Missense Variants of von Willebrand Factor in the Background of COVID-19 Associated Coagulopathy

Zsuzsanna Elek; Eszter Losoncz; Katalin Maricza; Zoltán Fülep; Zsófia Bánlaki; Réka Kovács-Nagy; Gergely Keszler; Zsolt Rónai

doi:10.3390/genes14030617

Missense Variants of von Willebrand Factor in the Background of COVID-19 Associated Coagulopathy

Genes (Basel). 2023 Feb 28;14(3):617. doi: 10.3390/genes14030617.

Authors

Zsuzsanna Elek¹, Eszter Losoncz^{2

3}, Katalin Maricza¹, Zoltán Fülep², Zsófia Bánlaki¹, Réka Kovács-Nagy¹, Gergely Keszler¹, Zsolt Rónai¹

Affiliations

¹ Institute of Biochemistry and Molecular Biology, Department of Molecular Biology, Semmelweis University, 1085 Budapest, Hungary.
² Department of Anesthesiology and Intensive Therapy, Bács-Kiskun County Teaching Hospital, 6000 Kecskemét, Hungary.
³ Doctoral School, Semmelweis University, 1085 Budapest, Hungary.

Abstract

COVID-19 associated coagulopathy (CAC), characterized by endothelial dysfunction and hypercoagulability, evokes pulmonary immunothrombosis in advanced COVID-19 cases. Elevated von Willebrand factor (vWF) levels and reduced activities of the ADAMTS13 protease are common in CAC. Here, we aimed to determine whether common genetic variants of these proteins might be associated with COVID-19 severity and hemostatic parameters. A set of single nucleotide polymorphisms (SNPs) in the vWF (rs216311, rs216321, rs1063856, rs1800378, rs1800383) and ADAMTS13 genes (rs2301612, rs28729234, rs34024143) were genotyped in 72 COVID-19 patients. Cross-sectional cohort analysis revealed no association of any polymorphism with disease severity. On the other hand, analysis of variance (ANOVA) uncovered associations with the following clinical parameters: (1) the rs216311 T allele with enhanced INR (international normalized ratio); (2) the rs1800383 C allele with elevated fibrinogen levels; and (3) the rs1063856 C allele with increased red blood cell count, hemoglobin, and creatinine levels. No association could be observed between the phenotypic data and the polymorphisms in the ADAMTS13 gene. Importantly, in silico protein conformational analysis predicted that these missense variants would display global conformational alterations, which might affect the stability and plasma levels of vWF. Our results imply that missense vWF variants might modulate the thrombotic risk in COVID-19.

Keywords: ADAMTS13; COVID-19 associated coagulopathy; immunothrombosis; missense variant; protein conformation; single nucleotide polymorphism (SNP); von Willebrand factor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blood Coagulation Disorders* / etiology
Blood Coagulation Disorders* / genetics
COVID-19* / complications
COVID-19* / genetics
Cross-Sectional Studies
Humans
Mutation, Missense
Polymorphism, Single Nucleotide
von Willebrand Factor* / genetics

Substances

von Willebrand Factor

Grants and funding

This research was funded by the National Research, Development, and Innovation Office (grant number: K-131680) and by the Semmelweis University STIA-18-KF/M funds.