A functional synonymous coding variant in the IL1RN gene is associated with survival in septic shock.

TitleA functional synonymous coding variant in the IL1RN gene is associated with survival in septic shock.
Publication TypeJournal Article
Year of Publication2014
AuthorsMeyer, NJ, Ferguson, JF, Feng, R, Wang, F, Patel, PN, Li, M, Xue, C, Qu, L, Liu, Y, Boyd, JH, Russell, JA, Christie, JD, Walley, KR, Reilly, MP
JournalAm J Respir Crit Care Med
Volume190
Issue6
Pagination656-64
Date Published2014 Sep 15
ISSN1535-4970
KeywordsAdipose Tissue, Adult, African Continental Ancestry Group, Allelic Imbalance, Cohort Studies, Double-Blind Method, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Humans, Inflammation, Interleukin 1 Receptor Antagonist Protein, Male, Sequence Analysis, RNA, Shock, Septic, Survival Rate
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 pre- and 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.

DOI10.1164/rccm.201403-0586OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID25089931
PubMed Central IDPMC4214110
Grant ListMCT-44152 / / Canadian Institutes of Health Research / Canada
P50-HL-083799 / HL / NHLBI NIH HHS / United States
R01-HL-113147 / HL / NHLBI NIH HHS / United States
UL1TR000003 / TR / NCATS NIH HHS / United States