In a study posted to the medRxiv* preprint server, a team of interdisciplinary research groups identified a genome-wide significant association (GWAS) for long coronavirus disease (COVID) at the FOXP4 locus, which has been previously associated with cancer, severe COVID 2019 (COVID-19), and lung function.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
Long COVID is also called post-acute sequelae of COVID-19. It is more common in patients hospitalized or admitted to an intensive care unit due to COVID-19 infection. However, it can also occur in patients who have mild COVID-19 symptoms.
The COVID-19 Host Genetics Initiative (HGI) has identified 51 distinct genome-wide significant loci linked to COVID-19 pathophysiology ranging from infection to hospitalization.
To understand the underlying causes of long COVID, it is imperative to assess these variants to elucidate viral pathways and entry mechanisms.
About the study
In this collaborative study, researchers performed the first GWAS focussing on long COVID. They conducted 24 independent GWAS conducted in 16 countries representing populations of 6 ancestries, 6,450 people with long COVID diagnoses, and 1,093,995 controls.
They conducted four GWAS meta-analyses based on a test-verified infection, which was listed as a strict case definition (included 11 studies, N = 3,018) and a self or clinician-reported SARS-CoV-2 infection listed as the broad control definition (all contributing 994,582 studies).
Individuals who survived SARS-CoV-2 infection without long COVID were classified as tight controls, while samples that were genetically ancestry-matched and had no long COVID were classified as population controls.
Additionally, a questionnaire-based approach was followed for symptom assessment.
Results
The analysis discovered a strong genome-wide relationship at the FOXP4 gene. It was also identified that the C allele at rs9367106 was linked to a higher risk of long COVID. Concordant results (although not genome-wide) were observed in all three meta-analyses. The rs9367106-C at the FOXP4 locus also demonstrated to have high epidemiological variability.
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The genomic area surrounding the primary variation linked to long COVID (+/-100 kilobases) comprises four genes (FOXP4-AS1, FOXP4, MIR4641, LINC01276).
Since all the variants in linkage disequilibrium (LD) with the lead variant were non-coding, the authors scanned the variants connected to nearby genes with differential expression spanning a 100 kb window.
They identified that rs12660421-A (a proxy allele that correlates with rs9367106-C, the long COVID risk allele) is connected to an increase in the expression of FOXP4 in the lung.
Since FOXP4 has a robust expression in nearly all tissues, including lung cells and immune cells, a colocalization analysis confirmed the same differential expression of long COVID.
Furthermore, the COVID meta-analyses and Biobank Japan labeled the variants in this region as risk factors for COVID-19-related hospitalization. Colocalization analysis conducted by the authors correlated the FOXP4 risk haplotype COVID-19 severity haplotype.
Furthermore, single-cell sequencing analysis suggested that FOXP4 is abundantly expressed in type 2 alveolar cells, which mount robust innate immune responses, secrete surfactant, maintain the alveoli dry, and act as progenitor cells in injured epithelium replenishment.
Additionally, granulocytes that regulate innate immunity also share the same level of FOXP4 expression.
The authors extracted data from the VannoPortal, Regulome, and ENCODE databases and discovered four variants of interest through Chip sequencing. POLR2A and EP300 bound rs2894439 at the start of the risk haplotypes, and EP300 and FOXA1 bound rs7741164 and rs55889968, among others.
Finally, one variant (rs9381074) was shown to be directly associated with DNA methylation signatures in immune and lung cells (H3K27me3 and H3K4me1, H3K27ac, H3K4me3, H3K4me2, H3K4me3), indicating that they are situated at the euchromatin.
A phenome-wide association study between all Biobank Japan phenotypes and rs9367106 identified that the long COVID risk allele was linked to lung cancer.
Additionally, the known risk mutations for lung cancer in non-smoking Asian women and non-small cell lung carcinoma in European and Chinese populations are in LD with the long COVID risk allele.
Colocalization analyses showed that lung cancer and long COVID shared the same genetic signal within 500 kb of rs9367106. Interestingly, the authors also found significant genetic associations between long COVID and symptoms of depression, asthma, and diabetes.
They also suggested that the FOXP4 signal demonstrated an unusually stronger association with long COVID, which cannot be caused by COVID-19 severity alone.
Conclusion
The present research offers direct genetic evidence that lung pathology could contribute substantially to the emergence of long COVID.
Like other post-viral conditions, long COVID is a heterogeneous disease entity where both genetic and epigenetic factors decide the patient’s fate in terms of disease risk, severity, and hospitalization.
Since FOXP4 is expressed in various tissues, including the lungs and gut, its polymorphisms can affect lung diseases like long COVID and cancer and other diseases.
Thus, this study paves the way for future research and gives more insight into the biological processes that underlie long COVID.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
The Canadian government says it will donate up to 200,000 vaccine doses to fight the mpox outbreak in Congo and other African countries.
It says the donated doses of Imvamune will come from Canada’s existing supply and will not affect the country’s preparedness for mpox cases in this country.
Minister of Health Mark Holland says the donation “will help to protect those in the most affected regions of Africa and will help prevent further spread of the virus.”
Dr. Madhukar Pai, Canada research chair in epidemiology and global health, says although the donation is welcome, it is a very small portion of the estimated 10 million vaccine doses needed to control the outbreak.
Vaccine donations from wealthier countries have only recently started arriving in Africa, almost a month after the World Health Organization declared the mpox outbreak a public health emergency of international concern.
A few days after the declaration in August, Global Affairs Canada announced a contribution of $1 million for mpox surveillance, diagnostic tools, research and community awareness in Africa.
On Thursday, the Africa Centres for Disease Control and Prevention said mpox is still on the rise and that testing rates are “insufficient” across the continent.
Jason Kindrachuk, Canada research chair in emerging viruses at the University of Manitoba, said donating vaccines, in addition to supporting surveillance and diagnostic tests, is “massively important.”
But Kindrachuk, who has worked on the ground in Congo during the epidemic, also said that the international response to the mpox outbreak is “better late than never (but) better never late.”
“It would have been fantastic for us globally to not be in this position by having provided doses a much, much longer time prior than when we are,” he said, noting that the outbreak of clade I mpox in Congo started in early 2023.
Clade II mpox, endemic in regions of West Africa, came to the world’s attention even earlier — in 2022 — as that strain of virus spread to other countries, including Canada.
Two doses are recommended for mpox vaccination, so the donation may only benefit 100,000 people, Pai said.
Pai questioned whether Canada is contributing enough, as the federal government hasn’t said what percentage of its mpox vaccine stockpile it is donating.
“Small donations are simply not going to help end this crisis. We need to show greater solidarity and support,” he said in an email.
“That is the biggest lesson from the COVID-19 pandemic — our collective safety is tied with that of other nations.”
This report by The Canadian Press was first published Sept. 13, 2024.
Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.
HALIFAX – The Nova Scotia government says it could be months before it reveals how many people are on the wait-list for a family doctor.
The head of the province’s health authority told reporters Wednesday that the government won’t release updated data until the 160,000 people who were on the wait-list in June are contacted to verify whether they still need primary care.
Karen Oldfield said Nova Scotia Health is working on validating the primary care wait-list data before posting new numbers, and that work may take a matter of months. The most recent public wait-list figures are from June 1, when 160,234 people, or about 16 per cent of the population, were on it.
“It’s going to take time to make 160,000 calls,” Oldfield said. “We are not talking weeks, we are talking months.”
The interim CEO and president of Nova Scotia Health said people on the list are being asked where they live, whether they still need a family doctor, and to give an update on their health.
A spokesperson with the province’s Health Department says the government and its health authority are “working hard” to turn the wait-list registry into a useful tool, adding that the data will be shared once it is validated.
Nova Scotia’s NDP are calling on Premier Tim Houston to immediately release statistics on how many people are looking for a family doctor. On Tuesday, the NDP introduced a bill that would require the health minister to make the number public every month.
“It is unacceptable for the list to be more than three months out of date,” NDP Leader Claudia Chender said Tuesday.
Chender said releasing this data regularly is vital so Nova Scotians can track the government’s progress on its main 2021 campaign promise: fixing health care.
The number of people in need of a family doctor has more than doubled between the 2021 summer election campaign and June 2024. Since September 2021 about 300 doctors have been added to the provincial health system, the Health Department said.
“We’ll know if Tim Houston is keeping his 2021 election promise to fix health care when Nova Scotians are attached to primary care,” Chender said.
This report by The Canadian Press was first published Sept. 11, 2024.
ST. JOHN’S, N.L. – Newfoundland and Labrador‘s chief medical officer is monitoring the rise of whooping cough infections across the province as cases of the highly contagious disease continue to grow across Canada.
Dr. Janice Fitzgerald says that so far this year, the province has recorded 230 confirmed cases of the vaccine-preventable respiratory tract infection, also known as pertussis.
Late last month, Quebec reported more than 11,000 cases during the same time period, while Ontario counted 470 cases, well above the five-year average of 98. In Quebec, the majority of patients are between the ages of 10 and 14.
Meanwhile, New Brunswick has declared a whooping cough outbreak across the province. A total of 141 cases were reported by last month, exceeding the five-year average of 34.
The disease can lead to severe complications among vulnerable populations including infants, who are at the highest risk of suffering from complications like pneumonia and seizures. Symptoms may start with a runny nose, mild fever and cough, then progress to severe coughing accompanied by a distinctive “whooping” sound during inhalation.
“The public, especially pregnant people and those in close contact with infants, are encouraged to be aware of symptoms related to pertussis and to ensure vaccinations are up to date,” Newfoundland and Labrador’s Health Department said in a statement.
Whooping cough can be treated with antibiotics, but vaccination is the most effective way to control the spread of the disease. As a result, the province has expanded immunization efforts this school year. While booster doses are already offered in Grade 9, the vaccine is now being offered to Grade 8 students as well.
Public health officials say whooping cough is a cyclical disease that increases every two to five or six years.
Meanwhile, New Brunswick’s acting chief medical officer of health expects the current case count to get worse before tapering off.
A rise in whooping cough cases has also been reported in the United States and elsewhere. The Pan American Health Organization issued an alert in July encouraging countries to ramp up their surveillance and vaccination coverage.
This report by The Canadian Press was first published Sept. 10, 2024.
