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.
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.
Authors: E Rivers; B Nguyen; S Havstad; J Ressler; A Muzzin; B Knoblich; E Peterson; M Tomlanovich Journal: N Engl J Med Date: 2001-11-08 Impact factor: 91.245
Authors: Fasil Tekola Ayele; Ayo Doumatey; Hanxia Huang; Jie Zhou; Bashira Charles; Michael Erdos; Jokotade Adeleye; Williams Balogun; Olufemi Fasanmade; Thomas Johnson; Johnnie Oli; Godfrey Okafor; Albert Amoah; Benjamin A Eghan; Kofi Agyenim-Boateng; Joseph Acheampong; Clement A Adebamowo; Alan Herbert; Norman Gerry; Michael Christman; Guanjie Chen; Daniel Shriner; Adebowale Adeyemo; Charles N Rotimi Journal: Immunogenetics Date: 2011-12-29 Impact factor: 2.846
Authors: Taka-Aki Nakada; James A Russell; Hugh Wellman; John H Boyd; Emiri Nakada; Katherine R Thain; Simone A Thair; Hiroyuki Hirasawa; Shigeto Oda; Keith R Walley Journal: Chest Date: 2011-02-17 Impact factor: 9.410
Authors: Anand Kumar; Paul Ellis; Yaseen Arabi; Dan Roberts; Bruce Light; Joseph E Parrillo; Peter Dodek; Gordon Wood; Aseem Kumar; David Simon; Cheryl Peters; Muhammad Ahsan; Dan Chateau Journal: Chest Date: 2009-08-20 Impact factor: 9.410
Authors: Mark M Wurfel; Anthony C Gordon; Tarah D Holden; Frank Radella; Jeanna Strout; Osamu Kajikawa; John T Ruzinski; Gail Rona; R Anthony Black; Seth Stratton; Gail P Jarvik; Adeline M Hajjar; Deborah A Nickerson; Mark Rieder; Jonathan Sevransky; James P Maloney; Marc Moss; Greg Martin; Carl Shanholtz; Joe G N Garcia; Li Gao; Roy Brower; Kathleen C Barnes; Keith R Walley; James A Russell; Thomas R Martin Journal: Am J Respir Crit Care Med Date: 2008-07-17 Impact factor: 21.405
Authors: N Chantratita; S Tandhavanant; S Seal; C Wikraiphat; G Wongsuvan; P Ariyaprasert; P Suntornsut; N Teerawattanasook; Y Jutrakul; N Srisurat; P Chaimanee; W Mahavanakul; P Srisamang; S Phiphitaporn; M Mokchai; J Anukunananchai; S Wongratanacheewin; P Chetchotisakd; M J Emond; S J Peacock; T E West Journal: Clin Microbiol Infect Date: 2016-09-08 Impact factor: 8.067
Authors: Benedikt H Siegler; Thorsten Brenner; Florian Uhle; Sebastian Weiterer; Markus A Weigand; Stefan Hofer Journal: J Thorac Dis Date: 2016-06 Impact factor: 2.895