An FcγRIIa polymorphism with decreased C-reactive protein binding is associated with sepsis and decreased monocyte HLA-DR expression in trauma patients

BACKGROUND A dysregulated immune response leading to sepsis is the most frequent cause of late posttraumatic deaths. We have found a novel anti-inflammatory pathway that is initiated by the acute phase protein, C-reactive protein (CRP), interacting with Fc receptor (FcR) on monocytes. This pathway is protective in animal models of endotoxin shock. We hypothesized that genetic polymorphisms in the FcR might contribute to monocyte responses and susceptibility to infectious complications after severe trauma. METHODS We conducted an observational study on a prospectively identified cohort of adult patients with convenience enrollment admitted after severe trauma. We enrolled 66 patients and collected blood samples at enrollment and again at 48 hours and 72 hours. Patients were followed through their hospital stay, and any septic events before 14 days were recorded. Cytokine and CRP levels were determined in the plasma from all three blood draws. In addition, DNA was extracted from blood and analyzed for the 131 H/R FcRIIa polymorphism that strongly affects the binding of IgG and CRP to this receptor. RESULTS Elevated levels of interleukin 8 (IL-8), IL-6, IL-10, monocyte chemotactic protein 1, and CRP were associated with reduced time to posttraumatic sepsis in Cox regression analysis. Expression of monocyte human leukocyte antigen DR less than 45% on patient monocytes was also associated with sepsis (hazard ratio, 3.15; 95% confidence interval, 1.45-6.93). Genetic analysis found that individuals with the polymorphism of the FcRIIa receptor that binds CRP poorly were also more likely to have decreased monocyte human leukocyte antigen DR and posttraumatic sepsis. In vitro studies showed that CRP could attenuate monocyte deactivation in volunteers with the polymorphism of the FcRIIa receptor that binds CRP. CONCLUSION Our findings suggest that a common genetic variation in the FcRIIa receptor may contribute to infectious susceptibility in trauma patients. In vitro experiments suggest that this association is related to the inability of CRP to bind to this FcRIIa receptor variant. LEVEL OF EVIDENCE Prognostic study, level III.