Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes

Luotola, Kari; Pietilä, Arto; Alanne, Mervi; Lanki, Timo; Loo, Britt-Marie; Jula, Antti; Perola, Markus; Peters, Annette; Zeller, Tanja; Blankenberg, Stefan; Salomaa, Veikko

doi:10.1016/j.metabol.2010.01.017

Cited by 17 publications

(25 citation statements)

References 26 publications

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“…Given our finding of dramatically increased plasma IL1RA levels on presentation with trauma or septic shock, we hypothesize that the reduced risk of ARDS is mediated through increased IL1RA levels. It is notable that, although our sample size for the plasma analysis is small, our results in critical illness are consonant with a large metaanalysis of European subjects, which identified rs315952 as a protein quantitative trait locus for circulating IL1RA (P ¼ 2.8 3 10 211 ), with increasing copies of the minor C allele associating with increased ambulatory plasma IL1RA levels (53). Among tagging SNPs, rs315952C was the strongest genetic predictor of IL1RA levels after adjusting for sex and age, accounting for 4% of the variation among myocardial infarction survivors and 0.7% among healthy population control subjects (53).…”

Section: Discussionsupporting

confidence: 83%

“…It is notable that, although our sample size for the plasma analysis is small, our results in critical illness are consonant with a large metaanalysis of European subjects, which identified rs315952 as a protein quantitative trait locus for circulating IL1RA (P ¼ 2.8 3 10 211 ), with increasing copies of the minor C allele associating with increased ambulatory plasma IL1RA levels (53). Among tagging SNPs, rs315952C was the strongest genetic predictor of IL1RA levels after adjusting for sex and age, accounting for 4% of the variation among myocardial infarction survivors and 0.7% among healthy population control subjects (53). Our results focus attention on the role of the inflammasome in ARDS pathogenesis (68), and the possibility that IL1RA may act as a molecular brake during trauma-or sepsis-driven injury.…”

Section: Discussionsupporting

confidence: 83%

“…In this study, we identified a synonymous coding SNP in IL1RN, which displays a consistent association with reduced risk of ARDS in heterogeneous critically ill populations, is distinct from the well described VNTR polymorphism, and which associates with circulating IL1RA protein level (53). Taken together, our findings suggest that the association of rs315952C with decreased ARDS risk occurs on the basis of carriers expressing higher levels of IL1RA, which is protective for ARDS from diverse causes.…”

Section: Discussionsupporting

confidence: 53%

“…In our previously reported study of African American patients with trauma, genotyping with the IBC chip did not demonstrate a statistically significant association with rs315952 or any other IL1RN variant, although that investigation was not powered to detect modest effect sizes (7). In addition, because the reported protein quantitative trait locus studies were performed exclusively in European populations (53), it remains unknown whether non-European populations manifest the same genetic determinants of circulating IL1RA. ARDS continues to inflict significant morbidity and mortality upon critically ill patients (2,3,21,78).…”

Section: Discussionmentioning

confidence: 89%

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IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

Meyer

Feng

et al. 2013

Am J Respir Crit Care Med

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Rationale: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete. Objectives: To identify genetic risk variants for ARDS using large scale genotyping. Methods: A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n ¼ 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P , 5 3 10 24 for replication in stage II, a trauma case-control population (n ¼ 778). SNPs replicating their association in stage II (P , 0.005) were tested in a stage III nested case-control population of mixed subjects in the intensive care unit (n ¼ 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDSassociated genotype and plasma protein levels. Measurements and Main Results: A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P , 0.004) and III (P , 0.02), and was robust to clinical adjustment (combined odds ratio ¼ 0.81; P ¼ 4.2 3 10 25 ). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN. Conclusions: The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk.Keywords: functional genetic polymorphism; acute lung injury; acute respiratory distress syndrome; IL-1 receptor antagonist; replication Acute respiratory distress syndrome (ARDS) is a syndrome characterized by acute bilateral alveolar flooding and severe hypoxemia in the absence of clinical heart failure (1, 2). ARDS afflicts an estimated 190,000 people annually in the United States, and carries a mortality of between 30 and 40% (3). The syndrome can emerge after a variety of potential inciting events, such as sepsis, pneumonia, aspiration, and trauma. However, the risk of ARDS after potential at-risk injuries is not uniform; it appears that individual genetic variation contributes to a patient's susceptibility to ARDS (4, 5). The pathophysiology underlying ARDS remains imprecisely understood, but dysregulated inflammation and altered permeability of the alveolocapillary membrane seem Supported by National Institutes of Health (NIH) grants to fund the study populations, Hospital of the University of Pennsylvania (HL060290, HL079063), Harborview (GM066946), and Massachusetts General Hospital (HL060710). Additional NIH grants RC2HL101770, HL081619, HL090021, and HL102254 supported the genetic and molecular investigations described herein. The genetic determinants of acute respiratory distress syndrome (ARDS) susceptibility remain incompletely u...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 89%

See 2 more Smart Citations

IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

Meyer

Feng

et al. 2013

Am J Respir Crit Care Med

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“…Low-dose LPS reliably induced a 100-fold increase in evoked plasma IL1RA. In this system, we replicated the association between rs315952C and increased plasma IL1RA levels (47), and this effect was most pronounced at the peak inflammatory response compared with baseline. Interestingly, the previously studied genetic variants affecting IL1RA response, rs4251961 and the VNTR tagged by rs419598, did not influence peak evoked IL1RA, and only rs4251961 associated with resting plasma IL1RA levels.…”

Section: Original Articlesupporting

confidence: 59%

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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Functional deficiency in endogenous interleukin‐1 receptor antagonist in patients with febrile infection‐related epilepsy syndrome

Clarkson

LaFrance‐Corey

Kahoud

et al. 2019

Annals of Neurology

125

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Objective We recently reported successful treatment of a child with febrile infection‐related epilepsy syndrome (FIRES), a subtype of new onset refractory status epilepticus, with the recombinant interleukin‐1 (IL1) receptor antagonist (IL1RA) anakinra. On this basis, we tested whether endogenous IL1RA production or function is deficient in FIRES patients. Methods Levels of IL1β and IL1RA were measured in serum and cerebrospinal fluid (CSF). The inhibitory activity of endogenous IL1RA was assessed using a cell‐based reporter assay. IL1RN gene variants were identified by sequencing. Expression levels for the secreted and intracellular isoforms of IL1RA were measured in patient and control cells by real‐time polymerase chain reaction. Results Levels of endogenous IL1RA and IL1β were elevated in the serum and CSF of patients with FIRES (n = 7) relative to healthy controls (n = 10). Serum from FIRES patients drove IL1R signaling activity and potentiated IL1R signaling in response to exogenous IL1β in a cell‐based reporter assay. Functional assessment of endogenous IL1RA activity in 3 FIRES patients revealed attenuated inhibition of IL1R signaling. Sequencing of IL1RN in our index patient revealed multiple variants. This was accompanied by reduced expression of intracellular but not secreted isoforms of IL1RA in the patient's peripheral blood mononuclear cells. Interpretation Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity. These observations may provide insight into disease pathogenesis for FIRES and other inflammatory seizure disorders and may provide a valuable biomarker for therapeutic decision‐making. Ann Neurol 2019;85:526–537

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Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes

Cited by 17 publications

References 26 publications

IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

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

Functional deficiency in endogenous interleukin‐1 receptor antagonist in patients with febrile infection‐related epilepsy syndrome

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