New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis

Abstract

Background: Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. Morbidity and mortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer and cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2 and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, but these factors are largely unknown. Main body: In this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from~81,000 human genomes. We found unique genetic susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, such as p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations for differential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the highrisk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective treatments (i.e., hydroxychloroquine and camostat) for COVID-19. Conclusion: This study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.

Characterization of neutralizing versus binding antibodies and memory B cells in COVID-19 recovered individuals from India

“…The reason why only half of the COVID-19 recovered individuals developed appreciable levels of neutralizing antibody titers requires further investigation. This may be related to inter-individual differences in human immune responses associated with the expected heterogeneity in initial viral inoculum (45), initial viral loads (46)(47)(48), incubation period (49), host genetic factors (50)(51)(52) and disease severity (53,54). This is consistent with previous studies that show relatively higher neutralizing antibodies in COVID-19 hospitalized patients during the acute febrile phase, or in recovered individuals that were previously hospitalized with severe COVID-19 disease (53,54).…”

Artificial intelligence in COVID-19 drug repurposing

“…67,68 Genotype-informed drug repurposing (termed personalised drug repurposing) might further improve the success rate of clinical trials. 69…”

“…69,78 For example, analysis of approximately 81 000 genomes and exomes from the general population suggested that hydroxychloroquine or chloroquine might only work for TMPRSS2-absent patients who are infected by SARS-CoV-2. 69 An international team showed that hydroxychloroquine has antiviral activity in the kidney cells of African green monkeys without TMPRSS2 expression (VeroE6) but not in the model of reconstituted human airway epithelium developed from primary nasal or bronchial cells. 67 Additionally, another team showed that chloroquine does not block SARS-CoV-2 infection of the TMPRSS2-positive lung cell line Calu-3.…”

Co-Evolution between New Coronavirus (SARS-CoV-2) and Genetic Diversity: Insights on Population Susceptibility and Potential Therapeutic Innovations

“…In prostate cancer, the rs12329760 (C > T) of TMPRSS2 has a higher frequency in men with prostate cancer in his family, while ERG gene fusion [90,91] Rs383510 (T > C) and rs2070788 (G > A) were correlated with aggressive H7N9, H1N1, and increased lung expression of TMPRSS2 [92]. A study by Hou et al, indicated that 4% of nonidentical variants of TMPRSS2 are stop-codon mutations, Meanwhile, 59% are harmful mutations in TMPRSS2 coding regions [93]. The harmful variants (p.Arg240Cys, p. Val160Met, p.Gly181Arg, p.Pro335Leu, p.Gly432Ala, and p.Gly259Ser) in the coding region of TMPRSS2, are the same with somatic alterations arising in various types of cancer.…”