In:
Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 8, No. 3 ( 2015-06), p. 498-506
Abstract:
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 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.
Type of Medium:
Online Resource
ISSN:
1942-325X
,
1942-3268
DOI:
10.1161/CIRCGENETICS.114.000724
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
2927603-2
detail.hit.zdb_id:
2457085-0
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