Understanding How Genes Predispose Humans to Allergies

New research is expanding the scientific understanding of why some people are more allergic than others. Researchers at the University of Pennsylvania’s Perelman School of Medicine discovered how genetic changes that modify a specific protein called ETS1 can affect our body’s response to allergens.

Understanding How Genes Predispose Humans to Allergies
Golnaz Vahedi, PhD, and Jorge Henao-Mejia, MD, PhD. Image Credit: University of Pennsylvania

The research team discovered that in an animal model, even minor alterations in ETS1 can enhance the likelihood of allergic reactions that result in inflammation. The results were recently reported in Immunity.

Allergies are the sixth most common cause of chronic illness in the United States, according to the Centers for Disease Control and Prevention, costing the country more than $18 billion annually.

It is still unknown how genes can alter the likelihood of acquiring an allergy, despite the fact that prior research has proven a strong genetic basis for allergies and discovered specific genetic sequence differences that predispose to these chronic diseases. But realizing this could result in better research and perhaps even new treatments.

Using innovative genomics and imaging methods, a team of researchers led by Golnaz Vahedi, Ph.D., an associate professor of genetics at Penn, and Jorge Henao-Mejia, MD, Ph.D., an associate professor of pathology and laboratory medicine, discovered that the ETS1 protein regulates CD4+ T helper cells, a type of immune cell that is crucial in allergic reactions and aids in orchestrating the immune response by activating and coordinating other immune cells.

The amount of ETS1 protein produced is regulated by DNA interactions within the genomic region containing the ETS1 gene.

We discovered that these interactions, work like a dimmer switch. 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.

Golnaz Vahedi, Ph.D., Associate Professor, Genetics, Perelman School of Medicine, University of Pennsylvania

Understanding genetic disorders that include numerous genes and are prevalent in populations has proven more difficult, despite advances in understanding genetic features that follow predictable patterns, such as those passed down from parents. Simply “turning off” one gene cannot adequately explain these complex disorders.

Instead, they could result from minute DNA alterations that alter how some genes interact. However, scientists are still largely in the dark regarding how these DNA modifications link to the way genes are set up or how they impact how genes are expressed in the majority of complicated disorders.

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.

Jorge Henao-Mejia, MD, Ph.D., Associate Professor, Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania

Journal reference:

Chandra, A., et al. (2023). Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation. Immunity. doi.org/10.1016/j.immuni.2023.05.004


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