Genetics May Be a Factor in Varying COVID-19 Severity

Someone may have been exposed but seems COVID-proof, or some were infected with barely noticeable symptoms, while some got really sick. Questions on why the virus acts so unpredictably are piling up as multivariant vaccine development remains slow, all while Omicron variant’s driving reinfections globally. Immunologists, microbiologists are now turning to human genetics for answers.

Human’s Built-In Resistance

Our evolution has been driven by sufficiently pathogenic microbes that apply selective pressure on genes crucial for defenses. In an international study published on Nature, researchers are screening and studying the genetics of individuals believed to be resistant to SARS-CoV-2 infection, trying to understand what might make a person extra vulnerable, or protected from COVID-19. 

At the pandemic’s beginning, studies identified that SARS-CoV-2 relies on ACE2 (angiotensin converting enzyme 2) receptors for cell entry, and protease TMPRSS2 for spike protein priming. The study suggested that rare genetic variants, such as ACE2 variant rs190509934 located close to the ACE2 sequence could contribute to decreased ACE2 expression, thereby protecting against COVID-19 infection. The team has already recruited over 400 individuals in their next dedicated resistance study cohort. 

Related article: Pfizer to Address COVID-19 Reinfection After Treated by Paxlovid 

Mild or Severe COVID-19?

Investigation of genetic diversity and detection of natural selection signatures in human genes related to COVID-19 infection will help identify functionally significant variations. According to University of Pennsylvania’s scientists, variants of four SARS-CoV-2 infection-related genes were targets of natural selection and linked to health conditions observed in patients. The genes are angiotensin converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), dipeptidyl peptidase 4 (DPP4), and lymphocyte antigen 6 complex locus E (LY6E).

Being the first study to look at ethnically diverse Africans and a highly diverse dataset from the Penn Medicine BioBank, the team discovered 41 global rare variants of the ACE2 gene that affected the amino acid sequence of the protein, as well as 48 variants of TMPRSS2, some are also found with unique characteristics that may be the answer to contrasting COVID-19 susceptibility. 

While above research shined a light on new understanding of SARS-CoV-2 and could be developed into treatments, more work is still required to investigate the impact of genetic variation on population’s response to COVID-19 infection.

Author

Fujie Tham