Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling.

Ho JE, Chen WY, Chen MH, Larson MG, McCabe EL, Cheng S, Ghorbani A, Coglianese E, Emilsson V, Johnson AD, Walter S, Franceschini N, O'Donnell CJ, CARDIoGRAM Consortium, CHARGE Inflammation Working Group, Dehghan A, Lu C, Levy D, Newton-Cheh C, CHARGE Heart Failure Working Group, Lin H, Felix JF, Schreiter ER, Vasan RS, Januzzi JL, Lee RT, Wang TJ
J Clin Invest. 2013 123 (10): 4208-18

PMID: 23999434 · PMCID: PMC3784527 · DOI:10.1172/JCI67119

The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.

MeSH Terms (23)

Amino Acid Substitution Female Gene Expression Gene Expression Regulation Genetic Association Studies HEK293 Cells Humans Interleukin-1 Receptor-Like 1 Protein Interleukin-33 Interleukins Male Middle Aged Models, Molecular Myelin and Lymphocyte-Associated Proteolipid Proteins Myeloid Differentiation Factor 88 NF-kappa B Polymorphism, Single Nucleotide Promoter Regions, Genetic Prospective Studies Protein Structure, Tertiary Receptors, Cell Surface Signal Transduction Transcription Factor AP-1

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