Hubungan Karakteristik Genetik SARS-CoV-2 dan Polimorfisme rs2074192 Gen ACE2 serta rs12329760 Gen TMPRSS2 terhadap Luaran dan Derajat Penyakit sebagai Prediktor Keparahan Covid-19

Abstract

Background: COVID-19 has caused dramatic number of infections and deaths worldwide. Its pathogenesis of severity was not fully recognized. ACE2 and TMPRSS2 act as the receptors and molecules whose responsible for virus entry to host. ACE2 and TMPRSS2 polymorphisms are widely studied in their relations to COVID-19. The SARS-CoV-2 has evolved to form new virus variants due to its amino acid ability for mutations. These mutations have change its characteristics and virulence. The virulence factors of SARS-CoV-2 are also assumed had contribution to the clinical manifestations of COVID-19 and mortality rates. Objective: This study aims to determine association of SARS-CoV-2 genetic characteristics and rs2074192 ACE2 and rs12329760 TMPRSS2 polymorphisms to the COVID-19 outcomes and severity predictors. Methods: The prospective cohort design was done to 151 subjects hospitalized in H. Adam Malik Hospital, a tertiary hospital located in Medan and owned by the Government. The study determined SARS-CoV-2 variants, its molecular characteristics and ACE2 gene rs2074192 and TMPRSS2 gene rs12329760 polymorphisms. Whole Genome Sequencing to 81 respondents to identify the variants, while the identification of polymorphism used TaqMan probe SNP genotyping assay in 151 respondents. Serum levels of ACE2 and TMPRSS2 were analysed using ELISA examination. Results: Age and severity were correlated to mortality, while age, kidney and lung diseases, and vaccination were correlated to diseases severity. Three genotypes have been documented as CC, CT, and TT in both genes of ACE2 rs2074192 and TMPRSS2 rs12329760. In the ACE2 rs2074192 gene, the CC>TT>CT genotype (p<0.001), while in the TMPRSS2 rs12329760 gene CC>CT>TT (p=0.148). The median concentrations of ACE2 and TMPRSS2 were 2.716 ng/mL and 6.142 ng/mL, respectively. There was a low relative risk of ACE2 and TMPRSS2 polymorphisms with disease severity and outcome. However there was significant association of TMPRSS2 polymorphism to male mortality. There was significant difference level of ACE2 concentrations between mild-moderate group and severe-critical group by 61% AUC. The variant identified in 81subjects was the Omicron with various types of sub-lineage. There was no significant association between BA and XBB sub-lineages to outcome and disease severity. Our study results revealed that amino acid mutations of S protein express 64 types of mutations and Q954H and N969K mutations were the most frequent mutations (100%). There was a significant association between F486V, V213G and H69-/V70- mutations to mortality but no significant association between all types of mutations to disease severity. Conclusions: Age and severity were COVID-19 mortality predictors, while age, kidney and lung diseases, and vaccination status were COVID-19 severity predictors. There was a wide distribution of rs2074192 and rs12329760 polymorphisms in COVID-19 patients. There was significant association of TMPRSS2 to male mortality. ACE2 concentration level had predicted value to mild-moderate and severe-critical with AUC 61%. Omicron variant was a dominant variant circulating during 2022.There was a significant association of F486V, V213G and H69-/V70- mutations to COVID-19 mortality.