locus, which includes a number of variants previously linked to disease like Crohn's disease, lupus, and allergies.

In combination with other findings that neutrophils mediate autoimmune response, the researchers wrote in their paper, their findings suggest that in some instances, they may even have a driver role in some conditions.

"Research such as this that integrates large-scale genetic research with functional analysis gives us essential data that widen our understanding of how differences in the human genome and epigenome interact to cause devastating common diseases," first author Stephen Watt, a senior staff scientist at the Wellcome Trust Sanger Institute, said in a statement. "Building on this understanding through further research will help inform new avenues for treating these conditions."