β<sub>2</sub>-Adrenergic Receptor Gene Polymorphism Is Associated with Mortality in Septic Shock

Nakada, Taka‐aki; Russell, James A.; Boyd, John H.; Aguirre-Hernández, Rosalía; Thain, Katherine R.; Thair, Simone A.; Nakada, Emiri; McConechy, Melissa K.; Walley, Keith R.

doi:10.1164/rccm.200903-0332oc

Cited by 74 publications

(69 citation statements)

References 36 publications

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“…NIK is important in the host response Table V. Baseline characteristics by NIK genotype rs7222094 for Caucasian patients with septic shock in both SPH and VASST cohorts 11 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) 11 (8)(9)(10)(11)(12)(13)(14)(15) 0.71…”

Section: Discussionmentioning

confidence: 99%

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A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

Thair

Walley

Nakada

et al. 2011

The Journal of Immunology

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We tested the hypothesis that single nucleotide polymorphisms (SNPs) within genes of the NF-κB pathway are associated with altered clinical outcome of septic shock patients. We genotyped 59 SNPs in the NF-κB pathway in a discovery cohort of septic shock patients (St. Paul’s Hospital [SPH], N = 589), which identified the C allele of rs7222094 T/C within MAP3K14 (NF-κB inducing kinase; NIK) associated with increased 28-d mortality (uncorrected p = 0.00024, Bonferroni corrected p = 0.014). This result was replicated in a second cohort of septic shock patients (Vasopressin and Septic Shock Trial [VASST; N = 616]) in which the CC genotype of rs7222094 was associated with increased 28-d mortality (Cox regression: SPH cohort hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.12–1.64; p = 0.002 Caucasian only; and VASST cohort HR, 1.24; 95% CI, 1.00–1.52; p = 0.048 Caucasian only). Patients having the CC genotype of rs7222094 in SPH experienced more renal and hematological dysfunction (p = 0.003 and p = 0.011), while patients of the VASST cohort with the rs7222094 CC genotype showed the same trend toward more renal dysfunction. In lymphoblastoid cell lines, we found the rs7222094 genotype most strongly associated with mRNA expression of CXCL10, a chemokine regulated by NF-κB. Accordingly, we measured CXCL10 protein levels and found that the CC genotype of rs7222094 was associated with significantly lower levels than those of the TT genotype in lymphoblastoid cell lines (p < 0.05) and in septic shock patients (p = 0.017). This suggests that the CC genotype of NIK rs7222094 is associated with increased mortality and organ dysfunction in septic shock patients, perhaps due to altered regulation of NF-κB pathway genes, including CXCL10.

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Section: Discussionmentioning

confidence: 99%

“…Genetic variation in key inflammatory genes contributes to outcome in sepsis (7)(8)(9)(10)(11)(12). Because NF-kB is a centrally important signaling pathway, we tested the hypothesis that genetic variation in genes involved in the NF-kB pathways would be associated with mortality in septic shock.…”

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confidence: 99%

A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

Thair

Walley

Nakada

et al. 2011

The Journal of Immunology

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“…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%

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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“…Another study described the CysGlyGln haplotype of the b 2 -adrenergic receptor gene (ADRB2), which has been associated with altered responses to adrenergic agonists, on outcome in septic shock. Patients with the AA genotype of ADRB2 rs1042717, homozygotes for the CysGlyGln haplotype, required higher norepinephrine dose, had higher heart rates, developed more often organ dysfunction, and displayed increased 28-day mortality in both cohorts (13).…”

Section: Genetics Genomics Proteomics and Metabolomicsmentioning

confidence: 98%

Update in Acute Lung Injury and Critical Care 2010

Vadász

Sznajder

2011

Am J Respir Crit Care Med

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β₂-Adrenergic Receptor Gene Polymorphism Is Associated with Mortality in Septic Shock

Abstract: The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.

Cited by 74 publications

References 36 publications

A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

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

Update in Acute Lung Injury and Critical Care 2010

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β2-Adrenergic Receptor Gene Polymorphism Is Associated with Mortality in Septic Shock

Abstract: The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.

Cited by 74 publications

References 36 publications

A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

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

Update in Acute Lung Injury and Critical Care 2010

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β₂-Adrenergic Receptor Gene Polymorphism Is Associated with Mortality in Septic Shock