How Our Genes Contribute to Allergy Susceptibility

Summary: New research reveals how small genetic differences affecting the ETS1 protein can influence an individual’s susceptibility to allergies. These small genetic changes can alter the production of ETS1, which plays a vital role in controlling immune cells known as CD4+ T helper cells, crucial orchestrators in allergic reactions.

Findings suggest that disturbances in the balance of these immune cells can lead to allergic inflammations. This breakthrough in understanding may pave the way for new therapeutic interventions in chronic allergic diseases.

Key Facts:

  1. ETS1 protein is crucial in regulating CD4+ T helper cells, immune cells integral to the body’s response to allergens.
  2. Small genetic changes can interfere with the ETS1 protein production, potentially leading to imbalances in immune cells and causing allergic inflammation.
  3. This research provides new insights into the complex relationship between our genes and susceptibility to common diseases like allergies, which may not be traced to a single gene but a complex interplay of genetic factors.

Source: University of Pennsylvania

New research is bolstering scientific understanding behind why some people are more prone to allergies than others.

Researchers in the Perelman School of Medicine at the University of Pennsylvania identified how genetic differences that alter a specific protein called ETS1 can affect our body’s response to allergies. They found that small changes in ETS1 in an animal model can lead to an increased likelihood for allergic reactions that cause inflammation.

The findings were published recently in Immunity.

The United States Centers for Disease Control and Prevention reports that allergies rank as the sixth most prevalent cause of chronic illness in the U.S., resulting in an annual expenditure exceeding $18 billion.

This shows a woman and pollen.
DNA interactions within the genomic segment encompassing the ETS1 gene control how much of the ETS1 protein is made. Credit: Neuroscience News

While previous research has established a strong genetic basis for allergies and identified specific genetic sequence variations which predispose for these chronic diseases, how our DNA can affect our chances of developing an allergy remains unclear. But understanding this could lead to improved research and potential new treatments.

By using modern genomics and imaging techniques, a collaborative team of researchers co-led by Penn’s Golnaz Vahedi, PhD, an associate professor of Genetics, and Jorge Henao-Mejia, MD, PhD, an associate professor of Pathology and Laboratory Medicine, found that the ETS1 protein plays a role in controlling a type of immune cell called CD4+ T helper cells, which are important in allergic reactions and help orchestrate the immune response by activating and coordinating other immune cells.

DNA interactions within the genomic segment encompassing the ETS1 gene control how much of the ETS1 protein is made. 

“We discovered that these interactions, work like a dimmer switch,” said Vahedi. “When there are changes in the DNA in this area, it can mess up the dimmer switch, causing problems with controlling the ETS1 protein. This can lead to imbalances in our immune cells and cause allergic inflammations.”

While there has been progress in understanding genetic traits that follow predictable patterns, like those passed down from parents, it’s been more challenging to understand conditions that involve many different genes and are common in populations. These complex conditions cannot be explained by simply “turning off” one gene.

Instead, they may be caused by small changes in the DNA that affect how genes work together. However, researchers still do not know much about how these changes in DNA relate to how our genes are organized or how they affect how genes are expressed in most complex diseases.

“This work demonstrates how small differences in our DNA can disturb the balance between our immune cells, resulting in significant observable characteristics in patients. This phenomenon may occur in other common diseases such as autoimmune disorders,” said Henao-Mejia.

Other co-authors of this study include Aditi Chandra, Sora Yoon, and Michael Michieletto.

Funding: This research was funded by the National Institutes of Health (R01AI168240, UC4 DK112217, U01 DK112217, R01 HL145754, U01 DK127768, U01 DA052715, R01 HL136572), the Burroughs Welcome Fund, the Chan Zuckerberg Initiative Award, W. W. Smith Charitable Trust, the Sloan Foundation, and the PEW Charitable Trust.

About this genetics research news

Author: Matthew Toal
Source: University of Pennsylvania
Contact: Matthew Toal – University of Pennsylvania
Image: The image is credited to Neuroscience News

Original Research: Closed access.
Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation” by Golnaz Vahedi et al. Immunity


Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation


  • Ets1 locus forms a multi-enhancer hub containing a super-enhancer called Ets1-SE
  • Ets1-SE is required for Th1 differentiation and the Ets1 gene dosage control
  • Deletion of Ets1-SE leads to protection against colitis and an overt allergic response
  • Ets1 dosage controls the Th1-specific genome topology through the recruitment of CTCF


Multi-enhancer hubs are spatial clusters of enhancers present across numerous developmental programs.

Here, we studied the functional relevance of these three-dimensional structures in T cell biology.

Mathematical modeling identified a highly connected multi-enhancer hub at the Ets1 locus, comprising a noncoding regulatory element that was a hotspot for sequence variation associated with allergic disease in humans.

Deletion of this regulatory element in mice revealed that the multi-enhancer connectivity was dispensable for T cell development but required for CD4+ T helper 1 (Th1) differentiation.

These mice were protected from Th1-mediated colitis but exhibited overt allergic responses. Mechanistically, the multi-enhancer hub controlled the dosage of Ets1 that was required for CTCF recruitment and assembly of Th1-specific genome topology.

Our findings establish a paradigm wherein multi-enhancer hubs control cellular competence to respond to an inductive cue through quantitative control of gene dosage and provide insight into how sequence variation within noncoding elements at the Ets1 locus predisposes individuals to allergic responses.

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  1. I would think that other than organic material allergens, that progressively over the years we have seen a significant increase in allergies from toxins, industrial pollutants, food contaminants, chronic medication/drug use, and a plethora of other man-made pollutants (including hairspray – which I believe has an association with lung cancer in non-smoking women; and cosmetics – where is the FDA on monitoring the lead in these products which is extremely high in many products).

    I am the last generation of the boomers, I can tell you that did many idiotic things as children, including running behind the “mosquito man’s” truck of toxic fog over summers. It certainly did not help that many of our parents were post-WW2 partiers frequently intoxicated on liquor and cigarettes. Some of the products were used were later found to be a health hazard as well. I remember in summertime being treated with infected scalp sores as youngster via the use of PHISOHEX. Quick Fix dinners were being mass produced, with an inordinate amount of high fructose corn syrup, thought to be associated with ADHD and learning disorders that crept up later.

    And of course, the list goes on and on.

    My question is what can be done about allergy treatments without relying on billion-dollar pharmaceutical companies and costly surgery? I am in my 50’s without health insurance and these things matter to me.

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