The ABO Histo-Blood Group, endothelial activation, and acute respiratory distress syndrome risk in critical illness.

Reilly, John P; Meyer, Nuala J; Shashaty, Michael Gs; Anderson, Brian J; Ittner, Caroline; Dunn, Thomas G; Lim, Brian; Forker, Caitlin; Bonk, Michael P; Kotloff, Ethan D; Feng, Rui; Cantu, Edward; Mangalmurti, Nilam S; Calfee, Carolyn S; Matthay, Michael A; Mikacenic, Carmen; Walley, Keith R; Russell, James A; Christiani, David C; Wurfel, Mark M; Lanken, Paul N; Reilly, Muredach P; Christie, Jason D

BACKGROUND The ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases including Acute Respiratory Distress Syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation. METHODS We conducted analyses in three cohorts of critically ill trauma and sepsis patients (n = 3,710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined if associations were present in FUT2 defined non-secretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested if blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP). RESULTS The A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all three populations. In sepsis, this relationship was strongest in non-pulmonary infections. The association persisted in non-secretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand Factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP. CONCLUSIONS We identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill possibly mediated through microvascular dysfunction and coagulation.