PMID- 36927455
OWN - NLM
STAT- MEDLINE
DCOM- 20230320
LR  - 20230320
IS  - 1466-609X (Electronic)
IS  - 1364-8535 (Print)
IS  - 1364-8535 (Linking)
VI  - 27
IP  - 1
DP  - 2023 Mar 16
TI  - Polymorphism in interferon alpha/beta receptor contributes to glucocorticoid 
      response and outcome of ARDS and COVID-19.
PG  - 112
LID - 10.1186/s13054-023-04388-8 [doi]
LID - 112
AB  - BACKGROUND: The use of glucocorticoids has given contradictory results for 
      treating acute respiratory distress syndrome (ARDS). The use of intravenous 
      Interferon beta (IFN beta) for the treatment of ARDS was recently tested in a phase 
      III ARDS trial (INTEREST), in which more than half of the patients simultaneously 
      received glucocorticoids. Trial results showed deleterious effects of 
      glucocorticoids when administered together with IFN beta, and therefore, we aimed at 
      finding the reason behind this. METHODS: We first sequenced the genes encoding 
      the IFN alpha/beta receptor of the patients, who participated in the INTEREST study 
      (ClinicalTrials.gov Identifier:  NCT02622724 , November 24, 2015) in which the 
      patients were randomized to receive an intravenous injection of IFN beta-1a (144 
      patients) or placebo (152 patients). Genetic background was analyzed against 
      clinical outcome, concomitant medication, and pro-inflammatory cytokine levels. 
      Thereafter, we tested the influence of the genetic background on IFN alpha/beta receptor 
      expression in lung organ cultures and whether, it has any effect on transcription 
      factors STAT1 and STAT2 involved in IFN signaling. RESULTS: We found a novel 
      disease association of a SNP rs9984273, which is situated in the interferon alpha/beta 
      receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of 
      the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates 
      with higher IFNAR expression, more rapid decrease of IFN gamma and interleukin-6 
      (IL-6) levels and better outcome in IFN beta treated patients with ARDS, while the 
      major allele associates with a poor outcome especially under concomitant IFN beta 
      and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates 
      with a less severe form of coronavirus diseases (COVID-19) according to the 
      COVID-19 Host Genetics Initiative database. CONCLUSIONS: The distribution of this 
      SNP within clinical study arms may explain the contradictory results of multiple 
      ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and 
      glucocorticoids.
CI  - (c) 2023. The Author(s).
FAU - Jalkanen, Juho
AU  - Jalkanen J
AD  - Faron Pharmaceuticals, Turku, Finland.
FAU - Khan, Sofia
AU  - Khan S
AD  - Turku Bioscience Centre, University of Turku and Abo Akademi University, Turku, 
      Finland.
AD  - InFLAMES Flagship, University of Turku and Abo Akademi University, Turku, 
      Finland.
FAU - Elima, Kati
AU  - Elima K
AD  - InFLAMES Flagship, University of Turku and Abo Akademi University, Turku, 
      Finland.
AD  - Institute of Biomedicine, University of Turku, Turku, Finland.
FAU - Huttunen, Teppo
AU  - Huttunen T
AD  - Estimates, Turku, Finland.
FAU - Wang, Ning
AU  - Wang N
AD  - Turku Bioscience Centre, University of Turku and Abo Akademi University, Turku, 
      Finland.
AD  - InFLAMES Flagship, University of Turku and Abo Akademi University, Turku, 
      Finland.
FAU - Hollmen, Maija
AU  - Hollmen M
AD  - InFLAMES Flagship, University of Turku and Abo Akademi University, Turku, 
      Finland.
AD  - MediCity Research Laboratory, University of Turku, Tykistokatu 6, 20520, Turku, 
      Finland.
FAU - Elo, Laura L
AU  - Elo LL
AD  - Turku Bioscience Centre, University of Turku and Abo Akademi University, Turku, 
      Finland.
AD  - InFLAMES Flagship, University of Turku and Abo Akademi University, Turku, 
      Finland.
AD  - Institute of Biomedicine, University of Turku, Turku, Finland.
FAU - Jalkanen, Sirpa
AU  - Jalkanen S
AD  - InFLAMES Flagship, University of Turku and Abo Akademi University, Turku, 
      Finland. sirpa.jalkanen@utu.fi.
AD  - Institute of Biomedicine, University of Turku, Turku, Finland. 
      sirpa.jalkanen@utu.fi.
AD  - MediCity Research Laboratory, University of Turku, Tykistokatu 6, 20520, Turku, 
      Finland. sirpa.jalkanen@utu.fi.
LA  - eng
SI  - ClinicalTrials.gov/NCT02622724
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20230316
PL  - England
TA  - Crit Care
JT  - Critical care (London, England)
JID - 9801902
RN  - 0 (Glucocorticoids)
RN  - 77238-31-4 (Interferon-beta)
RN  - 0 (Interferon-alpha)
SB  - IM
MH  - Humans
MH  - Glucocorticoids/pharmacology/therapeutic use
MH  - *COVID-19/genetics
MH  - Interferon-beta/pharmacology/therapeutic use
MH  - *Respiratory Distress Syndrome/drug therapy/genetics
MH  - Interferon-alpha
PMC - PMC10018638
OTO - NOTNLM
OT  - ARDS
OT  - COVID-19
OT  - Glucocorticoids
OT  - Type I interferons
COIS- JJ is an employee and TH consultant of Faron Pharmaceuticals, JJ, MH, and SJ own 
      stocks of Faron Pharmaceuticals.
EDAT- 2023/03/18 06:00
MHDA- 2023/03/21 06:00
PMCR- 2023/03/16
CRDT- 2023/03/17 08:22
PHST- 2022/10/17 00:00 [received]
PHST- 2023/03/01 00:00 [accepted]
PHST- 2023/03/17 08:22 [entrez]
PHST- 2023/03/18 06:00 [pubmed]
PHST- 2023/03/21 06:00 [medline]
PHST- 2023/03/16 00:00 [pmc-release]
AID - 10.1186/s13054-023-04388-8 [pii]
AID - 4388 [pii]
AID - 10.1186/s13054-023-04388-8 [doi]
PST - epublish
SO  - Crit Care. 2023 Mar 16;27(1):112. doi: 10.1186/s13054-023-04388-8.