Beyond GWAS-Could Genetic Differentiation within the Allograft Rejection Pathway Shape Natural Immunity to COVID-19?

Int J Mol Sci. 2022 Jun 3;23(11):6272. doi: 10.3390/ijms23116272.


COVID-19 infections pose a serious global health concern so it is crucial to identify the biomarkers for the susceptibility to and resistance against this disease that could help in a rapid risk assessment and reliable decisions being made on patients' treatment and their potential hospitalisation. Several studies investigated the factors associated with severe COVID-19 outcomes that can be either environmental, population based, or genetic. It was demonstrated that the genetics of the host plays an important role in the various immune responses and, therefore, there are different clinical presentations of COVID-19 infection. In this study, we aimed to use variant descriptive statistics from GWAS (Genome-Wide Association Study) and variant genomic annotations to identify metabolic pathways that are associated with a severe COVID-19 infection as well as pathways related to resistance to COVID-19. For this purpose, we applied a custom-designed mixed linear model implemented into custom-written software. Our analysis of more than 12.5 million SNPs did not indicate any pathway that was significant for a severe COVID-19 infection. However, the Allograft rejection pathway (hsa05330) was significant (p = 0.01087) for resistance to the infection. The majority of the 27 SNP marking genes constituting the Allograft rejection pathway were located on chromosome 6 (19 SNPs) and the remainder were mapped to chromosomes 2, 3, 10, 12, 20, and X. This pathway comprises several immune system components crucial for the self versus non-self recognition, but also the components of antiviral immunity. Our study demonstrated that not only single variants are important for resistance to COVID-19, but also the cumulative impact of several SNPs within the same pathway matters.

Keywords: COVID-19 infection; GWAS; KEGG pathways; allograft rejection; genetic variants; immunisation; resistance; single nucleotide polymorphism; susceptibility; whole genome sequencing.

MeSH terms

  • Allografts
  • COVID-19* / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Immunity, Innate
  • Polymorphism, Single Nucleotide

Grants and funding

This research was partially funded by the National Centre for Research and Development project “Szpitale Jednoimienne/02/2020”, “Development of an innovative diagnostic test to assess the course of COVID-19 and post-death complications with the aid of whole genome analysis”, as well as The Medical Research Agency project 2020/ABM/COVID19/0022 “A clinical trial in the search for genetic markers responsible for the intensity of the course of the COVID-19 disease, with particular emphasis on patients with accompanying cardiopulmonary diseases”. The publication cost was financed by Wroclaw University of Environmental and Life Sciences.