Association of common genetic variation in the protein C pathway genes with clinical outcomes in acute respiratory distress syndrome.

Anil Sapru,Annie Poon,Michael A Matthay,Joseph Wiemels,Eric Jorgenson,Lorraine B Ware,John S Witte,Ludmilla Pawlikowska,Kathleen D Liu,Helen Hansen,Carolyn S Calfee

doi:10.1186/s13054-016-1330-5

Abstract

BackgroundAltered plasma levels of protein C, thrombomodulin, and the endothelial protein C receptor are associated with poor clinical outcomes in patients with acute respiratory distress syndrome (ARDS). We hypothesized that common variants in these genes would be associated with mortality as well as ventilator-free and organ failure-free days in patients with ARDS.MethodsWe genotyped linkage disequilibrium-based tag single-nucleotide polymorphisms in the ProteinC, Thrombomodulin and Endothelial Protein C Reptor Genes among 320 self-identified white patients of European ancestry from the ARDS Network Fluid and Catheter Treatment Trial. We then tested their association with mortality as well as ventilator-free and organ-failure free days.ResultsThe GG genotype of rs1042580 (p = 0.02) and CC genotype of rs3716123 (p = 0.002), both in the thrombomodulin gene, and GC/CC genotypes of rs9574 (p = 0.04) in the endothelial protein C receptor gene were independently associated with increased mortality. An additive effect on mortality (p < 0.001), ventilator-free days (p = 0.01), and organ failure-free days was observed with combinations of these high-risk genotypes. This association was independent of age, severity of illness, presence or absence of sepsis, and treatment allocation.ConclusionsGenetic variants in thrombomodulin and endothelial protein C receptor genes are additively associated with mortality in ARDS. These findings suggest that genetic differences may be at least partially responsible for the observed associations between dysregulated coagulation and poor outcomes in ARDS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1330-5) contains supplementary material, which is available to authorized users.

Highlights

Altered plasma levels of protein C, thrombomodulin, and the endothelial protein C receptor are associated with poor clinical outcomes in patients with acute respiratory distress syndrome (ARDS)
Genotype frequencies of the assayed single-nucleotide polymorphism (SNP) in the protein C, endothelial protein C receptor (EPCR), and TM genes and the frequencies stratified by mortality at 60 days are depicted in Tables 2, 3 and 4
The results of this study indicate that common genetic variations in the protein C pathway are associated with adverse clinical outcomes in adult patients with ARDS

Summary

Introduction

Altered plasma levels of protein C, thrombomodulin, and the endothelial protein C receptor are associated with poor clinical outcomes in patients with acute respiratory distress syndrome (ARDS). We hypothesized that common variants in these genes would be associated with mortality as well as ventilator-free and organ failure-free days in patients with ARDS. Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure characterized by acute pulmonary edema and lung inflammation [1]. A number of experimental and human studies suggest that excessive activation of coagulation is associated with increased mortality in patients with ARDS [5,6,7,8,9,10,11]. Alterations in plasma levels of protein C, TM, and soluble EPCR are associated with increased mortality

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Conclusion