New gene variant ‘uncovers root cause’ of lung disease in Inuit

For decades, northern physicians have had difficulty understanding why breathing disorders are so common in Arctic communities.

Inuit children would come to clinics presenting all the classic symptoms of primary ciliary dyskinesia – a genetic disorder known as PCD that results in chronic cough, congestion, ear infections and pneumonia – but tests would come back negative.

While PCD is relatively rare, its diagnosis is important to understand the best course of treatment and care for patients. PCD causes issues with cilia, which line our airways and help create a natural flow of mucus. It’s also linked to several other health conditions – up to 50 percent of people with PCD have situs inversus, which means their organs are on the opposite side of the body compared to the average person.

The issue was that until recently, none of the children presenting these symptoms were being diagnosed. Now, scientists say they know what was happening.

The previous route to diagnosis involved taking a sample from inside the nose and studying the cells under a microscope.

But a new study from the Children’s Hospital of Eastern Ontario (CHEO) Research Institute and the Research Institute of the McGill University Health Centre says this method doesn’t work for Inuit.

“The belief was Inuit do not get PCD, period,” said one of the study’s senior authors, Tom Kovesi.

Kovesi, a pediatric respirologist at CHEO, was treating an Inuk child from Nunavut whose symptoms felt like a classic case of the disease, despite normal-looking results from a microscope test.

On a hunch, he tried genetic testing and stumbled across a never-before-discovered gene variant that causes PCD.

Thus began a flurry of emails with colleagues treating northern patients.

“Pediatric respirology is a very small field in Canada,” said Kovesi. “You could fit us all together in one room. So we all know each other pretty well.”

Adam Shapiro – the study’s other senior author – found the same gene in several other Inuit patients he was treating in in Nunavik. That made them think about the genetic pattern behind the disease.

As a number of Nunavut patients come to CHEO in Ottawa for healthcare, the study’s first author and hospital resident physician Julia Hunter-Schouela was able to access charts and clinical data to support their thesis after receiving permission from the families, the hospital, and Nunavut ethics boards.

“In small communities, it’s common to find things like the gene that causes cystic fibrosis localized in one area as local people marry each other,” said Kovesi. “But to find the same gene, thousands of kilometres away?”

They began to wonder if the gene had been present in Inuit for a very long time, potentially unravelling an old mystery.

“When I first arrived in Canada, 11 years ago, I was shocked by the amount of lung disease and severity of lung disease in Inuit children and Indigenous children in general,” said Shapiro, who also noted that Indigenous people in Australia and New Zealand seem to be particularly affected by recurrent lung infections.

“After 10 years of watching this, I just said: we’ve got to understand this.”

Shapiro, who serves as an associate professor of pediatrics and internal medicine at McGill University, said marginalized populations with genetic disorders are often under-diagnosed. He said colonialism in medicine has formed doctors that lack curiosity about what they assume to be lifestyle-related medical issues when they treat Indigenous patients.

“Frankly, we should have been doing genetic studies on patients with severe lung diseases like this a long time ago,” Shapiro said.

“There’s a lot of excuses for it, such as poor housing, early-life infections and cigarette smoke exposure, but I call those excuses because they may be additive, but they are not the standalone cause of all the lung disease we see in Inuit.

“Now that we’re looking at genetics, we’re finally uncovering the root cause of this. It’s easy to blame someone for their illness but in reality, if you look, this is genetic, and none of us choose our genetics.”

The researchers are now working on a partnership with the Silent Genomes Project, a BC-based research coalition working to address the lack of genetic variation data for Indigenous populations. Their collaboration will focus on determining how many people are affected by the gene.

While genetic testing continues to raise ethical questions – many scientists view race as a social construct rather than a true biological category – Shapiro said there are benefits to a better understanding of patients who self-identify as Indigenous.

“Genetics in the past has been used to suggest people are inferior, but what we want to use genetics for here is to show that people are blameless,” Shapiro said, “that they have diseases we can diagnose, radically change our therapies based on those diagnoses, and improve their quality of life.”

‘Profound implications’ for NWT Inuit

While the study was conducted in Nunavut and Nunavik, the researchers believe their findings will translate to all Inuit communities, from Alaska and Greenland to Denmark.

“It could have profound implications for the Northwest Territories,” said Shapiro, who said feedback from patients has been overwhelmingly positive. “Parents want to know why their children are sick.”

The Inuvialuit Regional Corporation and the Pauktuutit Inuit Women of Canada declined to comment on the significance of the finding.

But a healthcare worker who frequently treats Inuit patients in the Northwest Territories said the study will have a direct impact their work and the work of their colleagues.

“Just knowing a that a population is more vulnerable, I think you come in with a different perspective,” said the worker, who asked to remain anonymous due to the terms of their employment. “It’s an eye-opener, and I would hope it will help with healthcare bias.”

The healthcare worker shared that there is a tendency to see repeat lung infections as a failure to complete treatment or make lifestyle changes rather than an indication of a more serious medical issue.

“[Healthcare workers] sometimes have this reaction of, ‘oh, you’re sick again, you’re always sick.’ And you know, maybe they’re always sick because there’s something medical going on.”

Kovesi said the revelation has been an eye-opener for quite a number of researchers and clinicians.

“The medical community is really fascinated by this,” he said. “There’s been a lot of interest. We’ve been working with a lot of other physicians in other northern communities.”

While the researchers stress that their study doesn’t provide a full explanation for the severity of lung disease in Inuit, they say this finding is “a piece of the puzzle.”

“We believe this could be as common, or more common, as cystic fibrosis is in white people,” said Kovesi. “As many as one in 20 Inuit could have this.”

They believe newborn screening could help by giving parents and physicians the opportunity to take preventative health measures, such as installing a ventilation system in the home, chest physiotherapy and additional immunizations.

But even for adults, the earlier a patient receives their diagnosis, the earlier they can initiate therapies known to help.

“There are many treatment options for PCD,” said Kovesi.

At the same time, those treatments are limited – there’s currently no way to make the cilia in PCD patients function as they ought to. But Shapiro believes a better understanding of the genetic factors behind the disease could lead to more effective treatments.

“Maybe, in the next 10 years, we’ll no longer be saying: ‘Make sure you cough out the infected mucus because that’ll make you feel better,'” he said.

“We will actually be giving medications that go in and actually fix the problem at its root. And genetics is the linchpin to understand how that might work.”