A Functional Synonymous Coding Variant in theIL1RNGene Is Associated with Survival in Septic Shock

Abstract

Rationale: Death from infection is a highly heritable trait, yet there are few genetic variants with known mechanism influencing survival during septic shock.Objectives: We hypothesized that a synonymous coding variant in the IL-1 receptor antagonist gene (IL1RN), rs315952, previously associated with reduced risk for acute respiratory distress syndrome, would be functional and associate with improved survival in septic shock.Methods: We used a human endotoxin (LPS) model of evoked inflammatory stress to measure plasma IL-1 receptor antagonist (IL1RA) following low-dose Food and Drug Administration-grade LPS injection (1 ng/kg) in 294 human volunteers. RNA sequencing of adipose tissue preand post-LPS was used to test for allelic imbalance at rs315952. In the Vasopressin and Septic Shock Trial cohort, we performed a genetic association study for survival, mortality, and organ failure-free days.Measurements and Main Results: Adipose tissue displayed significant allelic imbalance favoring the rs315952C allele in subjects of European ancestry. Consistent with this, carriers of rs315952C had slightly higher plasma IL1RA at baseline (0.039) and higher evoked IL1RA post-LPS (0.011). In the Vasopressin and Septic Shock Trial cohort, rs315952C associated with improved survival (P = 0.028), decreased adjusted 90-day mortality (P = 0.044), and faster resolution of shock (P = 0.029).Conclusions: In European ancestry subjects, the IL1RN variant rs315952C is preferentially transcribed and associated with increased evoked plasma IL1RA and with improved survival from septic shock. It may be that genetically determined IL1RA levels influence survival from septic shock.

Human Experimental Endotoxemia in Modeling the Pathophysiology, Genomics, and Therapeutics of Innate Immunity in Complex Cardiometabolic Diseases

“…For example, our group has shown recently that genetic variation associated with the evoked IL1RA response during experimental endotoxemia is also predictive of patient survival in septic shock. 129 Further, as noted above, evoked endotoxemia revealed a novel genomic locus for the febrile response to LPS (but not resting body temperature) and this locus also associates with outcomes following severe trauma and sepsis. 91 Other common genetic variants influencing both response to evoked endotoxemia and disease risk have been described.…”

“…A pragmatic approach to overcome limitations on predictive capacity of the model is to use the endotoxemia model as a tool to focus on specific responses or characteristics of interest and then to assess the relation of those characteristics to incident clinical disease in independent epidemiological studies. 129 …”

“…98 Our recent work, however, show that genetic variation associated with the evoked IL1RA response to experimental endotoxemia is predictive of patient survival in clinical cohorts with septic shock. 129 These data have re-ignited a discussion on whether IL-1 pathway modulation might provide clinical benefit in sepsis if targeted to subsets of patients with specific genetic or biomarker features i.e., a “precision medicine” approach. As noted also, TNF pathway blockers and IL-1 antagonists ultimately succeeded in clinical translation and are now mainstays in the treatment of several rheumatological and inflammatory disorders.…”

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

“…In addition, recent studies could demonstrate that genetic variances of intra-and extracellular signaling molecules influence the individual inflammatory response and mortality in critical illness. For instance, in case of endogenous IL-1RA, a current trial discovered the preferentially transcription of a synonymous coding variant in the IL-1RA gene in European ancestry patients associated with elevated IL-1RA blood concentrations and higher survival rates in septic shock (55). Since sepsis and septic shock remain a serious threat associated with high mortality (1), future research may provide further insights into the (epi-) genetic heterogeneity and thus support individual treatment approaches as well as the avoidance of potentially harmful therapies in patients with sepsis and/or immunologic disorders.…”

Personalized medicine, endotypes, and intensive care medicine

“…For example, over 16 years ago, Mira and colleagues reported a single nucleotide polymorphism in the tumor necrosis factor-a promoter region that was independently associated with increased risk of mortality in patients with sepsis [8]. More recently, Meyer and colleagues reported on a coding variant of the interleukin-1 receptor antagonist (IL1RA) gene that is associated with increased plasma levels of IL1RA and decreased mortality in patients with acute respiratory distress syndrome or septic shock [9,10]. These findings are particularly germane given the availability of recombinant IL1RA for clinical use [11].…”