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

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Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. / Ho, Jennifer E; Chen, Wei-Yu; Chen, Ming-Huei; Larson, Martin G; McCabe, Elizabeth L; Cheng, Susan; Ghorbani, Anahita; Coglianese, Erin; Emilsson, Valur; Johnson, Andrew D; Walter, Stefan; Franceschini, Nora; O'Donnell, Christopher J; Dehghan, Abbas; Lu, Chen; Levy, Daniel; Newton-Cheh, Christopher; Lin, Honghuang; Felix, Janine F; Schreiter, Eric R; Vasan, Ramachandran S; Januzzi, James L; Lee, Richard T; Wang, Thomas J; CARDIoGRAM Consortium.

In: J CLIN INVEST, Vol. 123, No. 10, 10.2013, p. 4208-4218.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Ho, JE, Chen, W-Y, Chen, M-H, Larson, MG, McCabe, EL, Cheng, S, Ghorbani, A, Coglianese, E, Emilsson, V, Johnson, AD, Walter, S, Franceschini, N, O'Donnell, CJ, Dehghan, A, Lu, C, Levy, D, Newton-Cheh, C, Lin, H, Felix, JF, Schreiter, ER, Vasan, RS, Januzzi, JL, Lee, RT, Wang, TJ & CARDIoGRAM Consortium 2013, 'Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling', J CLIN INVEST, vol. 123, no. 10, pp. 4208-4218. https://doi.org/10.1172/JCI67119

APA

Ho, J. E., Chen, W-Y., Chen, M-H., Larson, M. G., McCabe, E. L., Cheng, S., Ghorbani, A., Coglianese, E., Emilsson, V., Johnson, A. D., Walter, S., Franceschini, N., O'Donnell, C. J., Dehghan, A., Lu, C., Levy, D., Newton-Cheh, C., Lin, H., Felix, J. F., ... CARDIoGRAM Consortium (2013). Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. J CLIN INVEST, 123(10), 4208-4218. https://doi.org/10.1172/JCI67119

Vancouver

Ho JE, Chen W-Y, Chen M-H, Larson MG, McCabe EL, Cheng S et al. Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. J CLIN INVEST. 2013 Oct;123(10):4208-4218. https://doi.org/10.1172/JCI67119

Bibtex

@article{676935a08a3544958eb523f8aefff3fe,
title = "Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling",
abstract = "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. ",
keywords = "Amino Acid Substitution, Female, Gene Expression, Gene Expression Regulation, Genetic Association Studies, HEK293 Cells, Humans, Interleukin-1 Receptor-Like 1 Protein, Interleukin-33, Interleukins/genetics, Male, Middle Aged, Models, Molecular, Myelin and Lymphocyte-Associated Proteolipid Proteins/metabolism, Myeloid Differentiation Factor 88/metabolism, NF-kappa B/metabolism, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Prospective Studies, Protein Structure, Tertiary, Receptors, Cell Surface/chemistry, Signal Transduction, Transcription Factor AP-1/metabolism",
author = "Ho, {Jennifer E} and Wei-Yu Chen and Ming-Huei Chen and Larson, {Martin G} and McCabe, {Elizabeth L} and Susan Cheng and Anahita Ghorbani and Erin Coglianese and Valur Emilsson and Johnson, {Andrew D} and Stefan Walter and Nora Franceschini and O'Donnell, {Christopher J} and Abbas Dehghan and Chen Lu and Daniel Levy and Christopher Newton-Cheh and Honghuang Lin and Felix, {Janine F} and Schreiter, {Eric R} and Vasan, {Ramachandran S} and Januzzi, {James L} and Lee, {Richard T} and Wang, {Thomas J} and {CARDIoGRAM Consortium} and Stefan Blankenberg",
year = "2013",
month = oct,
doi = "10.1172/JCI67119",
language = "English",
volume = "123",
pages = "4208--4218",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

RIS

TY - JOUR

T1 - Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling

AU - Ho, Jennifer E

AU - Chen, Wei-Yu

AU - Chen, Ming-Huei

AU - Larson, Martin G

AU - McCabe, Elizabeth L

AU - Cheng, Susan

AU - Ghorbani, Anahita

AU - Coglianese, Erin

AU - Emilsson, Valur

AU - Johnson, Andrew D

AU - Walter, Stefan

AU - Franceschini, Nora

AU - O'Donnell, Christopher J

AU - Dehghan, Abbas

AU - Lu, Chen

AU - Levy, Daniel

AU - Newton-Cheh, Christopher

AU - Lin, Honghuang

AU - Felix, Janine F

AU - Schreiter, Eric R

AU - Vasan, Ramachandran S

AU - Januzzi, James L

AU - Lee, Richard T

AU - Wang, Thomas J

AU - CARDIoGRAM Consortium

AU - Blankenberg, Stefan

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - Amino Acid Substitution

KW - Female

KW - Gene Expression

KW - Gene Expression Regulation

KW - Genetic Association Studies

KW - HEK293 Cells

KW - Humans

KW - Interleukin-1 Receptor-Like 1 Protein

KW - Interleukin-33

KW - Interleukins/genetics

KW - Male

KW - Middle Aged

KW - Models, Molecular

KW - Myelin and Lymphocyte-Associated Proteolipid Proteins/metabolism

KW - Myeloid Differentiation Factor 88/metabolism

KW - NF-kappa B/metabolism

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Prospective Studies

KW - Protein Structure, Tertiary

KW - Receptors, Cell Surface/chemistry

KW - Signal Transduction

KW - Transcription Factor AP-1/metabolism

U2 - 10.1172/JCI67119

DO - 10.1172/JCI67119

M3 - SCORING: Journal article

C2 - 23999434

VL - 123

SP - 4208

EP - 4218

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 10

ER -