Association of angiotensin II type 1 receptor-associated protein gene polymorphism with increased mortality in septic shock*

Nakada, Taka‐aki; Russell, James A.; Boyd, John H.; McLaughlin, Luke; Nakada, Emiri; Thair, Simone A.; Hirasawa, Hiroyuki; Oda, Shigeto; Walley, Keith R.

doi:10.1097/ccm.0b013e318218665a

Cited by 45 publications

(36 citation statements)

References 41 publications

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“…The Vasopressin and Septic Shock Trial (VASST) was a multicenter, double-blind, randomized controlled trial evaluating vasopressin versus norepinephrine for septic shock (30). The study enrolled 778 patients with septic shock and requiring at least 5 mg/min norepinephrine infusion; details have been published (30,31). The research ethics boards of all participating institutions approved the trial, and written informed consent was obtained from all patients or their authorized representatives, including permission to perform downstream mechanistic testing.…”

Section: Methods Study Populationsmentioning

confidence: 99%

“…The research ethics boards of all participating institutions approved the trial, and written informed consent was obtained from all patients or their authorized representatives, including permission to perform downstream mechanistic testing. Of 778 patients in the VASST trial, 632 had available DNA and were included in this study (8,31,32). A subgroup of subjects, determined by study personnel availability, also had plasma collected at study enrollment (n = 399).…”

Section: Methods Study Populationsmentioning

confidence: 99%

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

Meyer

Ferguson

Feng

et al. 2014

Am J Respir Crit Care Med

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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.

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Section: Methods Study Populationsmentioning

confidence: 99%

Section: Methods Study Populationsmentioning

confidence: 99%

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

Meyer

Ferguson

Feng

et al. 2014

Am J Respir Crit Care Med

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“…Pharmacogenomics are applicable to norepinephrine [73], epinephrine, vasopressin [74] and corticosteroids [75,76] that could better decrease vasopressor dose, duration and adverse effects. Predictive biomarkers could also enrich signal for vasopressors in development such as the V1a agonist selepressin (plasma angiopoietin-2 because selepressin decreases plasma angiopoietin-2, a mediator of increased permeability and the leucyl/cystinyl aminopeptidase (LNPEP) genotype, which has been associated with altered vasopressin clearance and activity [74]) and angiotensin-II (such as variants of angiotensin II type 1 receptor-associated protein [77]). Protein biomarkers (such as cytokines) are also under-evaluated and could also enrish response to vasopresors and corticosteroids [76].…”

Section: Vasopressorsmentioning

confidence: 99%

Sepsis: frontiers in diagnosis, resuscitation and antibiotic therapy

et al. 2016

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Sepsis is a major growing global burden and a major challenge to intensive care clinicians, researchers, guideline committee members and policy makers, because of its high and increasing incidence and great pathophysiological, molecular, genetic and clinical complexity. In spite of recent progress short term mortality remains high and there is growing evidence of long term morbidity and increased long term mortality in survivors of sepsis both in developed and developing countries. Further improvement in the care of patients with sepsis will impact upon global health.In this narrative review, invited experts describe the expected challenges and progress to be made in the near future. We focus on resuscitation (fluids, vasopressors, inotropes, blood transfusion and hemodynamic targets) and infection control (antibiotics and infection biomarkers) as these areas are key, if initial management and subsequent outcomes are to be improved in patients with sepsis.

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“…Angiotensin II receptor-associated protein is a small (17-kDa) integral membrane protein with three transmembrane domains and a C terminus projecting into the cytoplasm (40). Angiotensin II receptor-associated protein and PLD2 can regulate the endocytosis of the angiotensin II receptor, and single nucleotide polymorphisms in either gene is associated with increased blood pressure and hypertension (41,42). We are currently examining the inter-relationship among angiotensin II receptor endocytosis, angiotensin II receptor-associated protein, and RdgB␤ to decipher the significance of PA binding by RdgB␤ (Fig.…”

Section: Figure 12mentioning

confidence: 99%

Phosphatidylinositol Transfer Protein, Cytoplasmic 1 (PITPNC1) Binds and Transfers Phosphatidic Acid

Garner

Hunt

Koster

et al. 2012

Journal of Biological Chemistry

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Background: Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) (alternative name, RdgB␤) promotes metastatic colonization and angiogenesis in humans. Results: We demonstrate that RdgB␤ is a phosphatidic acid (PA)-and phosphatidylinositol-binding protein and binds PA derived from the phospholipase D pathway. Conclusion: RdgB␤ is the first lipid-binding protein identified that can bind and transfer PA. Significance: PA bound to RdgB␤ is a likely effector downstream of phospholipase D.

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Association of angiotensin II type 1 receptor-associated protein gene polymorphism with increased mortality in septic shock*

Cited by 45 publications

References 41 publications

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

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

Sepsis: frontiers in diagnosis, resuscitation and antibiotic therapy

Phosphatidylinositol Transfer Protein, Cytoplasmic 1 (PITPNC1) Binds and Transfers Phosphatidic Acid

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