Clues to the contribution of genetic variation to disease risk lie not only in the genes, but also in the molecular switches that control those genes, according to a study published today.

The study suggested that the effects of genetic variation on immune response are often hidden if not searched for thoroughly. The results, published in Nature Genetics, showed for the first time how immune cells created from human induced pluripotent stem cells (iPSCs) can model immune response variation between people.

Researchers found that the differences in immune responses due to genetic variation were only visible at certain stages of the experiment, when the immune cells were in particular states (e.g., upon activation).

In other states, only “footprints” of the genetic variation effects could be seen. However, by looking at genes and regulatory regions—the molecular “switches” that control the expression of those genes—the researchers were able to identify the true impact of genetic differences on immune response. Researchers say a better understanding of how genetic variants aid the immune system may led to better targeted therapies.

“We have found that the impact of genetic variants on how people's immune cells respond to a pathogen like Salmonella are condition-specific. They are only visible at certain stages of infection,” Dan Gaffney, Ph.D., of the Wellcome Sanger Institute, one of the study’s two corresponding authors, said in a statement. “This means that the effects of genetic differences in immune disorders could be missed in research, if scientists aren't studying both the genes and their control regions—the regulatory elements of immune cells at all stages of an infection.”

The researchers said their results “illustrate how pre-existing genetic effects on chromatin propagate to gene expression during immune activation, and highlights the relevance of these hidden genetic effects for deciphering the molecular architecture of disease-associated variants.”

They said their study, “Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response,” was the first they were aware of that used iPSC-derived cells to study genetic effects in immune response: “We believe a major future use of this system will be the systematic exploration of gene-environment interactions across large numbers of cell states.”

Impact on Immune Cell Readiness

In their study, the researchers differentiated human iPSCs into macrophages that were then studied in four different states: unstimulated, after 18 hours of stimulation with a signaling molecule interferon-gamma, after five hours infection with Salmonella, and after interferon-gamma stimulation followed by Salmonella infection.

Researchers discovered that genetic variation impacted on the readiness of the immune cells to tackle an infection. Some individuals’ immune cells were ready to deal with the Salmonella infection, whereas other individuals' macrophages were less ready and took longer to respond.

That level of readiness was due to enhancer priming, where some of the switches were already turned on in the unstimulated cells to facilitate a quicker response. In some cases, the immune cells could be overly eager, which can lead to an inflammatory response associated with immune disorders.

“These results offer important new insights into studying the mechanisms behind infection and disease,” stated Gordon Dougan, Ph.D., of the Wellcome Sanger Institute, another co-author of the study. “If the genetic variant being studied is associated with disease, such as an immune disorder, one needs to be sure of which gene the variant is affecting in order to develop an effective therapy. This may only be visible in a small time-window of the infection.”

The human iPSCs were obtained from the Human Induced Pluripotent Stem Cell Initiative (HipSci). HipSci aims to create a global iPSC resource for the research community by bringing together researchers specializing in genomics, proteomics, cell biology, and clinical genetics.

“A benefit of using stem cells rather than pre-existing blood cells is they're very flexible, and enabled us to study the effects of stimulation at two different levels,” added Kaur Alasoo, Ph.D., previously of the Wellcome Sanger Institute and now of the University of Tartu, Estonia. “We analyzed which genes in the genome were expressed during each stage of infection, but also looked at the activity of enhancers—the molecular 'switches' that controlled the expression of those genes. This novel combination of tools enabled us to see otherwise hidden effects of genetic variation on immune response.”

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