Association of ACE2, IFNL3 and IFNL4 Gene Polymorphisms with COVID-19 Severity and Outcome

[S. D. Matić]

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Uvod: Brojni faktori domaćina, uklučujući i genetičke polimorfizme, mogu uticati na kompleksan mehanizam različitih infektivnih bolesti, poput COVID-19. Genotipizacijom funkcionalnih polimorfizama relevantnih gena u izloženim populacijama mogu se identifikovati genetički prediktori teške bolesti i smrtnog ishoda. Cilj: Studija ima za cilj da utvrdi povezanost prisustva polimorfizama ACE2, IFNL3 i IFNL4 gena, kao i koncentracija sACE2, IFN-λ3 i IFN-λ4 u serumu, sa težinom bolesti i ishodom COVID-19. Ispitanici i metode: Ova opservaciona studija obuhvatila je 178 hospitalizovanih pacijenata sa SARS-CoV-2 infekcijom. Genotipizacija polimorfizama ACE2, IFNL3 i IFNL4 izvršena je Real-Time PCR metodom, dok su serumski nivoi sACE2, IFN-λ3 i IFN-λ4 na prijemu određeni ELISA metodom. Rezultati: Prisustvo varijantnog alela ACE2 rs2106809 kod žena donosi 12 puta veći rizik od teške forme bolesti, ali i 10 puta manji rizik od kritično teške i smrtnog ishoda. Varijantni aleli IFNL3 (rs8099917 i rs12980275) i IFNL4 (rs12979860 i rs368234815) smanjuju rizik od umerene infekcije najmanje 5 puta. Prisustvo oba varijantna alela bilo kog ispitivanog IFNL4 polimorfizma smanjuje rizik od pneumonije kod žena 29 puta i smrtnog ishoda za 93,6%. Šansa za smrtni ishod veća je kod nosilaca varijantnog alela IFNL3 rs8099917. Niži nivoi IFN-λ3 i viši nivoi sACE2 u serumu pacijenata na prijemu ukazuju na povećan rizik od ozbiljnijih kliničkih manifestacija i smrtnog ishoda infekcije SARS-CoV-2. Zaključak: Polimorfizmi ACE2, IFNL3 i IFNL4, kao i serumske koncentracije sACE2 i IFNλ3 na prijemu, povezani su sa težinom i ishodom COVID-19. Genotipizacija ovih gena i merenje serumskih nivoa njihovih produkata u ranim fazama infekcije mogu pomoći u proceni rizika od progresije bolesti i smrtnog ishoda.

Introduction: Host factors, including genetic polymorphisms, impact the mechanisms of infectious diseases such as COVID-19. Genotyping exposed populations for functional polymorphisms of relevant genes might predict severe disease and fatal outcome. Aim: This research explores the association of ACE2, IFNL3, and IFNL4 gene polymorphisms and the sACE2, IFN-λ3, and IFN-λ4 serum levels with COVID-19 severity and outcome. Participants and methods: This observational study included 178 hospitalized patients with SARS-CoV-2 infection. Genotyping of ACE2, IFNL3, and IFNL4 polymorphisms was performed by the Real-Time PCR method; serum levels of sACE2, IFN-λ3, and IFN-λ4 were determined upon admission using the ELISA method. Results: The variant allele of ACE2 rs2106809 in females indicates a 12-fold higher risk of severe disease and a 10-fold lower risk of critical severity and fatal outcome. IFNL3 (rs8099917 and rs12980275) and IFNL4 (rs12979860 and rs368234815) variant alleles are associated with at least a 5-fold reduced risk of moderate disease. Both variant alleles of any IFNL4 polymorphisms are linked to a 29-fold lower risk of pneumonia in females and a 93.6% diminished risk of fatal outcome. The chance of a fatal outcome is higher in carriers of the IFNL3 rs8099917 variant allele. Lower IFN-λ3 and higher sACE2 levels in patients' serum at hospital admission indicate an increased risk of severe and fatal SARS-CoV-2 infection. Conclusion: ACE2, IFNL3, and IFNL4 polymorphisms, along with serum concentrations of sACE2 and IFN-λ3 upon hospital admission, correlate with the COVID-19 severity and outcome. Genotyping these genes and measuring their product serum levels during the early stages of infection could assist in assessing the risk of disease progression and fatal outcome.

ACE2; IFNL3; IFNL4; COVID-19; SARS-CoV-2; težina; ishod bolesti; ženski pol

ACE2; IFNL3; IFNL4; COVID-19; SARS-CoV-2; severity; outcome; females

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