Why some people get seriously ill while others experience mild symptoms
Exploring the genetic factors behind COVID-19 susceptibility and severity
Since the beginning of the COVID-19 pandemic, it became evident that the virus affects people selectively. While advanced age, chronic diseases, and male sex were identified as risk factors, they didn't provide a complete explanation for the observed patterns. Why do some young and healthy individuals become seriously ill? Why do family members experience the infection differently? These questions prompted scientists to closely examine the genetic characteristics of the host organism.
Genetic factors determine approximately 4.6% of susceptibility to COVID-19 and 7.6% of disease severity according to the COVID-19 Host Genetics Initiative 9 .
Research into the role of genetics in COVID-19 susceptibility and severity began almost simultaneously with the spread of the pandemic. Scientists used two main approaches:
Targeted study of already known genes that theoretically could influence susceptibility to the virus or disease severity.
In 2020, the international COVID-19 Host Genetics Initiative was created, uniting scientists from different countries for joint data analysis 1 .
Large-scale international studies have identified specific chromosomal regions and genes associated with severe coronavirus infection.
One of the most significant findings was an area on chromosome 3 that demonstrated a clear association with COVID-19 severity. This region contains several genes that may influence disease development 1 9 :
According to Oxford University research, this gene may almost double the risk of respiratory failure in COVID-19 . It occurs in 60% of people of South Asian ancestry and only 15% of Europeans.
Encodes a protein that interacts with ACE2 - the receptor that SARS-CoV-2 uses to enter cells 1 .
Genes associated with chemokines - proteins controlling immune cell movement and crucial for innate immune system function 1 .
A 2025 study published in Nature Genetics revealed a connection between the FOXP4 gene and the development of long COVID-19. Researchers analyzed data from 15,950 people with long COVID and 1,892,830 control participants from 19 countries 3 .
A specific variant of the FOXP4 gene increases the risk of developing long COVID by 63%. This gene is particularly active in lung tissue, highlighting the importance of preserving lung function in long COVID pathophysiology 3 .
Early in the pandemic, reports emerged about a connection between blood type and COVID-19 severity. However, subsequent large-scale analyses conducted as part of the Host Genetics Initiative did not confirm a statistically significant association between the ABO blood group gene and COVID-19 1 .
60% of South Asians carry LZTFL1 risk variant
15% of Europeans carry LZTFL1 risk variant
2% of Afro-Caribbeans carry LZTFL1 risk variant
| Chromosomal Region | Genes | Risk Impact | Population Prevalence |
|---|---|---|---|
| 3p21.31 | LZTFL1, SLC6A20, CCR1 | Up to 2x increased risk of severe course | 60% South Asians, 15% Europeans, 2% Afro-Caribbeans |
| 9q34.2 | ABO blood group gene | Contradictory data | Varies |
| 6p21.33 | FOXP4 | Increased risk of long COVID | 1.6% non-Finnish Europeans, 7.1% Finns, 36% East Asians 3 |
Genes of the major histocompatibility complex (HLA) deserve special attention as they play a crucial role in presenting viral peptides to immune cells. Different HLA alleles can present different peptide repertoires, potentially affecting the efficiency of the immune response 6 .
Russian scientists from the Institute of Immunology of the FMBA of Russia studied polymorphisms of HLA-A, -B, -DRB1 genes in COVID-19 patients and identified specific alleles associated with disease severity:
| HLA Allele | Association | Age Group |
|---|---|---|
| B*08:01 | Severe course with favorable outcome | ≤65 years |
| DRB1*11:03 | Severe course with favorable outcome | ≤65 years |
| B*57:01 | Milder disease course | >65 years |
| B*15:01 | Lethal outcome in severe cases | >65 years |
The study showed that the examined HLA genes are more associated with the severity and outcome of infection than with the fact of infection itself 6 .
One of the most illustrative studies was the large-scale genome-wide study conducted by the international COVID-19 HGI consortium in 2020.
Comparison of genetic variants in patients with severe COVID-19 (cases) and people from the general population (control) 1 .
Combined data from eight studies covering 3,199 COVID-19 cases and 897,488 people in the comparison group 1 .
Genome-wide association analysis (GWAS) to identify statistical links between the observed trait (COVID-19) and individual genetic markers 1 .
The study identified one statistically significant genome region on chromosome 3 associated with COVID-19 severity 1 . This region contained several genes, including chemokine genes (CXCR6, CCR1) and the SLC6A20 gene encoding a protein that binds to the ACE2 receptor 1 .
The discovery of this locus was an important step in understanding the molecular mechanisms of severe COVID-19. Subsequent functional studies allowed better understanding of how genetic variations affect the interaction of the virus with the host organism.
Modern genetic research relies on complex technologies and analysis methods:
| Method/Reagent | Purpose | Example Use |
|---|---|---|
| Single-cell RNA sequencing | Analysis of genetic code of individual cells | Study of lung cells from healthy people and patients with chronic diseases 7 |
| Genome-wide association analysis (GWAS) | Identification of links between genetic markers and disease | Discovery of locus 3p21.31 associated with severe course 1 5 |
| HLA typing by NGS method | Determination of alleles of major histocompatibility complex genes | Identification of HLA alleles associated with COVID-19 severity 6 |
| Machine learning | Analysis of complex genetic data | Identification of LZTFL1 gene as potentially responsible for respiratory failure risk |
Understanding the genetic basis of COVID-19 susceptibility and severity opens new opportunities for personalized medicine:
Genetic testing can help identify people with increased risk of severe COVID-19 for priority vaccination and early treatment initiation.
Deciphering molecular mechanisms through which genetic variants influence the disease points to new targets for pharmaceutical drugs.
Studying the relationship between HLA genotype and immune response to vaccines can help develop more effective vaccine strategies.
Importantly, according to researchers, increased genetic risk can be neutralized through vaccination . Genetic predisposition is not a sentence, but knowledge that allows for a more conscious approach to prevention and treatment.
Genetic research on COVID-19 has traveled an impressive path from the first observations about differences in susceptibility to the identification of specific genes and biological mechanisms underlying these differences. Heredity is just one factor in the complex mosaic determining the course of coronavirus infection, where social conditions, age, comorbidities, and chance play equally important roles.
Discoveries in the field of COVID-19 genetics not only help in fighting the current pandemic but also expand our understanding of the mechanisms of infectious diseases in general, paving the way for more effective and personalized medicine of the future.