New research from an international collaboration, including researchers from the Garvan Institute of Medical Research, has identified a rare genetic mutation in people of Polynesian descent, which increases their risk of severe viral infection or death.
Researchers studied the highly unusual cases of seven Polynesian previously healthy children. Still, they developed severe or fatal reactions to live attenuated vaccines such as the measles, mumps, and rubella (MMR) and yellow fever vaccines or following influenza infection.
Whole-genome sequencing pinpointed the culprit, an error in the IFNAR1 gene that led to a deficiency in the IFNAR1 protein, a key player in the immune system’s first response to foreign pathogens such as viruses. Without this first line of defense, some infections can overwhelm the body and cause severe illness or death.
The findings mean that genetic screening for people of Polynesian descent could help identify a higher risk of an adverse reaction to some live viral vaccines or severe diseases following natural infection with some viruses—including SARS-CoV2—and ensure more careful monitoring and potentially alternate vaccine treatments for those patients.
“This is a remarkable finding. This genetic variant is absent from all other ancestries but is common in some areas of western Polynesia. It highlights the need to study the genetics of all ancestries to understand the causes of immune diseases that are incredibly rare in other parts of the world. It is terrific to contribute to a study that will have such profound impact in this region, and hopefully enable implementation of genetic screening programs and heightened awareness around risks of viral infection in some individuals” says Professor Stuart Tangye, co-head of the Immunology and Immunodeficiency Lab at Garvan, and co-author of the research published in the Journal of Experimental Medicine.
Genetic mutation weakens the immune system
IFNAR1 is a key component of the innate immune system, responding rapidly to cytokines to hold off infections until the adaptive immune system can mobilize the T cells and B cells to hunt down and attack the specific pathogen. Inheriting two copies of the mutated IFNAR1 gene—one from each parent—leads to a deficiency of the protein and a weakened immune response.
“However, an adverse response to infection is still unpredictable,” says Professor Tangye. While some people with IFNAR1 deficiency have severe or fatal reactions, some are unaffected but, even into adulthood, can later develop a severe illness from another virus.
Identification of other cases of people with IFNAR1 deficiency showed they are more likely to develop severe COVID-19 infection, which may explain why some people develop severe COVID-19 when they are otherwise healthy. “It is also important to inform affected families, so they’re aware of the higher risk of severe illness,” says Professor Tangye.
The next step in the research is to investigate precisely how people with the IFNAR1 mutation cannot launch the appropriate immune response necessary to protect them from viral infection.
Genetic databases for minority populations
IFNAR1 deficiency is incredibly rare, with only ten other cases reported globally before this study. However, in Western Polynesian populations—particularly Samoa, Tonga, or Niue—around 1/40 people carry one copy of the mutated IFNAR1 allele, meaning it is “genetically common,” says Professor Tangye.
The discovery of the IFNAR1 mutation highlights the importance of building genetic databases of minority populations who may have unique genetic mutations and are not be seen as insignificant people.
“Understanding isolated populations, like Indigenous Australians, is important for better diagnosis and treatment and health care,” Professor Tangye says.
Source: Garvan Institute
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