Study identifies gene variant in Inuit causing more severe reactions to infections

A global team of scientists have discovered a gene variant in Inuit that may be responsible for worse outcomes from viral infections.

People with the gene deficiency fail to produce certain types of interferons, which are proteins that fight infection. This can result in severe illness when faced with certain viruses, such as measles, influenza or COVID-19.

"If you have this variant, you will have a problem with viruses," said Trine Mogensen, a biomedical researcher at Denmark's Aarhus University and the lead author of the study published in the Journal of Experimental Medicine.

"It's a significant risk factor."

The findings are the result of a global network of researchers who studied the cases of five Inuit children from Canada, Greenland, and Alaska who were hospitalized with unusually severe viral infections.

In two of the cases, children with histories of troublesome infections were hospitalized with serious colds. But doctors found few treatments were effective, and normally harmless live-virus childhood vaccines seemed to make things worse.

As their conditions worsened, doctors discovered they tested positive for not one but several viral infections, from Epstein-Barr to chicken pox.

Two other cases involved children who developed high fevers and seizures within a few weeks of receiving a common childhood vaccine against measles, mumps and rubella (MMR), which contains a weakened version of the virus. While both recovered, one later died of a COVID-19 infection highly unusual in young children. The sister of one of these patients was also made severely ill by the flu, though she was able to receive the MMR vaccine without incident.

Researchers suspected there may be an underlying genetic explanation for why these children suffered such unusually severe responses to common childhood viruses. When the children were tested, they found the previously undocumented gene variant that meant these children were worse-equipped to fight off infectious disease.

1 in 1,500 Inuit affected

Researchers then searched a database of more than 4,600 Greenlanders and just over 100 Inuit from 10 communities in Nunavik to see how common the gene deficiency was.

They estimate roughly one in 1,500 Inuit are impacted, putting them at risk of severe reactions to COVID-19, the flu, and some common childhood vaccines, because they can't fight off many viruses.

By comparison, the gene is virtually non-existent in other populations. The authors say more testing of Inuit should be done to pin down exactly how many may be affected.

Michael Patterson, the chief medical officer of health for Nunavut, questioned the paper's numbers, saying the study does not provide enough data to form a "firm or reliable estimate." He said that more genetic sampling is needed among Canadian Inuit to say whether "it's appropriate to start screening for this condition."

But other experts say the finding is unsurprising.

"I wasn't surprised," said Shirley Tagalik, chair of the Aqqiumavvik Wellness Society in Arviat, Nunavut, and a longtime community researcher in Inuit health. "We've known for a number of years that Inuit kids especially may react differently to various vaccines."

Anna Banerji, an expert in Indigenous health, pediatrics and infectious disease at the University of Toronto's Dalla Lana School of Public Health, was also unsurprised. She's studied respiratory infections in Inuit babies for decades, and found they occur 20 to 40 times as often as in non-Inuit, even when controlling for environmental factors.

"I always believed that there was a genetic component," she said.

Should not lead to vaccine hesitancy, researchers stress

One in 1,500 sounds like a lot of people, but among the relatively small Inuit population, it works out to about 100 Inuit worldwide, and about 50 in Canada.

For that handful of people, a flu or COVID-19 infection will likely cause hospitalization or death. They're also at serious risk from what are known as live-virus vaccines, such as MMR and yellow fever, which use a weakened form of a particular virus to teach the body's immune system how to respond when it faces the real thing.

But experts stress that the findings should not make people wary of vaccines in general. First of all, many modern vaccines, such as the COVID-19 vaccine, carry no live virus at all, and pose no risk to those with the gene variant.

"All other vaccinations in the childhood program, influenza and COVID-19" are still safe for those with the gene to receive, Mogensen said.

Secondly, for those without the variant including the vast majority of Inuit it's vital that live-virus vaccinations continue. Childhood immunizations, such as the MMR vaccine, have been instrumental in reducing the severity of disease in the North, which has experienced devastating outbreaks of measles and tuberculosis barely a generation ago.

"Some communities are extinct because of these viruses," Banerji said. "The worst thing we can start saying is that we shouldn't be vaccinating Inuit babies because of this risk."

Patterson encouraged parents to stick to the routine vaccine schedule, and stressed that even using the paper's population estimates, only roughly "one child every two years or so" would be affected.

"Avoiding vaccines because of that would be, for the vast majority of people, greatly increasing their risk of severe infection."

Screening possible, but far off

As with many genetic disorders, it's possible to screen for the deficiency before a child is even born, or alongside tests for other disorders, like cystic fibrosis, after the child is delivered.

Mogensen says children found to be positive for the deficiency could be put on a course of antivirals that would protect them from the worst childhood infections. She is working with pediatricians in Denmark to implement one there as soon as possible.

But Patterson said it's impossible to say when Inuit in Nunavut could start being screened for the deficiency.

At the moment, newborn babies in Nunavut are automatically screened for a variety of genetic disorders, which occur, albeit rarely, in Inuit and non-Inuit alike. But the labs that test for those disorders "may or may not be able to easily test for this one," Patterson said.

Mogensen and independent genetic testing labs contacted by CBC suggested otherwise. Aaron Goldman, the chief science officer at DNALabs Canada, said it would cost "a couple of thousand dollars max" to redesign a test, and about $100 per sample after that. Set against the cost of medevacs and hospitalizations, Mogensen calls screening "cost-effective".

Banerji suggested there is a "lack of political will" to tackle something that impacts a small, Indigenous population.

"There's a systematic bias against Indigenous people," she said. "We're willing to find genetic testing for rare diseases where there's more of a lobby."

Tagalik, the community health researcher in Arviat, said the paper presented "a minefield" to health authorities. Implementing a screening program, or even just collecting more data, would require "buy-in and commitment and agreement from not just the people at the top and the people at the bottom, but all those people in between."

In the past, she's seen her own recommendations on childhood health stymied by government protests over cost, turnover in community leadership, and objections from the medical establishment.

"Nothing is going to move forward if you don't have the government behind you," she said, "and even if you do have the government behind you, it's not enough."

Unique among Inuit

Though the gene variant, known as IFNAR2 deficiency, has only been documented in Inuit, researchers also found a similar variant, affecting the IFNAR1 gene, in western Polynesians in a parallel study.

Researchers attribute that commonality to the relatively isolated existence of these communities for much of their history. It may also be a reason why outbreaks of infectious diseases, such as measles and tuberculosis, were so devastating to these communities.

"We think that some of these severe infections, which were thought to be meningitis or tuberculosis, could have been due to this defect," Mogensen said.

Inuit have not often been the subject of genetic studies, partly because projects to map the human genome have historically focused on caucasian populations.

"We have a biased map of the genome," said Mogensen. "We have been doing gene sequencing for not much more than 20 years, and most of the patients are white."

But researchers acknowledge getting more Inuit genetic data will be a serious challenge.

"Genetic testing can be very stigmatizing," said Patterson. "It can lead to inappropriate medical responses, it can lead to unnecessary fear, and the feeling that by getting genetic testing done they've lost a bit of bodily autonomy."

Tagalik, who is not an Inuk herself but whose husband and children are, says genetic studies on Inuit is "a challenging area to be working in for many reasons."

With all health research in Nunavut, she said, "there needs to be a commitment to really acting in the best interest of our communities."

Even so, she said, the paper presents "indicators that need to be followed up on."

"We would be negligent and remiss if there was no work done to explore these initial findings in more detail," she said, "and across all Inuit jurisdictions."