In a recent study published on the preprint server medRxiv*, researchers assessed whether loss-of-function (pLOF) variants of type I interferon (IFN) immunity genes are associated with coronavirus disease 2019 (COVID- 19) that threatens life.
Study: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with critical COVID-19. Image credit: Billion Photos
background
Critical COVID-19 can be caused by autosomal congenital defects of type I IFN receptor 3-dependent and -independent immunity (TLR3), such as autosomal recessive (AR) deficiencies of IFNAR1 or IRF7. Studies have found that patients under the age of 60 were more likely to suffer from innate immune errors (IEIs). These results imply that type I IFNs are crucial for protective airway immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with low type I IFN activity responsible for up to 15% to 20% of life cases. threatening COVID-19. Despite this high percentage, in approximately 80% of cases, the causes of severe pneumonia due to COVID-19 are still unknown.
About the study
In the present study, the researchers investigated the association between patients suffering from severe variants of COVID-19 and type I IFN-immune pLOF.
Through the COVID Human Genetics Endeavor (CHGE), the team recruited more than 9,000 SARS-CoV-2-infected individuals with clinical symptoms. The team defined life-threatening cases of COVID-19 as patients with pneumonia who developed severe disease or when the patient requires mechanical ventilation or high-flow oxygen, septic shock, or any other organ damage requiring admission to the intensive care unit (ICU). Plasma samples obtained from patients were screened for the presence of autoantibodies (auto-Abs) against type I IFNs.
People infected with SARS-CoV-2 who were asymptomatic or paucisymptomatic and had mild, ambulatory disease were included as controls. A positive polymerase chain reaction (PCR) test, a positive serological test, or the presence of characteristic symptoms such as anosmia or ageusia after exposure to a confirmed SARS-CoV-2 infected patient determined the existence of infection Whole-exome or whole-genome sequencing (WGS) was performed on cases and controls, and sequencing data were used to identify high-quality variations.
A genome-wide gene-based analysis of the burden of rare variants was performed. Three genetic models were used to calculate a genetic score for each gene from genotypic data for putative rare variants: (1) Codominant: samples were coded 2 if at least one homozygous variant was present, 1 if at least one heterozygous variant. was present, and 0 otherwise; (2) heterozygous: specimens were coded 1 if at least one heterozygous variant was present, and 0 otherwise; (3) recessive: samples were coded 1 if at least one homozygous variant was present, and 0 otherwise. Using the Efficient and Parallelizable Association Container Toolbox (EPACTS), a logistic regression-based likelihood ratio test (LRT) was used to examine the relationship between the genetic score corresponding to each gene and disease status.
results
Through the CHGE, the team gathered whole-exome sequencing (WES) or WGS data for 1,573 people with moderate or asymptomatic disease, meaning no pneumonia, and 3,503 patients with COVID-19 pneumonia who life threatening With 34 carriers present in the patient group compared to six among the controls, the study confirmed the high enrichment in rare pLOF mutations at a total of 13 loci in patients suffering from severe COVID-19.
In addition, 31 of 34 pLOF variant carriers were heterozygous, while three were homozygous: one for an IRF7 frameshift variant, a 4,394 bp IFNAR1 deletion, and a 6,624 bp IFNAR1 deletion of bases Patients had all homozygous pLOF mutations. As a result, the odds ratio (OR) associated with homozygous carriers was higher than with heterozygous carriers.
A highly significant enrichment was discovered by analyzing the rare pLOF variations at 14 loci together with biological LOF (bLOF) variants of TLR7. For homozygous/hemizygous carriers compared to heterozygous carriers, the effect was larger. In addition, heterozygous carriers were significantly older than homozygous/hemizygous carriers. Taken together, these findings showed that individuals with severe COVID-19 pneumonia had an enrichment in rare pLOF mutations at 15 loci that were involved in type I IFN immunity.
Overall, the study results showed that together with X-linked TLR7 deficiency, rare autosomal inborn errors related to type I IFN-dependent immunity to influenza viruses can cause significant types of SARS-CoV-2 infections, especially in people under 60 years of age. Future research should investigate young patients with critical COVID-19 who lack auto-Ab against type I IFNs to determine mutations with a strong tendency toward life-threatening COVID-19.
*Important news
medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as established information.