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NLRC4 Inflammasome ...
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Johansson, ÅsaUppsala universitet,Medicinsk genetik och genomik,Uppsala kliniska forskningscentrum (UCR)
(author)
NLRC4 Inflammasome Is an Important Regulator of Interleukin-18 Levels in Patients With Acute Coronary Syndromes Genome-Wide Association Study in the PLATelet inhibition and patient Outcomes Trial (PLATO)
- Article/chapterEnglish2015
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LIBRIS-ID:oai:DiVA.org:uu-258783
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-258783URI
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https://doi.org/10.1161/CIRCGENETICS.114.000724DOI
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Background Interleukin 18 (IL-18) promotes atherosclerotic plaque formation and is increased in patients with acute coronary syndromes. However the relative contribution of genetic variants to the IL-18 levels has not been fully determined. Methods and Results Baseline plasma IL-18 levels were measured in 16633 patients with acute coronary syndrome, of whom 9340 had genetic data that passed genotype quality control. A 2-stage genome-wide association study was performed, followed by combined analyses using >10 million genotyped or imputed genetic markers. Single nucleotide polymorphisms at 3 loci (IL18, NLRC4, and MROH6) were identified (P<3.15x10(-8)) in the discovery cohort (n=3777) and replicated in the remaining patients (n=5563). In the pooled data (discovery+replication cohort), 7 independent associations, in 5 chromosomal regions, were associated with IL-18 levels (minimum P=6.99x10(-72)). Six single nucleotide polymorphisms are located in predicted promoter regions of which one disrupts a transcription factor binding site. One single nucleotide polymorphism in NLRC4 is a rare missense variant, predicted to be deleterious to the protein. Altogether, the identified genetic variants explained 8% of the total variation in IL-18 levels in the cohort. Conclusions Our results show that genetic variants play an important role in determining IL-18 levels in patients with acute coronary syndrome and we have identified genetic variants located in the IL-18 gene (IL18) or close to genes that are involved in procaspase-1 activation (NLRC4 and CARD16, CARD17, and CARD18). These associations also highlight the importance of the NLRC4 inflammasome for IL-18 production in acute coronary syndrome patients.
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Eriksson, NiclasUppsala universitet,Uppsala kliniska forskningscentrum (UCR)(Swepub:uu)nieri103
(author)
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Becker, Richard C.
(author)
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Storey, Robert F.
(author)
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Himmelmann, Anders
(author)
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Hagström, EmilUppsala universitet,Kardiologi(Swepub:uu)emhag677
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Varenhorst, ChristophUppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi(Swepub:uu)chrva923
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Axelsson, TomasUppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylär medicin(Swepub:uu)toaxe957
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Barratt, Bryan J.
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James, Stefan K.Uppsala universitet,Kardiologi,Uppsala kliniska forskningscentrum (UCR)(Swepub:uu)stjam367
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Katus, Hugo A.
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Steg, Philippe Gabriel
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Syvänen, Ann-ChristineUppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab(Swepub:uu)anncsyva
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Wallentin, LarsUppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi(Swepub:uu)larswall
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Siegbahn, AgnetaUppsala universitet,Uppsala kliniska forskningscentrum (UCR),Koagulation och inflammationsvetenskap(Swepub:uu)agsie424
(author)
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Uppsala universitetMedicinsk genetik och genomik
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In:Circulation8:3, s. 498-5061942-325X1942-3268
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Johansson, Åsa
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Eriksson, Niclas
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Becker, Richard ...
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Storey, Robert F ...
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Himmelmann, Ande ...
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Hagström, Emil
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Varenhorst, Chri ...
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Axelsson, Tomas
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Barratt, Bryan J ...
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James, Stefan K.
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Katus, Hugo A.
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Steg, Philippe G ...
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Syvänen, Ann-Chr ...
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Wallentin, Lars
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Siegbahn, Agneta
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