Rare variant analysis of PF. (A) Simplified schematic of the complement system. The complement system is broadly divided into 2 subpathways: humoral and opsonophagocytic. The humoral subpathway is comprised of soluble plasma proteins responsible for destroying microorganisms via formation of the membrane attack complex, which lyses the target cell by permeabilizing its surface. The opsonophagocytic subpathway is comprised of cellular receptors that recognize complement fragments deposited on microbial surfaces and facilitate phagocytosis and pathogen clearance. (B) Heterodimerization of integrin β₂ (B2) with integrin α_M (M) forms the anti-inflammatory signaling mediator CR3 whereas heterodimerization of B2 with integrin α_X (X) forms the proinflammatory signaling mediator CR4. (C) RVTT analyses comparing the European PF cohort (PF) and the NHLBI ARDSnet iSPAAR cohort (unselected sepsis) in terms of ΔP variants (left panel), neutral missense variants (middle panel), and synonymous variants (right panel). (D) RVTT analyses comparing the same 2 cohorts in terms of ΔP variants in procoagulant genes (left panel), anticoagulant genes (middle panel), and glycolysis pathway genes (right panel).