Heightened Risk of Intense Cellular Mortality Linked to Genetic Variant in 3% of Global Population

Scientists have pinpointed a genetic alteration in the MLKL gene, prevalent in approximately 3% of the worldwide population, that amplifies the phenomenon known as ‘explosive’ cellular death. This increased susceptibility could elevate the risk of inflammatory disorders and severe responses to bacterial infections. Such findings may lead to the development of more targeted therapeutic interventions and a deeper understanding of individual susceptibility to inflammatory conditions.

Australian researchers from the Walter and Eliza Hall Institute (WEHI) have unearthed a genetic variant, present in roughly 3% of individuals globally, that exacerbates the risk of inflammation via a process labeled ‘explosive’ cellular death.

This research could illuminate the reasons why certain people are more prone to conditions such as inflammatory bowel disease or are more severely affected by bacterial infections like those caused by Salmonella.

The Role of Intense Cellular Death in Immunity

Ordinarily, millions of cells in the human body undergo programmed death every minute. This regulated cell death serves a protective role, eliminating cells that are damaged, harmful, or unnecessary, thus preventing the propagation of harmful agents like bacteria, viruses, and even cancerous cells.

According to Dr. Sarah Garnish, the primary author of the study from WEHI, there are multiple forms of cellular death, but necroptosis stands out due to its intense nature. In necroptosis, cells essentially rupture, serving as a signal to activate additional cellular responses within the body.

Necroptosis, an inflammatory form of cellular death, is controlled by the MLKL protein. In cases of viral infections, necroptosis can be advantageous by not only annihilating the infected cells but also by alerting the immune system for a more specialized and enduring response. However, unregulated or excessive necroptosis can incite disease through heightened inflammatory responses.

Genetic Regulatory Mechanisms

The MLKL gene acts as the regulator of necroptosis. Under certain conditions, the cellular mechanisms that usually restrain MLKL are disengaged. However, some individuals possess a variant of MLKL that is less responsive to these restraining signals. Dr. Garnish and colleagues have quantified this phenomenon on a population scale for the first time.

“Though it affects only 2-3% of the population, considering the global numbers, this amounts to a considerable number of individuals carrying this particular gene variant,” Dr. Garnish noted.

The study’s project leader, Dr. Joanne Hildebrand, elaborated that this common genetic variant could interact with an individual’s lifestyle, infection history, and broader genetic landscape to elevate the risk of inflammatory diseases and severe infection responses. This is referred to as polygenic risk, which involves the cumulative effect of multiple genes on the likelihood of developing certain conditions.

Toward Personalized Medical Treatments

Over two decades since the MLKL gene was first discovered in a WEHI lab, the latest research allows for the possibility of future diagnostic tests and risk screenings. As genomic sequencing becomes more cost-effective and widespread, the likelihood of linking such common genetic variants to diseases increases. Future studies aim to identify genetic alterations that could predispose individuals to severe instances of conditions such as COVID-19 or reduce their resiliency following treatments like chemotherapy.

“Each new piece of information brings us closer to making personalized medicine an achievable goal,” Dr. Garnish stated.

The research team is also probing the potential advantages of uncontrolled necroptosis. For example, could individuals with this specific MLKL gene variant display a heightened cellular defense against particular viruses?

“Genetic alterations like this generally persist across generations for a reason; they usually confer some form of advantage,” explained Dr. Garnish. “While we are examining the drawbacks of this particular gene alteration, we are also seeking to understand its benefits.”

Reference: The study titled “A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation” was authored by a team led by Dr. Joanne M. Hildebrand and Dr. Sarah E. Garnish and was published in Nature Communications on September 28, 2023. DOI: 10.1038/s41467-023-41724-6

Frequently Asked Questions (FAQs) about Genetic variant in MLKL gene