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)

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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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2015
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LIBRIS-ID:oai:DiVA.org:uu-258783
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-258783URI
https://doi.org/10.1161/CIRCGENETICS.114.000724DOI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype
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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Kardiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cardiac and Cardiovascular Systems hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Medicinsk genetik hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medical Genetics hsv//eng
acute coronary syndrome
genome-wide association study
interleukins

Added entries (persons, corporate bodies, meetings, titles ...)

Eriksson, NiclasUppsala universitet,Uppsala kliniska forskningscentrum (UCR)(Swepub:uu)nieri103 (author)
Becker, Richard C. (author)
Storey, Robert F. (author)
Himmelmann, Anders (author)
Hagström, EmilUppsala universitet,Kardiologi(Swepub:uu)emhag677 (author)
Varenhorst, ChristophUppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi(Swepub:uu)chrva923 (author)
Axelsson, TomasUppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylär medicin(Swepub:uu)toaxe957 (author)
Barratt, Bryan J. (author)
James, Stefan K.Uppsala universitet,Kardiologi,Uppsala kliniska forskningscentrum (UCR)(Swepub:uu)stjam367 (author)
Katus, Hugo A. (author)
Steg, Philippe Gabriel (author)
Syvänen, Ann-ChristineUppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab(Swepub:uu)anncsyva (author)
Wallentin, LarsUppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi(Swepub:uu)larswall (author)
Siegbahn, AgnetaUppsala universitet,Uppsala kliniska forskningscentrum (UCR),Koagulation och inflammationsvetenskap(Swepub:uu)agsie424 (author)
Uppsala universitetMedicinsk genetik och genomik (creator_code:org_t)

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In:Circulation8:3, s. 498-5061942-325X1942-3268

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By the author/editor: Johansson, Åsa; Eriksson, Niclas; Becker, Richard ...; Storey, Robert F ...; Himmelmann, Ande ...; Hagström, Emil; show more...; Varenhorst, Chri ...; Axelsson, Tomas; Barratt, Bryan J ...; James, Stefan K.; Katus, Hugo A.; Steg, Philippe G ...; Syvänen, Ann-Chr ...; Wallentin, Lars; Siegbahn, Agneta; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cardiac and Card ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

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