Covid-19

Human genetic variants that determine COVID-19 susceptibility

The key distinguishing feature of the SARS-CoV-2 virus is that it can present itself from asymptomatic infection to life-threatening, viral pneumonia and acute respiratory distress syndrome depending on the individual. There are several host factors that determine disease severity (e.g., increasing age, comorbidities, and higher body mass index) however, these risk factors alone do not explain all the variations of disease intensity observed in individuals. Understanding the genetic factors involved in the pathogenesis of a COVID-19 infection can help to identify the possible targets for drugs since treating the disease remains the primary goal despite the development of vaccines. 

There is a genetic predisposition that influences the severity of infectious diseases, including infection with SARS-CoV-2. The effects of genetic factors range from those of rare, high-impact mutations that can make the difference between individuals developing mild symptoms and life-threatening illnesses, to more common genetic variants that only moderately affect symptom severity. 

The problem is that there are very few human genomic studies related to infectious diseases compared to those of other immune-mediated conditions, such as autoimmune disorders. Most infectious diseases are typically studied with a focus on the disease-causing microorganism, rather than the host. Human genetic variants also do not have much of an effect on infection outcomes compared to socio-demographic factors such as age or access to health care. Unlike chronic diseases, the period of a symptomatic infectious disease is very short, which makes it difficult to understand the genetic involvement in such infections. Identifying these effects requires studies of large, well-characterized groups of people to produce sufficient statistical power to reveal the relevant genetic factors. 

Members of the COVID-19 Host Genetics Initiative reported results of a large human genetics study of SARS-CoV-2 infection and they found 13 locations (loci) on the human genome that influence COVID-19 susceptibility and severity. This collaboration consisted of more than 3000 scientists and clinicians. They included data from 46 studies involving more than 49000 individuals who suffered from a SARS-CoV-2 infection and 2 million control individuals. The participants were recruited from 6 different ancestries and 19 countries. The researchers also took into account various socio-demographic factors such as age and gender and were able to account for statistical significance due to the large sample size. 

The authors defined three categories of analysis: infection, which included people with physician-confirmed, laboratory-confirmed, or self-reported COVID-19; hospitalization, which consisted of individuals with laboratory-confirmed moderate to severe COVID-19; and critical illness, patients with laboratory-confirmed infection who were hospitalized and required respiratory support or died. They were able to identify 13 loci on the human genome that were associated with SARS-CoV-2 infection and disease severity with four loci influencing general susceptibility and nine loci influencing with disease severity.

The scientists also looked for genes that were in the proximity of each locus (that is, ‘candidate genes’) to get a clearer picture of how these genetic variants influence COVID-19 severity. They identified more than 40 candidate genes, several of which have previously been implicated in immune function or have known functions in the lungs, suggesting that variants in the vicinity of the suspected genomic regions might exert their effect on COVID-19 outcome through the respiratory system.

Variations and mutations in one such gene TYK2 can increase susceptibility to infections by other viruses, bacteria, and fungi and are at increased risk of being hospitalized or developing critical illness from infection with SARS-CoV-2. Variants of another gene, DPP9 increases the chances of becoming critically ill with COVID-19 and elevates the risk of a rare pulmonary disease characterized by scarring of the lung tissue. A locus on the genome, 3p21.31, is associated with COVID-19 susceptibility rather than severity. The locus overlaps SLC6A20, which encodes an amino acid transporter that interacts with the ACE-2 receptor. 

There were some limitations to this study. The scientists were not able to address the combined effect of specific SARS-CoV-2 variants and variants in the human genome on disease outcome. They also did not fully account for all the socio-demographic factors, such as access to health care.  Future studies containing a larger number of individuals from various other ancestry groups are needed to identify other loci that might be associated with risk in people of other ancestries.

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