ABO blood type: a window into the genetics of acute respiratory distress syndrome susceptibility

Abstract

The genetic factors that determine a patient's risk for developing the acute respiratory distress syndrome (ARDS) remain understudied. In this issue of the JCI, Reilly and colleagues analyzed data from three cohorts of critically ill patients and observed an association between the ABO allele A1 and the onset of moderate-severe ARDS. This association was most notable in patients with non-pulmonary sepsis (an indirect, vasculature-targeted mechanism of lung injury) and persisted in patients who lacked epithelial expression of the A antigen, suggesting an endothelial mechanism of A1-associated ARDS susceptibility. Critically ill patients with blood type A had increased circulating concentrations of endothelium-derived glycoproteins such as von Willebrand factor and soluble thrombomodulin, and marginal lungs from blood type A donors were less likely to recover function during ex vivo perfusion. These findings implicate A antigen glycosylation of endothelial cells as a critical, genetically determined risk factor for indirect lung injury that may contribute to the mechanistic heterogeneity of ARDS.

Figure 1. Cell-specific expression of ABH antigens.

(A) Cell type–specific fucosyltransferases (FUT1 in multiple cell types; FUT2 in epithelial and secretory cells) create H antigens by adding a fucose monosaccharide to the nonreducing (free) ends of glycans anchored to glycolipids or glycoproteins. H antigens are then modified by glycosyltransferases encoded by the ABO genes. ABO allele A1 produces a highly active glycosyltransferase that imparts high A antigen density on cell surfaces. ABO allele O produces a nonfunctional glycosyltransferase, leaving the H antigen unmodified. A, B, or H antigens on red blood cells (RBCs) impart blood types A, B, or O, respectively. Simplified schema does not show nature of glycan linkages (i.e., α2 linkage of fucose). (B) Approximately 20% of European populations have loss-of-function mutations in FUT2, leading to an inability to form H antigens (and consequently, A or B antigens) on epithelial surfaces. As such, FUT2^–/– individuals with ABO A1 alleles will express a high density of A antigens on erythrocytes and endothelial cells but have no expression of A antigens on epithelial surfaces or mucosal secretions. Simplified schema excludes underlying glycan core structures. A antigens can be further modified into hyperglycosylated A1 and A2 antigen subtypes; only A antigens are shown for simplicity.