Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2016

Open Access 01-12-2016 | Research

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

Authors: Anil Sapru, Kathleen D. Liu, Joseph Wiemels, Helen Hansen, Ludmilla Pawlikowska, Annie Poon, Eric Jorgenson, John S. Witte, Carolyn S. Calfee, Lorraine B. Ware, Michael A. Matthay, the NHLBI ARDS Network

Published in: Critical Care | Issue 1/2016

Login to get access

Abstract

Background

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.

Methods

We 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.

Results

The 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.

Conclusions

Genetic 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.
Appendix
Available only for authorised users
Literature
1.
Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334–49.CrossRefPubMed
2.
Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685–93.CrossRefPubMed
3.
Zimmerman JJ, Akhtar SR, Caldwell E, Rubenfeld GD. Incidence and outcomes of pediatric acute lung injury. Pediatrics. 2009;124(1):87–95.CrossRefPubMed
4.
Khadaroo RG, Marshall JC. ARDS and the multiple organ dysfunction syndrome: common mechanisms of a common systemic process. Crit Care Clin. 2002;18(1):127–41.CrossRefPubMed
5.
Tuinman PR, Dixon B, Levi M, Juffermans NP, Schultz MJ. Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations. Crit Care. 2012;16:R70.CrossRefPubMedPubMedCentral
6.
Vadasz I, Morty RE, Olschewski A, Konigshoff M, Kohstall MG, Ghofrani HA, et al. Thrombin impairs alveolar fluid clearance by promoting endocytosis of Na+, K + -ATPase. Am J Respir Cell Mol Biol. 2005;33(4):343–54.CrossRefPubMed
7.
Gunther A, Mosavi P, Heinemann S, Ruppert C, Muth H, Markart P, et al. Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia: comparison with the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2000;161(2 Pt 1):454–62.CrossRefPubMed
8.
Bertozzi P, Astedt B, Zenzius L, Lynch K, LeMaire F, Zapol W, et al. Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med. 1990;322(13):890–7.CrossRefPubMed
9.
Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, et al. Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest. 1989;84(2):695–705.CrossRefPubMedPubMedCentral
10.
Idell S, Koenig KB, Fair DS, Martin TR, McLarty J, Maunder RJ. Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. Am J Physiol. 1991;261(4 Pt 1):L240–8.PubMed
11.
Schultz MJ, Millo J, Levi M, Hack CE, Weverling GJ, Garrard CS, et al. Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia. Thorax. 2004;59(2):130–5.CrossRefPubMedPubMedCentral
12.
Nick JA, Coldren CD, Geraci MW, Poch KR, Fouty BW, O’Brien J, et al. Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood. 2004;104(13):3878–85.CrossRefPubMed
13.
Ware LB, Fang X, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2003;285(3):L514–21.CrossRefPubMed
14.
Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol. 2004;24(8):1374–83.CrossRefPubMed
15.
Wang L, Bastarache JA, Wickersham N, Fang X, Matthay MA, Ware LB. Novel role of the human alveolar epithelium in regulating intra-alveolar coagulation. Am J Respir Cell Mol Biol. 2007;36(4):497–503.CrossRefPubMed
16.
McClintock D, Zhuo H, Wickersham N, Matthay MA, Ware LB. Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care. 2008;12:R41.CrossRefPubMedPubMedCentral
17.
Matthay MA, Ware LB. Plasma protein C levels in patients with acute lung injury: prognostic significance. Crit Care Med. 2004;32(5 Suppl):S229–32.CrossRefPubMed
18.
Orwoll BE, Spicer AC, Zinter MS, Alkhouli MF, Khemani RG, Flori HR, et al. Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study. Crit Care. 2015;19:435.CrossRefPubMedPubMedCentral
19.
Aiach M, Nicaud V, Alhenc-Gelas M, Gandrille S, Arnaud E, Amiral J, et al. Complex association of protein C gene promoter polymorphism with circulating protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol. 1999;19(6):1573–6.CrossRefPubMed
20.
Binder A, Endler G, Rieger S, Geishofer G, Resch B, Mannhalter C, et al. Protein C promoter polymorphisms associate with sepsis in children with systemic meningococcemia. Hum Genet. 2007;122(2):183–90.CrossRefPubMed
21.
Medina P, Navarro S, Estelles A, Espana F. Polymorphisms in the endothelial protein C receptor gene and thrombophilia. Thromb Haemost. 2007;98(3):564–9.PubMed
22.
Medina P, Navarro S, Estelles A, Vaya A, Woodhams B, Mira Y, et al. Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk. Thromb Haemost. 2004;91(5):905–11.PubMed
23.
Norlund L, Holm J, Zoller B, Ohlin AK. A common thrombomodulin amino acid dimorphism is associated with myocardial infarction. Thromb Haemost. 1997;77(2):248–51.PubMed
24.
Saposnik B, Reny JL, Gaussem P, Emmerich J, Aiach M, Gandrille S. A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood. 2004;103(4):1311–8.CrossRefPubMed
25.
Spek CA, Koster T, Rosendaal FR, Bertina RM, Reitsma PH. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol. 1995;15(2):214–8.CrossRefPubMed
26.
Walley KR, Russell JA. Protein C −1641 AA is associated with decreased survival and more organ dysfunction in severe sepsis. Crit Care Med. 2007;35(1):12–7.CrossRefPubMed
27.
Russell JA. Genetics of coagulation factors in acute lung injury. Crit Care Med. 2003;31(4 Suppl):S243–7.CrossRefPubMed
28.
Uitte de Willige S, Van Marion V, Rosendaal FR, Vos HL, de Visser MC, Bertina RM. Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost. 2004;2(8):1305–10.CrossRefPubMed
29.
Endler G, Mannhalter C. Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis. Clin Chim Acta. 2003;330(1–2):31–55.CrossRefPubMed
30.
Herrera-Ramos E, López-Rodríguez M, Ruíz-Hernández JJ, Horcajada JP, Borderías L, Lerma E, et al. Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection. Crit Care. 2014;18:R127.CrossRefPubMedPubMedCentral
31.
Acosta-Herrera M, Pino-Yanes M, Blanco J, Ballesteros JC, Ambrós A, Corrales A, et al. Common variants of NFE2L2 gene predisposes to acute respiratory distress syndrome in patients with severe sepsis. Crit Care. 2015;19:256.CrossRefPubMedPubMedCentral
32.
Auro K, Alanne M, Kristiansson K, Silander K, Kuulasmaa K, Salomaa V, et al. Combined effects of thrombosis pathway gene variants predict cardiovascular events. PLoS Genet. 2007;3(7), e120.CrossRefPubMedPubMedCentral
33.
Gong MN. Genetic epidemiology of acute respiratory distress syndrome: implications for future prevention and treatment. Clin Chest Med. 2006;27(4):705–24.CrossRefPubMedPubMedCentral
34.
35.
36.
Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, Wiedemann HP, de Boisblanc B, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med. 2006;354(21):2213–24.CrossRefPubMed
37.
Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, de Boisblanc B, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564–75.CrossRefPubMed
38.
Schoenfeld D. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med. 2002;30:1772–7.CrossRefPubMed
39.
Zaitlen N, Pasaniuc B, Gur T, Ziv E, Halperin E. Leveraging genetic variability across populations for the identification of causal variants [abstract]. Am J Hum Genet. 2010;86(1):23–33.CrossRefPubMedPubMedCentral
40.
Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet. 2004;74(1):106–20.CrossRefPubMed
41.
Hsu TM, Kwok PY. Homogeneous primer extension assay with fluorescence polarization detection. Methods Mol Biol. 2003;212:177–87.PubMed
42.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.CrossRefPubMedPubMedCentral
43.
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5.CrossRefPubMed
44.
Stephens M, Donnelly P. A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003;73(5):1162–9.CrossRefPubMedPubMedCentral
45.
Prudhomme JB, Wang L, Wickersham N, Matthay MA, Ware LB. Tissue factor levels in ARDS are 100-fold higher in edema fluid compared to plasma and correlate with mortality [abstract]. Proc Am Thorac Soc. 2005;2:A826.
46.
Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner MD, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med. 2002;346(17):1281–6.CrossRefPubMed
47.
Aleksic N, Folsom AR, Cushman M, Heckbert SR, Tsai MY, Wu KK. Prospective study of the A455V polymorphism in the thrombomodulin gene, plasma thrombomodulin, and incidence of venous thromboembolism: the LITE Study. J Thromb Haemost. 2003;1(1):88–94.CrossRefPubMed
48.
Sugiyama S, Hirota H, Kimura R, Kokubo Y, Kawasaki T, Suehisa E, et al. Haplotype of thrombomodulin gene associated with plasma thrombomodulin level and deep vein thrombosis in the Japanese population. Thromb Res. 2007;119(1):35–43.CrossRefPubMed
49.
Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004;96(6):434–42.CrossRefPubMed
Metadata
Title
Association of common genetic variation in the protein C pathway genes with clinical outcomes in acute respiratory distress syndrome
Authors
Anil Sapru
Kathleen D. Liu
Joseph Wiemels
Helen Hansen
Ludmilla Pawlikowska
Annie Poon
Eric Jorgenson
John S. Witte
Carolyn S. Calfee
Lorraine B. Ware
Michael A. Matthay
the NHLBI ARDS Network
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2016
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-016-1330-5

Other articles of this Issue 1/2016

Critical Care 1/2016 Go to the issue

Research

Contribution of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU patients with severe abdominal conditions

Review

Current evidence for the effectiveness of heated and humidified high flow nasal cannula supportive therapy in adult patients with respiratory failure

Research

Decreased CX3CR1 messenger RNA expression is an independent molecular biomarker of early and late mortality in critically ill patients

Research

Application of a simplified definition of diastolic function in severe sepsis and septic shock

Research

Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury

Review

Efficacy of prothrombin complex concentrates for the emergency reversal of dabigatran-induced anticoagulation