Genome-wide association study identifies common and rare genetic variants in caspase-1-related genes that influence IL-18 regulation in patients with Acute Coronary Syndrome. A. Johansson1, 2, N. Eriksson1, E. Hagström1,3, C. Varenhorst1,3, A. Åkerblom1,3, M. Bertilsson1, T. Axelsson4, B. J. Barratt5, R. C. Becker6, A. Himmelmann7, S. James1,3, H. A. Katus8, G. Steg9, R. F. Storey10, A. Syvänen4, L. Wallentin1,3, A. Siegbahn1,11 1) Uppsala Clinical Research Center, Uppsala University, Sweden; 2) Department of Immunoloy, Genetics and Pathology, Uppsala University, Sweden; 3) Department of Medical Sciences, Cardiology, Uppsala University, Sweden; 4) Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Sweden; 5) AstraZeneca R&D, Alderley Park, Cheshire, UK; 6) Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA; 7) AstraZeneca Research and Development, Mölndal, Sweden; 8) Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany; 9) INSERM-Unité 698, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France; Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France; 10) Department of Cardiovascular Science, University of Sheffield, Sheffield, UK; 11) Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden.

   Interleukin 18 (IL-18) levels are increased in patients with acute coronary syndromes (ACS) and correlated with myocardial injury. We performed a genome-wide association study (GWAS) to identify genetic determinants of IL-18 levels in patients with ACS. In the PLATelet inhibition and patient Outcomes (PLATO) trial, enrolling a broad selection of ACS patients, baseline plasma IL-18 levels were measured in 16633 patients. Of these, 9340 were successfully genotyped using Illumina HumanOmni2.5 or HumanOmniExpressExome BeadChip and SNPs imputed using 1000 Genomes Phase I integrated variant set. Seven independent associations, in five chromosomal regions, were identified. The first region, with two independent (r2 = 0.11) association signals (rs34649619, p = 1.17*10-50 and rs360718, p = 2.03*10-12), is located within IL18. Both top SNPs are located in predicted promoter regions, and the insertion polymorphism rs34649619 (T/TA) disrupts a transcription factor binding site for FOXI1, FOXD3 and FOXA2. The second region, also represented by two independent (r2 = 0.003) association signals (rs385076, p = 6.99*10-72 and rs149451729, p = 3.79*10-16), is located in NLRC4. While rs385076 overlaps with a regulatory region, rs149451729 is a rare coding variant resulting in an amino acid substitution, predicted to be deleterious. The third region is located upstream of CARD16, CARD17, and CARD18 and one of the top SNPs (rs17103763, p = 6.19*10-9) has previously been associated with expression levels of CARD16. The two remaining chromosomal regions are located within GSFMF/MROH6 (rs2290414, p = 5.66*10-17) and RAD17 (rs17229943, p = 5.00*10-12). While the latter genes have not been associated with IL-18 production previously, others are known to be involved in IL-18 release. NLRC4 is an inflammasome that activates the inflammatory cascade in the presence of bacterial molecules. It recruits and activates procaspase-1, which in its turn is responsible for the maturation of pro-IL-18. CARD16-18, also known as COP1, INCA and ICEBERG, encode caspase inhibitors, known to bind to and prevent procaspase-1 activation. Our results suggest that SNPs in IL18 and caspase-1-associated genes are important for IL-18 production. By combining the identified SNPs in a Mendelian randomization study, the causal effect of IL-18 on clinical endpoints could be further evaluated in a longitudinal study.

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