A new study published on the preprint server medRxiv* investigates the genetic overlap between the coronavirus disease 2019 (COVID-19) and idiopathic pulmonary fibrosis (IPF) to identify possible shared biological mechanisms using Genome-wide association studies (GWAS).
Study: Genetic overlap between idiopathic pulmonary fibrosis and COVID-19. Image Credit: Chinnapong / Shutterstock.com
COVID-19 is an infectious disease that primarily affects the lungs and can lead to long-lasting respiratory symptoms. To date, COVID-19 has caused over 5.3 million deaths worldwide.
Comparatively, IPF is a progressive and chronic interstitial lung disease (ILD). Individuals with IPF have an aberrant response to alveolar injury leading to progressive scarring of the lungs. Individuals with ILD have a higher risk of death from COVID-19.
Large GWAS have identified multiple genetic loci associated with severe COVID-19. The DPP9 gene locus is associated with COVID-19 and increased IPF risk.
Likewise, GWAS has identified 20 genome-wide loci associated with IPF risk. The largest genetic risk factor is a common variant located in the promoter region of MUC5B.
One study suggests that IPF is a causal risk factor for severe COVID-19. Notably, this study reports that rs35705950, the allele associated with increased risk of IPF was protective against severe COVID-19.
About the study
Data from the largest GWAS of IPF risk consisting of unrelated European individuals from five studies were taken for the current study. Cases from centers in the United States, United Kingdom and Spain, diagnosed using American Thoracic Society and European Respiratory Society guidelines, were taken. Data from the summary statistics from version 6 of the COVID-19 Host Genetics Initiative were also used for this study.
Within this analysis, COVID-19 phenotypes were divided into four categories according to the severity of the disease and the controls used: These included A2, which indicated very severe respiratory confirmed COVID-19 compared to the population, B1, which consisted of hospitalized COVID-19 versus not hospitalized COVID-19 patients, B2, which included hospitalized COVID-19 compared to the population, and fourthly C2, which included COVID-19 compared to the population.
Using this data, genome-wide genetic correlation analyses were conducted to identify genetic overlap. A phenome-wide association study (PheWAS) was performed to identify putative causal genes and pleiotropic effects.
There was a weak but significant positive genome-wide correlation between IPF and severe COVID-19. There was no correlation between IPF and COVID-19 infection.
Four genetic loci were found to be likely shared causal variants between severe COVID-19 and IPF. These four loci included 7q22.1 locus, near MUC5B, near ATP11A, and near DPP9. This is the first report of 7q22.1 locus association with COVID-19.
There were three IPF genetic loci at 17q21.31, DSP, and DEPTOR that showed an association with COVID-19. However, these did not colocalize, thus suggesting there are different causal variants between IPF and COVID-19 at these loci.
Colocalization analyses could not determine whether the causal variants were shared or distinct. MUC5B, ATP11A, and DPP9 loci colocalized with the expression of the single nearest gene in blood or lung.
The allele at 7q22.1 locus associated with increased IPF and COVID-19 risk was linked to decreased expression of ZKSCAN1 and TRIM4 in blood. TRIM4 is a regulator of virus-induced interferon induction pathways.
Viral infection-induced micro-injury to the alveolar epithelium is considered a trigger for IPF. Thus, the interferon-mediated innate immune response could be common to the risk of chronic lung disease and worse outcomes due to COVID-19.
The locus on chromosome 7 was associated with several blood traits, whereas the signal near ATP11A was associated with blood traits and HbA1c, which denotes average blood glucose levels used in diagnosing diabetes. The IPF and HbA1c loci did not colocalize. There was no association with ATP11A expression in blood.
IPF-associated genetic variants related to telomere dysfunction and spindle assembly showed no association with COVID-19 phenotypes. MUC5B and ATP11A loci were found to have opposite directions of effect on risk for the two diseases.
Limitations of the study
All causal variants may not have been measured in this study. The current study used whole blood and lung tissue gene expression data; therefore, cell-specific effects cannot be ruled out.
Further analyses using data from non-European populations should be done to help identify other ancestry-specific overlapping variants. This will increase the generalizability of the results.
There appears to be a positive genetic correlation between IPF and severe COVID-19 risk. However, some of the IPF-related pathways may have an opposite effect on severe COVID-19 risk. Thus, there are both shared and distinct biological processes driving IPF and severe COVID-19 phenotypes.
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.