SELP Asp603Asn and severe thrombosis in COVID-19 males

AbstractThromboembolism 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.

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

10.1101/2021.05.25.21257803 ◽

2021 ◽

Author(s):

Chiara Fallerini ◽

Sergio Daga ◽

Elisa Benetti ◽

Nicola Picchiotti ◽

Kristina Zguro ◽

...

Keyword(s):

Logistic Regression ◽

Monoclonal Antibodies ◽

Cell Adhesion ◽

Androgen Receptor ◽

Adjuvant Therapy ◽

Odds Ratio ◽

Cell Adhesion Molecule ◽

Common Coding ◽

Whole Exome ◽

Coding Variants

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.

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Identification of rare coding variants associated with Kawasaki disease by whole exome sequencing

Genomics & Informatics ◽

10.5808/gi.21046 ◽

2021 ◽

Vol 19 (4) ◽

pp. e38

Author(s):

Jae-Jung Kim ◽

Young Mi Hong ◽

Sin Weon Yun ◽

Kyung-Yil Lee ◽

Kyung Lim Yoon ◽

...

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Odds Ratio ◽

Coronary Artery Aneurysms ◽

Whole Exome ◽

Pediatric Vasculitis ◽

Coding Variants

Kawasaki disease (KD) is an acute pediatric vasculitis that affects genetically susceptible infants and children. To identify coding variants that influence susceptibility to KD, we conducted whole exome sequencing of 159 patients with KD and 902 controls, and performed a replication study in an independent 586 cases and 732 controls. We identified five rare coding variants in five genes (FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10) associated with KD (odds ratio [OR], 1.18–4.41; p = 0.0027–0.031). We also performed association analysis in 26 KD patients with coronary artery aneurysms (CAAs; diameter > 5 mm) and 124 patients without CAAs (diameter < 3 mm), and identified another five rare coding variants in five genes (FGFR4, IL31RA, FNDC1, MMP8, and FOXN1), which may be associated with CAA (OR, 3.89–37.3; p = 0.0058–0.0261). These results provide insights into new candidate genes and genetic variants potentially involved in the development of KD and CAA.

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The androgen receptor drives the sex-specific expression of vascular cell adhesion molecule-1 in endothelial cells but not lipid metabolism genes in monocyte-derived macrophages

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2010.022 ◽

2010 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Kristine C.-Y. McGrath ◽

Michelle D. Hill ◽

Lucinda S. McRobb ◽

Alison K. Heather

Keyword(s):

Endothelial Cells ◽

Cell Adhesion ◽

Androgen Receptor ◽

Cell Adhesion Molecule ◽

Expression Vector ◽

Monocyte Adhesion ◽

Vascular Cell Adhesion ◽

Vascular Cell ◽

Male Sex ◽

Cell Adhesion Molecule 1

Abstract: Anecdotal evidence suggests that male sex hormones are proatherogenic. We hypothesized that the male sex hormone receptor, the androgen receptor (AR), acts as a molecular switch in sex-specific inflammatory signaling in vascular cells.: AR expression in human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages (MDMs) or HeLa cells was modulated by transfection with AR siRNA or human AR cDNA expression vector. Activity and expression levels were measured by luciferase reporter assays, Western blotting or real-time PCR analysis.: AR knockdown reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in genetically male HUVECs. Conversely, AR upregulation in genetically female HUVECs induced VCAM-1 expression and increased dihydrotestosterone-stimulated monocyte adhesion. Co-transfection of an AR expression vector with VCAM-1 or NF-κB-reporter vectors into phenotypically female, AR-negative HeLa cells confirmed AR regulation of VCAM-1 expression as well as AR activation of NF-κB. AR upregulation was not sufficient to increase ICAM-1 levels in female HUVECs or lipoprotein metabolism gene expression in female MDMs, despite AR knockdown limiting expression in their male counterparts.: AR acts as a molecular switch to induce VCAM-1 expression. Low AR levels in female HUVECs limit NF-κB/VCAM-1 induction and monocyte adhesion and could contribute to the gender bias in cardiovascular disease. Unidentified factors in female cells limit induction of other proatherogenic genes not primarily regulated by NF-κB.

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