Abstract 13387: Genetic Variation in the NLRC4 Inflammasome Locus in Relation to Interleukin-18 Concentrations and Cardiovascular Disease
Background: Interleukin-18 (IL-18) has been related to pro-inflammatory states and cardiovascular disease risk. Little is known about the genetics of IL-18 beyond the genetic locus coding for the protein on chromosome 11.
Methods and Results: We explored the genetic underpinnings of circulating IL-18 concentrations by a genome-wide association study in two community-based cohorts (Gutenberg Heart Study, Framingham Heart Study) totaling 5,862 individuals of European ancestry. We confirmed the association of the chromosome 11 IL18-BCO2 locus with IL-18 concentrations (P=4.2*10-19). However, the strongest association was detected with a single nucleotide polymorphism (SNP) in the NLRC4 (NLR family, CARD domain containing 4) gene on chromosome 2, genome-wide P=7.0x10-29, with a decrease of 0.084 units of log-transformed biomarker concentrations per allele. The association of the top SNP with IL-18 was replicated in two independent cohorts (Prospective Epidemiological Study of Myocardial Infarction (PRIME), n=1,140; MONItoring of Trends and Determinants in CArdiovascular Disease/ Kooperative Gesundheitsforschung in der Region Augsburg (MONICA/KORA), n=1,945) with the SNP explaining 2% to 3% of the inter-individual variability of IL-18 concentrations. The SNP was not associated with cardiovascular mortality in the community-based MONICA/KORA Study. In a prospective study of 2,585 patients with manifest coronary artery disease (AtheroGene), the IL-18 lowering allele was associated with a protective effect on cardiovascular mortality (hazard ratio 0.78, 95% confidence interval 0.62-0.98, P=0.03).
Conclusions: This study identifies NLRC4 as a novel genomic region associated with IL-18 concentrations and potentially involved in cardiovascular diseases. Its role needs to be tested in other inflammatory and autoimmune disorders in which IL-18 plays a central role.
- © 2010 by American Heart Association, Inc.