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. 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.

Ämnesord

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)

Nyckelord

acute coronary syndrome

genome-wide association study

interleukins

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