Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19

Maryam B Khadzhieva; Dmitry S Kolobkov; Darya A Kashatnikova; Alesya S Gracheva; Ivan V Redkin; Artem N Kuzovlev; Lyubov E Salnikova

doi:10.3390/biom13091380

Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19

Biomolecules. 2023 Sep 12;13(9):1380. doi: 10.3390/biom13091380.

Authors

Maryam B Khadzhieva^{1

2

3}, Dmitry S Kolobkov², Darya A Kashatnikova², Alesya S Gracheva^{1

4}, Ivan V Redkin⁵, Artem N Kuzovlev¹, Lyubov E Salnikova^{1

2

3}

Affiliations

¹ The Laboratory of Clinical Pathophysiology of Critical Conditions, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia.
² The Laboratory of Ecological Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia.
³ The Laboratory of Molecular Immunology, National Research Center of Pediatric Hematology, Oncology and Immunology, 117997 Moscow, Russia.
⁴ The Department of Population Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia.
⁵ Competence Center for the Development of AI Technology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia.

Abstract

The development of severe COVID-19, which is a complex multisystem disease, is thought to be associated with many genes whose action is modulated by numerous environmental and genetic factors. In this study, we focused on the ideas of the omnigenic model of heritability of complex traits, which assumes that a small number of core genes and a large pool of peripheral genes expressed in disease-relevant tissues contribute to the genetics of complex traits through interconnected networks. We hypothesized that primary immunodeficiency disease (PID) genes may be considered as core genes in severe COVID-19, and their functional partners (FPs) from protein-protein interaction networks may be considered as peripheral near-core genes. We used whole-exome sequencing data from patients aged ≤ 45 years with severe (n = 9) and non-severe COVID-19 (n = 11), and assessed the cumulative contribution of rare high-impact variants to disease severity. In patients with severe COVID-19, an excess of rare high-impact variants was observed at the whole-exome level, but maximal association signals were detected for PID + FP gene subsets among the genes intolerant to LoF variants, haploinsufficient and essential. Our exploratory study may serve as a model for new directions in the research of host genetics in severe COVID-19.

Keywords: core and peripheral genes; functional partners (FPs) of PID genes; omnigenic model; primary immunodeficiency (PID) genes; protein-protein interaction (PPI); rare high-impact (HI) variants; severe COVID-19; whole-exome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19* / genetics
Exome / genetics
Humans
Multifactorial Inheritance
Patient Acuity
Protein Interaction Maps

Grants and funding

This work was supported by the state assignment of the Ministry of Education and Science of Russia (No. FGWS-2022-0001 “Multiple organ dysfunction and failure in critical conditions: leading mechanisms of development, new methods of diagnosis and treatment” and No. 0092-2022–0001 “Genetic processes in microorganisms, plants, animals, and humans”).