ABSTRACT
Thromboembolism is a frequent cause of severity and mortality in COVID-19. However, the etiology of this phenomenon is not well understood. A cohort of 1,186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity were stratified by sex and adjusted by age. Then, common coding variants from whole exome sequencing were mined by LASSO logistic regression. The homozygosity of the cell adhesion molecule P-selectin gene (SELP) rs6127 (c.1807G>A; p.Asp603Asn) which increases platelet activation is found to be associated with severity in the male subcohort of 513 subjects (Odds Ratio= 2.27, 95% Confidence Interval 1.54-3.36). As the SELP gene is downregulated by testosterone, the odd ratio is increased in males older than 50 (OR 2.42, 95% CI 1.53-3.82). Asn/Asn homozygotes have increased D-dimers values especially when associated with poly Q≥23 in the androgen receptor (AR) gene (OR 3.26, 95% CI 1.41-7.52). These results provide a rationale for the repurposing of antibodies against P-selectin as adjuvant therapy in rs6127 male homozygotes especially if older than 50 or with impaired AR gene.
Subject(s)
COVID-19 , Thrombosis , ThromboembolismABSTRACT
Background: COVID-19 presentation ranges from asymptomatic to fatal. The variability in severity is due in part to specific mutations in the host genome. GWAS effectively identifies genetic variability due to common biallelic polymorphisms. Efforts in genetic research are trying to identify significant associations in patients infected by SARS-CoV-2. Methods: We developed a synthetic approach to genetic data representation using machine learning methods to investigate complementary genetic variability in COVID-19 infected patients that might explain disease severity due to rare variants and poly-amino acids repeat polymorphisms. Using host whole-exome sequencing data, we compared extreme phenotypic presentations of an Italian cohort of 939 subjects infected with SARS-CoV-2. We then applied the LASSO Logistic Regression model on Boolean gene-based representation of the entire set of human genes. Findings: Polymorphisms/rare variants in certain genes, including short polyQ (≤22) of the androgen receptor ( AR ), conferred protection against severe forms of COVID-19. We then demonstrated that testosterone was higher in males with AR long-polyQ (≥23), confirming receptor resistance (p=0.004 Mann-Whitney U test). Finally, long-polyQ (≥23) correlates with increased inflammation markers (p=0.021) and fibrinogen consumption (p=0.039), confirming the anti-inflammatory role of testosterone. Interpretation: Our results contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone supplementation as adjuvant treatment in symptomatic COVID-19 men expressing AR polyQ longer than 23. Funding: MIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy; Private donors for COVID research (Italian D.L. n.18 March 17, 2020).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: The GEN-COVID study was approved by the University Hospital of Siena Ethics Review Board (Protocol n. 16917, dated March 16, 2020).