The Role of Genetics in COVID-19

Genetics and the COVID-19 Pandemic

The clinical spectrum of COVID-19-related disease ranges from asymptomatic to severe, fatal presentations.

Older age, gender and comorbidities being identified (hypertension, diabetes, respiratory system disease and cardiovascular disease). Fatal course also presenting in young, previously heathy individuals. Differences in clinical outcomes may be determined by genetic susceptibility.

An Obvious Candidate – ACE2

Genetic Differences – The Virus

SARS-CoV-2 differs from the original SARS-CoV by 380 amino acid substitutions including 5-6 vital amino acids in the receptor binding domain between viral spike protein with surface expressed ACE2.

The binding affinity of SARS-CoV-2 with ACE2 seems stronger than SARS-CoV and this could explain the differences in global effect of the current pandemic. Potential therapeutic strategies might include preventing the binding of human ACE2 and COVID-19 (blocking receptor domain or use of ACE2-derivatives, etc).

COVID-19 and ACE2

Severe lung interstitial edema and leukocyte infiltration in Ace2 KO mice are attenuated in homozygous (Ace-/-) or heterozygous (Ace+/-).

Balance of ACE2/ACE levels is the key to lung injury/lung protection during an inflammatory storm. The activation of the RAS axis due to binding of Covid19 to ACE2 partly drives the systemic manifestations of SARS-CoV-2.

COVID-19 Cell Entry Depends on ACE2 and TMPRSS2

TMPRSS2 is a host cell factor critical for spread of several relevant viruses, including influenza A viruses and coronaviruses.

TMPRSS2 is dispensable for development and homeostasis. A TMPRSS2 inhibitor (serine protease inhibitor camostat mesylate) is approved for (unrelated) clinical use, can block virus entry and might constitute a treatment option for current SARS-CoV-2 patients.

Human Genetic Susceptibility

Host (Human) Genome – Observations Suggesting Genetic Susceptibility

  • A recent report of fatal SARS-COV-2 in 3 brothers, aged 54–66 years, who lived in different locations in Tehran, Iran, and were previously healthy, without underlying diseases. They got infected and all deceased within 15 days with clinical features of fever, dry cough, and dyspnea followed by respiratory failure. The patients close relatives were not affected and tested negative for SARS-CoV-2.
  • Covid-19-associated sudden death in Africa Americans hospitalized patients treated with chloroquine/hydroxychloroquine and azithromycin had QTc values rise above the threshold.
  • Role for p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 in Drug-Induced Long QT Syndrome Risk - OR 8.7 (3.2-23.9) and 9.0 (3.5 –22.9).

Host (Human) Genome – An Ongoing Project

The COVID-19 host genetics initiative brings together the human genetics community to generate, share and analyze data to learn the genetic determinants of COVID-19 susceptibility, severity and outcomes.

Several biobanks from US and Europe have joined this initiative (UK, Biobank, deCode Genetics, Finngen, among others).