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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)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
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2015 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 8, no 3, 498-506 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 8, no 3, 498-506 p.
Keyword [en]
acute coronary syndrome, genome-wide association study, interleukins
National Category
Cardiac and Cardiovascular Systems Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-258783DOI: 10.1161/CIRCGENETICS.114.000724ISI: 000356418800010PubMedID: 25747584OAI: oai:DiVA.org:uu-258783DiVA: diva2:842400
Available from: 2015-07-20 Created: 2015-07-20 Last updated: 2017-12-04Bibliographically approved

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Johansson, ÅsaEriksson, NiclasHagström, EmilVarenhorst, ChristophAxelsson, TomasJames, Stefan K.Syvänen, Ann-ChristineWallentin, LarsSiegbahn, Agneta

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Johansson, ÅsaEriksson, NiclasHagström, EmilVarenhorst, ChristophAxelsson, TomasJames, Stefan K.Syvänen, Ann-ChristineWallentin, LarsSiegbahn, Agneta
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Medicinsk genetik och genomikUCR-Uppsala Clinical Research CenterCardiologyScience for Life Laboratory, SciLifeLabMolecular MedicineCoagulation and inflammation science
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Circulation: Cardiovascular Genetics
Cardiac and Cardiovascular SystemsMedical Genetics

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