Research shows how gene variant influences chronic pain outcomes after trauma

The FKBP5 gene is a critical regulator of the stress response and influences how we respond to environmental stimuli. Previous studies have shown that certain variants of this gene play a role in the development of neuropsychiatric disorders such as post-traumatic stress disorder, depression, suicide risk and aggressive behavior. But in 2013 UNC School of Medicine researchers first showed a link between genetic variants in FKBP5 and post-traumatic chronic pain. In particular, the study found that people with a variant or a small / risk allele on chromosome 6 known as rs3800373 are likely to experience more pain after exposure to trauma (such as assault or collision with motor vehicles) compared to people who do not suffer from trauma this variant.

Now a new study by the same research group, published in the Journal of Neuroscience, has confirmed this association in a cohort of more than 1,500 people of both European and African American descent who experienced a collision trauma of motor vehicles.

Sarah Linnstaedt, PhD, assistant professor of anesthesiology and a researcher at the Institute for Trauma Recovery, is the lead author of the study.

"In our current study we have shown that the reason that this variant affects chronic pain outcomes is because it changes the ability of FKBP5 to be regulated by a microRNA called miR-320a," Linnstaedt said. MicroRNAs play an important role in the regulation of gene expression, mainly by degrading or suppressing the conversion of messenger RNA (mRNA).

"In individuals with the minor / risk allele, the microRNA does not bind well to FKBP5," she said. "In other words, it does not negatively regulate FKBP5, which overexpresses FKBP5.High levels of FKBP5 can be harmful because it changes natural feedback mechanisms that control circulating cortisol (stress hormone) levels."

Cortisol has been shown to make the peripheral nerves immediately sensitive. Therefore, individuals with higher levels of this hormone (i.e., individuals with the risk allele) are likely to experience more pain than individuals who do not have the risk allele.

These results suggest certain therapeutic approaches that may be useful, Linnstaedt said.

"I think it suggests that we can use small molecules or RNA inhibitors to reduce expression or inhibit the activity of FKBP5, or we can use microRNA mimics to increase the expression of the microRNA, miR-320a, " she said. "I can also suggest an approach to gene processing that specifically turns the risk allele in FKBP5 into a protective allele."


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