Bi-directional Mendelian randomization analysis provides evidence for the causal  involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis

Jie Chen; Yajing Zhou; Yuhao Sun; Shuai Yuan; Rahul Kalla; Jing Sun; Jianhui Zhao; Lijuan Wang; Xuejie Chen; Xuan Zhou; Siqi Dai; Yu Zhang; Gwo-Tzer Ho; Dajing Xia; Qian Cao; Zhanju Liu; Susanna C. Larsson; Xiaoyan Wang; Kefeng Ding; Jonas Halfvarson; Xue Li; Evropi Theodoratou; Jack Satsangi

doi:10.1093/ecco-jcc/jjac191

Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis

Jie Chen, Yajing Zhou, Yuhao Sun, Shuai Yuan, Rahul Kalla, Jing Sun, Jianhui Zhao, Lijuan Wang, Xuejie Chen, Xuan Zhou, Siqi Dai, Yu Zhang, Gwo-Tzer Ho, Dajing Xia, Qian Cao, Zhanju Liu, Susanna C. Larsson, Xiaoyan Wang, Kefeng Ding^*, Jonas HalfvarsonXue Li^*, Evropi Theodoratou, Jack Satsangi

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background and Aims
Systemic inflammation is well-recognized to be associated with ulcerative colitis (UC), but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence.

Methods
We firstly synthesized serum proteomic profiling data from two multi-centered observational studies, in which a panel of systemic inflammatory proteins was analyzed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomization (TSMR) analysis from both forward and reverse directions using five genome-wide association study (GWAS) summary level data for serum proteomic profiles and the largest GWAS of 28,738 European-ancestry individuals for UC risk.

Results
Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci (cis-pQTLs) or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 (CXCL9) (OR, 1.45, 95% CI, 1.08-1.95, P=.012) and C-C motif chemokine ligand 11 (CCL11) (OR, 1.14, 95%CI: 1.09-1.18, P=3.89×10-10). Using both cis- and trans-acting pQTLs, an association of caspase-8 (CASP8) (OR, 1.04, 95% CI, 1.03-1.05, P= 7.63×10-19) was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins.

Conclusions
Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.

Original language	English
Journal	Journal of Crohn's and Colitis
Early online date	28 Dec 2022
DOIs	https://doi.org/10.1093/ecco-jcc/jjac191
Publication status	E-pub ahead of print - 28 Dec 2022

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10.1093/ecco-jcc/jjac191

Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerAccepted author manuscript, 1.18 MBLicence: Creative Commons: Attribution (CC-BY)

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Chen, J., Zhou, Y., Sun, Y., Yuan, S., Kalla, R., Sun, J., Zhao, J., Wang, L., Chen, X., Zhou, X., Dai, S., Zhang, Y., Ho, G-T., Xia, D., Cao, Q., Liu, Z., Larsson, S. C., Wang, X., Ding, K., ... Satsangi, J. (2022). Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis. Journal of Crohn's and Colitis. https://doi.org/10.1093/ecco-jcc/jjac191

@article{ebebcdb0a69d48c2ae40980b5e8ccceb,

title = "Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis",

abstract = "Background and Aims Systemic inflammation is well-recognized to be associated with ulcerative colitis (UC), but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. Methods We firstly synthesized serum proteomic profiling data from two multi-centered observational studies, in which a panel of systemic inflammatory proteins was analyzed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomization (TSMR) analysis from both forward and reverse directions using five genome-wide association study (GWAS) summary level data for serum proteomic profiles and the largest GWAS of 28,738 European-ancestry individuals for UC risk. Results Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci (cis-pQTLs) or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 (CXCL9) (OR, 1.45, 95% CI, 1.08-1.95, P=.012) and C-C motif chemokine ligand 11 (CCL11) (OR, 1.14, 95%CI: 1.09-1.18, P=3.89×10-10). Using both cis- and trans-acting pQTLs, an association of caspase-8 (CASP8) (OR, 1.04, 95% CI, 1.03-1.05, P= 7.63×10-19) was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. Conclusions Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.",

author = "Jie Chen and Yajing Zhou and Yuhao Sun and Shuai Yuan and Rahul Kalla and Jing Sun and Jianhui Zhao and Lijuan Wang and Xuejie Chen and Xuan Zhou and Siqi Dai and Yu Zhang and Gwo-Tzer Ho and Dajing Xia and Qian Cao and Zhanju Liu and Larsson, {Susanna C.} and Xiaoyan Wang and Kefeng Ding and Jonas Halfvarson and Xue Li and Evropi Theodoratou and Jack Satsangi",

year = "2022",

month = dec,

day = "28",

doi = "10.1093/ecco-jcc/jjac191",

language = "English",

journal = "Journal of Crohn's and Colitis",

issn = "1873-9946",

publisher = "Elsevier",

}

Chen, J, Zhou, Y, Sun, Y, Yuan, S, Kalla, R, Sun, J, Zhao, J, Wang, L, Chen, X, Zhou, X, Dai, S, Zhang, Y, Ho, G-T, Xia, D, Cao, Q, Liu, Z, Larsson, SC, Wang, X, Ding, K, Halfvarson, J, Li, X, Theodoratou, E & Satsangi, J 2022, 'Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis', Journal of Crohn's and Colitis. https://doi.org/10.1093/ecco-jcc/jjac191

TY - JOUR

T1 - Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis

AU - Chen, Jie

AU - Zhou, Yajing

AU - Sun, Yuhao

AU - Yuan, Shuai

AU - Kalla, Rahul

AU - Sun, Jing

AU - Zhao, Jianhui

AU - Wang, Lijuan

AU - Chen, Xuejie

AU - Zhou, Xuan

AU - Dai, Siqi

AU - Zhang, Yu

AU - Ho, Gwo-Tzer

AU - Xia, Dajing

AU - Cao, Qian

AU - Liu, Zhanju

AU - Larsson, Susanna C.

AU - Wang, Xiaoyan

AU - Ding, Kefeng

AU - Halfvarson, Jonas

AU - Li, Xue

AU - Theodoratou, Evropi

AU - Satsangi, Jack

PY - 2022/12/28

Y1 - 2022/12/28

N2 - Background and Aims Systemic inflammation is well-recognized to be associated with ulcerative colitis (UC), but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. Methods We firstly synthesized serum proteomic profiling data from two multi-centered observational studies, in which a panel of systemic inflammatory proteins was analyzed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomization (TSMR) analysis from both forward and reverse directions using five genome-wide association study (GWAS) summary level data for serum proteomic profiles and the largest GWAS of 28,738 European-ancestry individuals for UC risk. Results Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci (cis-pQTLs) or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 (CXCL9) (OR, 1.45, 95% CI, 1.08-1.95, P=.012) and C-C motif chemokine ligand 11 (CCL11) (OR, 1.14, 95%CI: 1.09-1.18, P=3.89×10-10). Using both cis- and trans-acting pQTLs, an association of caspase-8 (CASP8) (OR, 1.04, 95% CI, 1.03-1.05, P= 7.63×10-19) was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. Conclusions Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.

AB - Background and Aims Systemic inflammation is well-recognized to be associated with ulcerative colitis (UC), but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. Methods We firstly synthesized serum proteomic profiling data from two multi-centered observational studies, in which a panel of systemic inflammatory proteins was analyzed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomization (TSMR) analysis from both forward and reverse directions using five genome-wide association study (GWAS) summary level data for serum proteomic profiles and the largest GWAS of 28,738 European-ancestry individuals for UC risk. Results Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci (cis-pQTLs) or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 (CXCL9) (OR, 1.45, 95% CI, 1.08-1.95, P=.012) and C-C motif chemokine ligand 11 (CCL11) (OR, 1.14, 95%CI: 1.09-1.18, P=3.89×10-10). Using both cis- and trans-acting pQTLs, an association of caspase-8 (CASP8) (OR, 1.04, 95% CI, 1.03-1.05, P= 7.63×10-19) was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. Conclusions Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.

U2 - 10.1093/ecco-jcc/jjac191

DO - 10.1093/ecco-jcc/jjac191

M3 - Article

JO - Journal of Crohn's and Colitis

JF - Journal of Crohn's and Colitis

SN - 1873-9946

ER -

Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis

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Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis

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