SELP Asp603Asn and severe thrombosis in COVID-19 males: implication for anti P-selectin monoclonal antibodies treatment

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. Key points ○ The functional polymorphism rs6127 (p.Asp603Asn) in the testosterone-regulated SELP gene associates with COVID-19 severity and thrombosis. ○ Conditions with decreased testosterone (old males), or decreased testosterone efficacy ( AR gene polyQ ≥ 23) strengthen the association.