The Role of ABO Glycosyltransferases in the Acute Respiratory Distress Syndrome



 DESCRIPTION (provided by applicant): 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.