The Role of Coagulation Gene Polymorphisms in Sars-CoV2 Infection in the Bergamo Area
Authors: Marchetti Marina , Villa Chiara , Gamba Sara , Conconi Donatella , Giaccherini Cinzia , Russo Laura , Bolognini Silvia , Tartari Carmen Julia , Ticozzi Chiara , Verzeroli Cristina , Schieppati Francesca , Barcella Luca , Lavitrano Marialuisa , Falanga Anna 
Published: December 2023

Introduction: Given the great variability of the individual response to SARS-CoV2 infection, it is important to understand whether and how biological and genetic factors might predispose to the infection and to the degree of severity, including the development of systemic coagulopathy and thrombosis. In this study, we evaluated the frequency of prothrombotic allelic variants (AVs) in coagulation genes in a population of COVID-19 patients, to verify whether these polymorphisms, alone or in combination, are associated to an increased susceptibility to develop COVID-19 and/or a greater severity.

Methods: A cohort of 358 patients (257M/101F; median age: 55 years) from the Bergamo area with two different degrees of COVID-19 severity, i.e., severe disease (hospitalized, n=212) or mild disease (non-hospitalized, n=146), was enrolled from April 2020 to June 2021 and followed-up for disease outcome and thrombosis. A cohort of 377 healthy subjects (177M/200F; median age: 49 years) from the same area without COVID-19 acted as a control group. DNA was analyzed for a panel of prothrombotic/inflammatory single nucleotide polymorphisms (SNPs) including FII rs1799963, FV rs6025, FV rs118203907, FXIIIA1 rs5985, FGB rs1800790, MTHFR rs1801131 and MTHFR rs1801133 as well as two SNPs located in the coding region of angiotensin-converting enzyme (ACE2) gene, namely ACE2 rs140312271 and ACE2 rs41303171. Statistical analysis was performed using SPSS statistical software.

Results: Among the AVs analyzed, the rs6025 polymorphism of FV gene (FV Leiden) was more frequent in COVID-19 patients than in the control group. By a logistic regression corrected for age and gender, FV Leiden was associated with a 3-fold risk of developing COVID-19 (OR: 3.2 [95% CI 1.02-10]). In contrast, the rs41303171 polymorphism of the ACE2 gene was more frequent in the control group and was a protective factor for COVID-19 (OR: 0.12 [95% CI 0.02-0.99]) even after correction for age and gender. No significant differences appeared in the frequency of the other SNPs alone or in combination. Within the COVID-19 patient cohort, the rs1801131 SNP of MTHFR gene was associated with less severe COVID-19 disease.

In the hospitalized severe cohort, 17 (8%) patients developed an overt venous thromboembolic event, and 7 COVID-19-related deaths (4%) were recorded. No significant associations were found between any of the AVs analyzed and the outcomes of thrombosis and death. However, the analyses of circulating biomarkers of clotting (i.e. D-dimer, FVIII, fibrinogen, prothrombin fragment 1+2 [F1+2], and FXIII), fibrinolysis (i.e. tissue plasminogen activator [tPA], and plasminogen activator inhibitor-1 [PAI-1]) and endothelial cell activation (i.e. thrombomodulin [TM], and von Willebrand Factor [vWF]), and the neutrophil-to-lymphocyte ratio (NLR) as an inflammatory biomarker revealed thathaving fibrinogen (OR: 4.9 [95% CI 1.04-23.1]), vWF:Ag (OR: 11.8 [95% CI 2.1-66.9]) and NLR (OR: 26.1 [95% CI 2.9-237] levels above the 75th percentile was significantly associated with death. Of interest, in the same hospitalized patient group, but not in the control group, the presence of FXIII SNPs was significantly associated with high levels of F1+2.

Conclusions: Our study shows that the FV Leiden polymorphism predisposes to COVID-19 infection, while the rs41303171 ACE2 polymorphism has a protective role. In addition, the rs1801131 SNP of gene MTHFR correlates with a milder COVID-19 disease. In patients with severe COVID-19, the inflammatory marker NLR, and the circulating hemostatic proteins vWF and fibrinogen are associated with mortality.