An interesting new study published on the preprint server medRxiv* discusses the role of a mucin gene enhancer on the clinical phenotype of the coronavirus disease 2019 (COVID-19), possibly by interacting with host innate immune defenses. The current study indicates a potential protective role for the MUC5B gene variant rs35705950-T in COVID-19.
Study: A MUC5B Gene Polymorphism, Rs35705950-T, Confers Protective Effects In COVID-19 Infection. Image Credit: NEW-LIGHT-VISUALS / Shutterstock.com
The COVID-19 pandemic poses a continuing threat to global stability in terms of health and economics. Public health interventions have been effective in limiting the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, many of these approaches are not compatible with open economies or free social interactions.
Vaccination has been deployed in most developed countries; however, the rise of newer SARS-CoV-2 variants that resist neutralization by antibodies elicited by ancestral strains of the virus raises new obstacles to the control of the viral transmission. SARS-CoV-2 not only causes critical and fatal illness in a minority of infections but can also cause permanent and debilitating complications following recovery.
One such complication is pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a condition in which the lungs develop progressive scarring, with survival for a median of only 2-3 years unless the patient gets a lung transplant.
IPF patients are more likely to be elderly, with cardiovascular disease, diabetes, or a history of smoking. Each of these factors also poses these individuals at a greater risk for severe COVID-19, thus indicating that the two may have common pathogenesis. This may involve both genetic and environmental factors, along with aging and epigenetic changes that promote fibrosis.
Among the genetic factors is the functional gene variant termed rs35705950-T, upstream of the mucin 5B, oligomeric mucus/gel-forming MUC5B gene. This gene is located within an enhancer region that can be modified epigenetically and is implicated in disease-causing gene expression in IPF.
The MUC5B variant rs35705950-T is found in about 20% of individuals of European origin. For this reason, the possibility of its involvement in IPF, as well as COVID-19 severity, was explored in a cohort of over 650,000 United States veterans who were part of the Million Veteran Program (MVP).
The researchers analyzed the health records of these individuals along with their genotyping data. This information was then compared with a similar study in the Host Genetics Initiative (HGI), which combines more than 160 genetic analyses to allow faster research into the current pandemic.
The MVP analysis shows that 12 respiratory illnesses are associated with the gene variant in people of European ancestry. This includes an increase of IPF risk by almost three times, other pneumonopathies by over 2.6 times, and a more than doubled risk of post-inflammatory pulmonary fibrosis.
The risks of respiratory failure, ventilator dependence, pneumonia, and lung transplant were also increased with the presence of this variant. Influenza was not associated with this gene, however.
In people of African ancestry, this variant was also linked to three lung illnesses including idiopathic alveolitis, pneumonopathy, and post-inflammatory pulmonary fibrosis. The closest link was with a raised level of neutrophils, which was reported by these researchers for the first time.
In the European ancestry cohort, many other markers were identified for this gene variant, such as a higher white cell count, neutrophil fraction, eosinophils, monocytes, platelets, and estimated glomerular filtration rate (eGFR). Serum albumin, lymphocyte fraction, and creatinine tended to be reduced in individuals with this variant.
Except for monocyte absolute counts, the other changes were not observed in the African or Hispanic ancestry cohorts.
The odds of developing pneumonia within 60 days of SARS-CoV-2 infection were lower in the MVP cohort who had this allele, with the chances dropping by 15% with each additional allele. In those who were not infected, however, the chances were 8% higher with each additional allele.
Severe COVID-19, including death, was not associated with the presence of a MUC5B rs35705950-T allele in the European ancestry cohort.
The MUC5B gene encodes major mucin that forms a gel in the lung, which, along with the MUC5AC gene product, enables mucociliary clearance (MCC) and is key to mucosal host defense. The mucin prevents bacterial infections of the airways and middle ear, as well as maintains immunity in the lungs.
Mucin is secreted by the airway secretory cells and submucosal glands to trap foreign particles and bacteria and subsequently expel them via ciliary movement and coughing. This mechanism also clears cell debris.
The rs35705950-T variant enhances the expression of the gene in lung tissue in healthy individuals and those with IPF. In the latter group of individuals, high levels of mucin are found within the respiratory bronchiolar epithelium and honeycomb cysts that are found in this condition.
In mice, a deficiency of MUC5B expression or function leads to chronic bacterial infections and inflammation of the airways. Impaired phagocytosis and the build-up of dying macrophages, along with a deficiency of interleukin-23 (IL-23), is also observed in these mice.
Conversely, overexpression of MUC5B predisposes individuals to enhanced fibrotic effects of bleomycin in exposed mice.
Interestingly, while this gene variant increases the chances of developing IPF, it reduces the odds of death among people with IPF.
These findings indicate that it may be worthwhile to explore the mechanism by which rs35705950-T protects COVID-19 patients against subsequent pneumonia. One potential explanation is by increasing the functionality of lung macrophages, or by alterations in the quality or quantity of mucus. The specificity of the protective effect to this subset of patients is another area that requires further work.
The presence of this allele is linked to fewer COVID-19-related hospitalizations and pneumonia among people of European ancestry in MVP. No effects on tissues outside the lungs have been observed, thereby indicating that this promoter variant has a very narrow field of activity.
A second important observation is that this allele by itself does not cause lung fibrosis, as shown by the prevalence of IPF in less than one in a thousand in the White population, despite the presence of this gene variant in 20% of these individuals.
The higher neutrophil counts may be due to the higher incidence of pneumonia in the MUC5B rs35705950-T-positive cohort. Since neutrophils secrete alpha-defensin, the levels of this molecule are higher in the blood of patients with IPF and are proportional to the extent of functional decline in the lungs of these patients.
The authors call for long-term monitoring of COVID-19 patients who have the MUC5B rs35705950-T allele to detect a possible fibrotic response, which is already known to be more common among the survivors of severe COVID-19. This knowledge is essential before considering the use of this gene variant as a protective factor in COVID-19.
The results offer potential insights into the use of therapies that block the aberrant expression of MUC5B genes, such as small molecules or inhibitors of IPF signaling pathways.
“Our study provides a strong rationale to stratify patient populations based on common and disease-related genetic polymorphism in order to better understand the mechanisms and their clinical implications in COVID-19.”
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.
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