The synergistic interaction between ACE and TMPRSS2 polymorphisms increases the risk of severe COVID-19
Odonchimeg Bayaraa, Chimedlkhamsuren Ganbold, Bayarlakh Byambadorj, Zolzaya Battulga, Ichinnorov Dashtseren, Sarantuya Jav
Abstract
Within a few years after the pandemic outbreak, several of evidence have found to suggest that the genetic factors influence the severity and mortality rate of COVID-19. In particular, the identification of genetic markers that increase the risk of severe or critical COVID-19 is important for public health management during the pandemic. By August 2021, 88.9% of Mongolian population had been vaccinated.
Introduction
The coronavirus disease 2019 (COVID-19) is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and according to WHO data, as of 15 September 2024, approximately 776 million cases and 7.07 million deaths had been recorded worldwide [1].
Materials and method
Study subject
This cross-sectional study was conducted following the STREGA (STrengthening the REporting of Genetic Association studies) guidelines to ensure standardized reporting and transparency. Between 1st of June and 31st of December 2021, a total of two hundred seventy five people infected with SARS-CoV-2 were collected using non-probability sampling in this study. The total sample consisted of 90 patients with severe COVID-19 and 95 patients with mild COVID-19 who were hospitalized at the First State Central Hospital of Mongolia, and 90 asymptomic volunteers who were visited as outpatient clinic.
Results
Ninety-patients with severe COVID-19, ninety-five patients with mild COVID-19 and ninety-patients with asymptomatic volunteers participated in this study. The general data of the study participants are compared between the groups and shown in Table 1. The study groups were similar in terms of age, gender ratio, BMI categories, education level, smoking and alcohol consumption.
Discussion
Recent studies reported a number of evidence that rs4646994 or rs75603675 polymorphisms were individually found to be significant for susceptibility to COVID-19 and disease mortality. In present study, the findings were novel in highlighting a strong positive interaction between rs4646994 and rs75603675 polymorphisms of ACE and TMPRSS2 genes, which strongly increase the risk of severe COVID-19 compared with mild COVID-19. However, this study had some limitations.
Conclusion
We found the strong positive-interaction between rs4646994 of ACE and rs75603675 of TMPRSS2 that increases the risk of severe COVID-19 and it supports the pathogenesis of COVID-19 might be driven with SNP-SNP interaction of these genes.
Citation: Bayaraa O, Ganbold C, Byambadorj B, Battulga Z, Dashtseren I, Jav S (2026) The synergistic interaction between ACE and TMPRSS2 polymorphisms increases the risk of severe COVID-19. PLoS One 21(2): e0343590. https://doi.org/10.1371/journal.pone.0343590
Editor: Antonio Carlos Vallinoto, Universidade Federal do Para, BRAZIL
Received: April 20, 2025; Accepted: February 9, 2026; Published: February 24, 2026
Copyright: © 2026 Bayaraa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting information files.
Funding: The present study funded by the Research and Development Foundation, the Ministry of Science and Education, Mongolia (Grant no. 2022/132).
Competing interests: The authors have declared that no competing interests exist.
