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).
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.


RESULTS
Baseline plasma IL-18 levels were measured in 16 633 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<3.15×10(-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=6.99×10(-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.
Åsa
Å
Johansson
Niclas
N
Eriksson
Richard C
RC
Becker
Robert F
RF
Storey
Anders
A
Himmelmann
Emil
E
Hagström
Christoph
C
Varenhorst
Tomas
T
Axelsson
Bryan J
BJ
Barratt
Stefan K
SK
James
Hugo A
HA
Katus
Philippe Gabriel
PG
Steg
Ann-Christine
AC
Syvänen
Lars
L
Wallentin
Agneta
A
Siegbahn
D054058:Acute Coronary Syndrome / Q000235:genetics* / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood*; D020641:Polymorphism, Single Nucleotide
D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D005819:Genetic Markers; D058847:Inflammasomes; D020382:Interleukin-18; C435692:NLRC4 protein, human
acute coronary syndrome; genome-wide association study; interleukins