The acute respiratory distress syndrome (ARDS) affects an estimated 190,000 people in the US annually, with high mortality and morbidity; however, there are minimal effective pharmacologic therapies for ARDS. Therefore, there is significant interest in identifying novel ARDS risk factors that could lead to future therapeutic targets and identify populations most likely to benefit from such therapies. The ABO gene encodes a family of glycosyltransferases that catalyze specific carbohydrate modifications on cells and characterize the ABO blood group. ABO genetic variation is known to influence risk of infectious and vascular diseases as well as plasma levels of glycoproteins implicated in ARDS, including von Willebrand factor (vWF) and soluble intercellular adhesion molecule-1 (sICAM-1). We recently reported a novel association between blood type A and increased ARDS risk, convergent with prior findings in vascular diseases. The broad objectives of this proposal are to 1) determine the role of ABO genetic variation in altering ARDS risk in cohorts of patients with trauma and severe sepsis; 2) determine the role of functional variation in related genes, FUT2 and FUT3, in ARDS and the role of FUT2 determined secretor status in modifying the associations between ABO and ARDS; 3) test the hypothesis that plasma levels of vWF and sICAM-1 are associated with ABO blood type in the critically ill and mediate the affects of ABO blood type on ARDS risk; and 4) train and mentor the applicant in the skills, knowledge, and experience required to develop into an independent investigator in patient oriented translational research. This proposal leverages existing infrastructure at the University of Pennsylvania to conduct cohort studies in patients with major trauma and, separately, severe sepsis. Subjects previously enrolled in existing cohorts and those enrolled during the award period will be genotyped at known polymorphisms in the ABO, FUT2, and FUT3 genes that determine ABO blood types, secretor status, and Lewis blood type. These variants will be tested for associations with ARDS risk in our well-phenotyped cohorts. Additionally, we will use causal pathway analyses to determine the relative contribution of vWF and sICAM-1 to observed associations between ABO and ARDS. Through a rigorous training plan involving research conduct, didactics in advanced statistical analysis and genetic epidemiology, and intensive mentorship, the candidate will gain skills in cohort study design and development, genetic and plasma protein processing and analysis, and advanced statistical techniques including causal pathway and longitudinal data analysis. His mentor and advisory committee will ensure the candidate's attainment of benchmarks in research, publication, and career development through regular discussion and review. The conduct of the proposed aims and training plan will allow the candidate to make significant contributions to the understanding of ARDS pathophysiology, mature as an investigator, and prepare to compete successfully for future independent research funding.
The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure with a high morbidity and mortality and frequently complicates critical illness. An individual's ABO blood type is genetically determined and has been identified as a risk factor for certain infectious and vascular diseases, in addition to ARDS. The aim of this research is to provide new knowledge about the role of the genetic variation that determines ABO blood type in ARDS and to elucidate mechanistic pathways that result in this relationship.
|Meyer, Nuala J; Reilly, John P; Anderson, Brian J et al. (2018) Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration. Crit Care Med 46:21-28|
|Reilly, John P; Christie, Jason D; Meyer, Nuala J (2017) Fifty Years of Research in ARDS. Genomic Contributions and Opportunities. Am J Respir Crit Care Med 196:1113-1121|
|Shashaty, Michael G S; Reilly, John P; Sims, Carrie A et al. (2016) Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients. Shock 46:139-43|
|Reilly, John P (2016) Predicting and Eventually Preventing the Future: Sepsis Risk in Community-Dwelling Adults. Crit Care Med 44:1425-6|
|Palakshappa, Jessica A; Anderson, Brian J; Reilly, John P et al. (2016) Low Plasma Levels of Adiponectin Do Not Explain Acute Respiratory Distress Syndrome Risk: a Prospective Cohort Study of Patients with Severe Sepsis. Crit Care 20:71|
|Anderson, Brian J; Reilly, John P; Shashaty, Michael G S et al. (2016) Admission plasma levels of the neuronal injury marker neuron-specific enolase are associated with mortality and delirium in sepsis. J Crit Care 36:18-23|
|Reilly, John P; Anderson, Brian J; Hudock, Kristin M et al. (2016) Neutropenic sepsis is associated with distinct clinical and biological characteristics: a cohort study of severe sepsis. Crit Care 20:222|
|Reilly, John P; Anderson, Brian J; Mangalmurti, Nilam S et al. (2015) The ABO Histo-Blood Group and AKI in Critically Ill Patients with Trauma or Sepsis. Clin J Am Soc Nephrol 10:1911-20|