Ancient gene offers new clue to disease susceptibility for First Nations people

First Nations people are five times more likely to be hospitalised with the flu than non-Indigenous people, according to research findings released today.

The world-first discovery has identified a previously unknown gene variant influencing first-line immune defences in First Nations people – who are at higher risk of severe respiratory viral diseases – and offers insights for improved disease prevention strategies. 

An international team of researchers, co-led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) and Monash University, with CQUniversity’s Professor Adrian Miller as the ethical advisor on the study, has gained new understanding of the immunity of First Nations people across Oceania, which includes Australasia, Melanesia, Micronesia and Polynesia. 

Published in one of the world’s most renowned peer-reviewed research journals Cell, the project was the first of its kind to comprehensively map a component of the first-line immune defences, termed natural killer cells, in Oceania’s First Nations populations, including First Nations Australians. 

Natural killer cells are part of the body’s first line of defence against viral intruders, which can restrict viruses from replicating in the earliest stages of infection. This is crucial because they can either eliminate low-level infection completely, or buy time for the generation of virus-specific immunity. Consequently, these immune cells play a key role in an individual’s ability to both prevent infection and recover from a virus. 

First Nations people globally, including Aboriginal and Torres Strait Islander people, are at high risk of severe respiratory viral diseases, including COVID-19, pandemic influenza and seasonal influenza. In addition to social determinants of health, genetic variations within immune cells may contribute to the increased risk. 

In partnership with Menzies School of Health Research (Northern Territory), the University of Colorado and Stanford University, the researchers evaluated natural killer cells in First Nations people, conducting in-depth genomic and molecular analyses at the Stanford University genomic facility and the Australian Synchrotron. 

Professor Miller, who is also CQUniversity’s Deputy Vice-President of Indigenous Engagement, Co-Director of the Jawun Research Centre, BMA Chair in Indigenous Engagement and proud Jirrbal man, was the only First Nations representative to contribute to the paper and said the research was 14 years in the making.

“We do get severe influenza outbreaks in Australia that cause death in all the Australian populations, but quite often, in many cases it affects First Nations peoples worse,” Prof Miller explained.

“There's a fair bit of mistrust in research in Australia from First Nations communities, so we didn't want to replicate any of that or even exacerbate any of that mistrust,” he said. 

“We wanted to ensure that Aboriginal people who donated those samples were fully informed on what we were doing with them, and those samples have helped a team of international researchers make a world-first discovery that could improve Indigenous People’s health.”

The study examined a highly variable natural killer cell receptor, called KIR3DL1, of which there are over 200 forms in humans, capable of binding to subsets of a person’s human leukocyte antigens (HLA) molecules, which present viral peptides for recognition by immune cells, and are themselves highly variable. 

The research team identified an ancient variant of the natural killer receptor that appears to be exclusive to the people of Oceania, binding more strongly to the HLA variants that are common to Oceanic peoples. 

The researchers analysed more than 1300 individuals which revealed that the frequency of the Oceanic variant was as high as 28 per cent among highland Papuans and around six per cent in First Nations people from Northern Australia, which could influence susceptibility to infection.

Professor Miller explained that genetic and immunological studies often did not involve First Nations and other minority populations around the world. 

“Recent studies including this one, underscore the importance of inclusively working with First Nations peoples. Our learnings may inform the design of new vaccines or vaccine regimens and immunotherapies, helping to ensure these agents are effective for the broad sweep of human populations.”