The Genetic Landscape of Plasma P-Selectin Glycoprotein Ligand Levels and Bidirectional Mendelian Randomization to
Christian Bime1, Yann C Klimentidis2, Xiaoguang Sun3
1Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, College of Medicine, University of Arizona, Phoenix, AZ 85004, USA.
Background:
Polymorphonuclear (PMN) leukocyte recruitment to activated pulmonary endothelium is a central mechanism in acute respiratory distress syndrome (ARDS). This process is mediated by selectins and their counter-ligand, P-selectin glycoprotein ligand-1 (PSGL-1), encoded by SELPLG. Genetic variation in SELPLG has been associated with ARDS susceptibility, while disruption of PSGL-1/P-selectin interactions attenuates lung injury in preclinical models. Because inflammatory stimuli increase both SELPLG expression and circulating PSGL-1 levels, PSGL-1 represents a promising biomarker and therapeutic target. We sought to define the genetic determinants of plasma PSGL-1 levels and evaluate their causal relationships with key inflammatory and endothelial biomarkers.
Methods:
Genome-wide association study (GWAS) summary statistics for plasma PSGL-1 levels were obtained from the UK Biobank Pharma Proteomics Project (n = 35,571) and the SCALLOP consortium (n = 21,758 across 13 cohorts). Associated variants underwent functional annotation and in silico analyses to identify potential effects on protein structure and gene regulation. Bidirectional Mendelian randomization (MR) was performed using GWAS summary statistics for C-reactive protein (CRP), E-selectin, GlycA, and soluble intercellular adhesion molecule-1 (sICAM-1) to assess potential causal relationships with PSGL-1 levels.
Results:
Multiple cis- and trans-acting loci were significantly associated with plasma PSGL-1 concentrations. Three coding SELPLG variants (rs201689859, rs74792300, and rs139943851) were predicted to alter PSGL-1 protein structure and were associated with lower circulating PSGL-1 levels. Four promoter variants (rs1420663, rs1833245, rs1420664, and rs8179110) were linked to altered transcriptional activity, including a potential effect of rs1420664 on hypoxia-inducible factor binding. Bidirectional MR demonstrated that genetically predicted CRP, E-selectin, GlycA, and sICAM-1 levels were associated with increased plasma PSGL-1 concentrations. Additional loci implicated pathways related to immune signaling, cell adhesion, and protein stability.
Conclusions:
Large-scale GWAS and Mendelian randomization analyses identified genetic variants that regulate plasma PSGL-1 levels and demonstrated causal links between inflammatory and endothelial biomarkers and PSGL-1 expression. These findings provide new insights into the genetic regulation of leukocyte trafficking pathways and support a role for PSGL-1 in inflammatory diseases, including ARDS, sepsis, and cardiovascular disorders.
Insights
Genetic variants influence P-selectin glycoprotein ligand-1 (PSGL-1) levels, impacting leukocyte trafficking. This study reveals causal links between inflammation, endothelial biomarkers, and PSGL-1, offering insights into ARDS and related disorders.
Area of Science:
- Genetics and Molecular Biology
- Immunology and Inflammation
- Cardiovascular and Respiratory Medicine
Background:
- Polymorphonuclear (PMN) leukocyte recruitment to pulmonary endothelium is key in acute respiratory distress syndrome (ARDS).
- P-selectin glycoprotein ligand-1 (PSGL-1), encoded by SELPLG, mediates this process; genetic variations in SELPLG are linked to ARDS susceptibility.
- Elevated SELPLG expression and circulating PSGL-1 levels during inflammation highlight PSGL-1 as a potential biomarker and therapeutic target.
Purpose of the Study:
- To identify genetic determinants of plasma PSGL-1 levels.
- To evaluate the causal relationships between PSGL-1 levels and key inflammatory and endothelial biomarkers.
Main Methods:
- Utilized genome-wide association study (GWAS) summary statistics from UK Biobank Pharma Proteomics Project and SCALLOP consortium (total n = 57,329).
- Performed functional annotation and in silico analyses on associated variants to assess effects on protein structure and gene regulation.
- Conducted bidirectional Mendelian randomization (MR) using GWAS data for C-reactive protein (CRP), E-selectin, GlycA, and soluble intercellular adhesion molecule-1 (sICAM-1).
Main Results:
- Identified multiple cis- and trans-acting loci significantly associated with plasma PSGL-1 concentrations.
- Three coding SELPLG variants were predicted to alter PSGL-1 protein structure, correlating with lower PSGL-1 levels.
- Bidirectional MR revealed that genetically predicted CRP, E-selectin, GlycA, and sICAM-1 levels are associated with increased plasma PSGL-1.
Conclusions:
- Large-scale GWAS and MR analyses identified genetic variants regulating plasma PSGL-1 and established causal links with inflammatory/endothelial biomarkers.
- Findings offer novel insights into the genetic regulation of leukocyte trafficking pathways.
- Results support PSGL-1's role in inflammatory diseases like ARDS, sepsis, and cardiovascular disorders.
