SELP Asp603Asn and severe thrombosis in COVID-19 males

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 1186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity was 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 has been already associated with thrombotic risk 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 (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 an impaired androgen receptor.

Keywords: Anti-selectin P monoclonal antibodies; COVID-19; P-selectin; Thromboembolism; Thrombus; Venous thromboembolism.

Fig. 1

Homozygous genotype Asn/Asn at the polymorphic locus Asp603Asn (rs6127) is related to severity and to D-dimer pick. a Selection of SELP gene as relevant for severity. LASSO logistic regression on Boolean representation of homozygous common bi-allelic polymorphism of autosomal genes in males is presented (see paper Picchiotti et al. 2021 for complete representations)²⁰. The LASSO logistic regression model provides an embedded feature selection method within the binary classification tasks (severe vs mild). The upward histogram means positive weights, i.e., the specific variant at the specific locus (feature) contributes to severity of COVID-19. SELP_1_homo = homozygous genotype Asn/Asn at the polymorphic locus Asp603Asn (rs6127). The downward histograms mean negative weights, contributing to mildness of COVID-19. COG3_1_homo = homozygous genotype Ser/Ser at the polymorphic locus Leu825Ser (rs3014902). COG3 gene encodes for a vesicle docking protein involved in viral trafficking. TMEM221_2_homo = homozygous genotype Ala/Ala at the polymorphic locus Thr66Ala (rs4808641). TMEM221 gene encodes for a transmembrane protein. b–e Longitudinal laboratory data related to thrombosis and severity. Linear graphs of four laboratory values: D-dimer μg/L (b), platelets 10³/mmc (c), lymphocytes 10³/mmc (d), LDH UI/L (n.v. 135- 225 UI/L) (e). As expected, the Asn/Asn homozygous genotype was over-represented (36.53%). Values are reported on the Y-axis. In each graph, the time point “0” (X-axis) represents the day of onset of COVID-19 symptoms. Each line represents each severe hospitalized patient (see methods). Each point represents the different time point (day) in which the different values have been measured. Patients aged ≥ 55 years are indicated in blue, while patients aged < 55 years are in red. From left to right patients having Asp/Asp homozygous; Asp/Asn heterozygous; and Asn/Asn homozygous genotype. Older patients only (blue) and Asp/Asn-Asn/Asn genotype only show the D-dimer pick. Accordingly, older patients of these two genotypes have more platelet consumption and higher LDH values. A total of 51 patients have been included in c. Among these, 23 patients have a platelet count value below 150 × 10³/mmc: 9 with the Asn/Asn genotype, 13 with Asn/Asp and 1 with Asp/Asp. A total of 48 patients have been included in panel D. Among these, 27 patients have lymphocyte count below 0.9 10^3/mmc: 4 Asn/Asn, 19 Asn/Asp and 4 Asp/Asp. A total of 50 patients have been included in panel E. Among these, 44 have LDH values above 225 UI/L: 16 Asn/Asn, 23 Asn/Asp and 5 Asp/Asp. f The D-dimer pick is earlier in the Asn/Asn (median = 7.5 days) than the Asp/Asn genotype (p = 3 × 10^–2 by Mann–Whitney test). Box plots of patients with D-dimer values above 2000 µg/l were represented. Only Asp/Asn (light blue) and Asn/Asn (pink) genotypes are represented because patients with the Asp/Asp genotype do not have the pick and do not show values above 2.000. A total of 47 patients have been included in panel B. Among these, 20 patients show D-Dimer values above 2000 µg/L: 7 Asn/Asn, 12 Asn/Asp and 1 Asp/Asp. g, h The nonzero group associates with higher D-dimer (g) and LDH values (h). Severe hospitalized patients with 0 blood group = light blue; non-0 blood group = pink in box plots