Illustration of a cross section of human kidneys to illustrate kidney disease
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Research from the Garvan Institute of Medical Research in New South Wales shows that mutations in the TNFAIP3 gene can influence the outcome of kidney disease, with some variants linked to inflammation acting to protect the kidneys.

“We wanted to investigate whether inherited differences in how people regulate inflammation could lead to better or worse kidney health outcomes,” said Shane Grey, a professor and head of the Transplant Immunology Lab at Garvan, in a press statement.

Writing in the journal Kidney International, co-lead author Grey and colleagues explain that the tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) gene produces an enzyme known as A20, which acts to slow down inflammation.

“Common variants of TNFAIP3 have been linked to autoimmune disease, but their role in kidney disease was unknown,” explained Grey.

Acute kidney injury, where kidney function rapidly declines at least in part because of inflammation, is a strong risk factor for developing chronic kidney disease, a significant health problem impacting almost 40 million Americans. There are limited treatment options available for acute kidney injury and predicting who is most at risk of a poor outcome, such as chronic kidney disease, is difficult.

In this study, Grey and colleagues assessed the impact of different TNFAIP3 genetic variants on A20 function and found some rarer variants reduced its inflammatory action. They also created a mouse model of one of the inflammation-promoting mutations to study the impact of this variant after acute kidney injury.

“Despite increasing inflammation, this rare variant surprisingly protected the kidneys from injury. We found this protection to be due to another of A20’s functions: preventing cells from self-destructing,” said Natasha Rogers, a professor, nephrologist and Head of Transplantation at Westmead Hospital, who co-led the study.

“Our study indicates that these ‘hot’ TNFAIP3 variants can alter the outcome of kidney injury, and they do so through complex effects on inflammation and cell survival.”

This work is still at an early stage, but the research shows how TNFAIP3 coding variants can influence the outcome of acute kidney injury and the action of the nuclear factor κB (NF-κB) pathway, which “dynamically regulates responses to external stress stimuli and has emerged as an important determinant of the severity of acute kidney injury by coordinating inflammation and cell death.”

Following replication and confirmation of these findings, the next step could be to create a genetic test to help clinicians assess a person’s risk for a poor outcome when experiencing acute kidney injury.

“Some studies show that acute kidney injury incidence segregates by population ethnicity. The defined population distribution of specific TNFAIP3 variants may be analogous to the impact of APOL1 variants on focal segmental glomerular sclerosis in African Americans, and further highlights how health differences ascribed to ethnicity could be attributable to segregating genetic variants,” write the authors.

“This has relevance for personalized medicine, by increasing the importance of data collected from different ethnic groups to identify protective and risk alleles and also to identify the genetic causes rather than race as the source of attributable risk.”

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