Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study

Guannan Su; Zhenyu Zhong; Qingyun Zhou; Liping Du; Zi Ye; Fuzhen Li; Wenjuan Zhuang; Chaokui Wang; Liang Liang; Yan Ji; Qingfeng Cao; Qingfeng Wang; Rui Chang; Handan Tan; Shenglan Yi; Yujing Li; Xiaojie Feng; Weiting Liao; Wanyun Zhang; Jia Shu; Shiyao Tan; Jing Xu; Su Pan; Hongxi Li; Jing Shi; Zhijun Chen; Ying Zhu; Xingsheng Ye; Xiao Tan; Jun Zhang; Zhangluxi Liu; Fanfan Huang; Gangxiang Yuan; Tingting Pang; Yizong Liu; Jiadong Ding; Yingnan Gao; Meifen Zhang; Wei Chi; Xiaoli Liu; Yuqin Wang; Ling Chen; Akira Meguro; Masaki Takeuchi; Nobuhisa Mizuki; Shigeaki Ohno; Xianbo Zuo; Aize Kijlstra; Peizeng Yang

doi:10.1002/art.41998

Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study

Guannan Su, Zhenyu Zhong, Qingyun Zhou, Liping Du, Zi Ye, Fuzhen Li, Wenjuan Zhuang, Chaokui Wang, Liang Liang, Yan Ji, Qingfeng Cao, Qingfeng Wang, Rui Chang, Handan Tan, Shenglan Yi, Yujing Li, Xiaojie Feng, Weiting Liao, Wanyun Zhang, Jia ShuShiyao Tan, Jing Xu, Su Pan, Hongxi Li, Jing Shi, Zhijun Chen, Ying Zhu, Xingsheng Ye, Xiao Tan, Jun Zhang, Zhangluxi Liu, Fanfan Huang, Gangxiang Yuan, Tingting Pang, Yizong Liu, Jiadong Ding, Yingnan Gao, Meifen Zhang, Wei Chi, Xiaoli Liu, Yuqin Wang, Ling Chen, Akira Meguro, Masaki Takeuchi, Nobuhisa Mizuki, Shigeaki Ohno, Xianbo Zuo^*, Aize Kijlstra, Peizeng Yang^*

^*Corresponding author for this work

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

Abstract

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD).

METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.

RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.

CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Original language	English
Article number	41998
Pages (from-to)	671-681
Number of pages	11
Journal	Arthritis & Rheumatology
Volume	74
Issue number	4
Early online date	15 Oct 2021
DOIs	https://doi.org/10.1002/art.41998
Publication status	Published - Apr 2022

Keywords

BINDING
EXPRESSION
GENETICS
IL10
IL23R-IL12RB2
INSIGHTS
MHC CLASS-I
SUSCEPTIBILITY
T-CELLS

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10.1002/art.41998

Cite this

Su, G., Zhong, Z., Zhou, Q., Du, L., Ye, Z., Li, F., Zhuang, W., Wang, C., Liang, L., Ji, Y., Cao, Q., Wang, Q., Chang, R., Tan, H., Yi, S., Li, Y., Feng, X., Liao, W., Zhang, W., ... Yang, P. (2022). Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study. Arthritis & Rheumatology, 74(4), 671-681. Article 41998. https://doi.org/10.1002/art.41998

@article{d1479d63846b4f298274894909465303,

title = "Identification of Novel Risk Loci for Beh{\c c}et's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study",

abstract = "OBJECTIVE: To explore susceptibility loci associated with uveitis in Beh{\c c}et's disease (BD).METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.",

keywords = "BINDING, EXPRESSION, GENETICS, IL10, IL23R-IL12RB2, INSIGHTS, MHC CLASS-I, SUSCEPTIBILITY, T-CELLS",

author = "Guannan Su and Zhenyu Zhong and Qingyun Zhou and Liping Du and Zi Ye and Fuzhen Li and Wenjuan Zhuang and Chaokui Wang and Liang Liang and Yan Ji and Qingfeng Cao and Qingfeng Wang and Rui Chang and Handan Tan and Shenglan Yi and Yujing Li and Xiaojie Feng and Weiting Liao and Wanyun Zhang and Jia Shu and Shiyao Tan and Jing Xu and Su Pan and Hongxi Li and Jing Shi and Zhijun Chen and Ying Zhu and Xingsheng Ye and Xiao Tan and Jun Zhang and Zhangluxi Liu and Fanfan Huang and Gangxiang Yuan and Tingting Pang and Yizong Liu and Jiadong Ding and Yingnan Gao and Meifen Zhang and Wei Chi and Xiaoli Liu and Yuqin Wang and Ling Chen and Akira Meguro and Masaki Takeuchi and Nobuhisa Mizuki and Shigeaki Ohno and Xianbo Zuo and Aize Kijlstra and Peizeng Yang",

note = "{\textcopyright} 2021 American College of Rheumatology.",

year = "2022",

month = apr,

doi = "10.1002/art.41998",

language = "English",

volume = "74",

pages = "671--681",

journal = "Arthritis & Rheumatology",

issn = "2326-5191",

publisher = "Wiley",

number = "4",

}

Su, G, Zhong, Z, Zhou, Q, Du, L, Ye, Z, Li, F, Zhuang, W, Wang, C, Liang, L, Ji, Y, Cao, Q, Wang, Q, Chang, R, Tan, H, Yi, S, Li, Y, Feng, X, Liao, W, Zhang, W, Shu, J, Tan, S, Xu, J, Pan, S, Li, H, Shi, J, Chen, Z, Zhu, Y, Ye, X, Tan, X, Zhang, J, Liu, Z, Huang, F, Yuan, G, Pang, T, Liu, Y, Ding, J, Gao, Y, Zhang, M, Chi, W, Liu, X, Wang, Y, Chen, L, Meguro, A, Takeuchi, M, Mizuki, N, Ohno, S, Zuo, X, Kijlstra, A & Yang, P 2022, 'Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study', Arthritis & Rheumatology, vol. 74, no. 4, 41998, pp. 671-681. https://doi.org/10.1002/art.41998

TY - JOUR

T1 - Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study

AU - Su, Guannan

AU - Zhong, Zhenyu

AU - Zhou, Qingyun

AU - Du, Liping

AU - Ye, Zi

AU - Li, Fuzhen

AU - Zhuang, Wenjuan

AU - Wang, Chaokui

AU - Liang, Liang

AU - Ji, Yan

AU - Cao, Qingfeng

AU - Wang, Qingfeng

AU - Chang, Rui

AU - Tan, Handan

AU - Yi, Shenglan

AU - Li, Yujing

AU - Feng, Xiaojie

AU - Liao, Weiting

AU - Zhang, Wanyun

AU - Shu, Jia

AU - Tan, Shiyao

AU - Xu, Jing

AU - Pan, Su

AU - Li, Hongxi

AU - Shi, Jing

AU - Chen, Zhijun

AU - Zhu, Ying

AU - Ye, Xingsheng

AU - Tan, Xiao

AU - Zhang, Jun

AU - Liu, Zhangluxi

AU - Huang, Fanfan

AU - Yuan, Gangxiang

AU - Pang, Tingting

AU - Liu, Yizong

AU - Ding, Jiadong

AU - Gao, Yingnan

AU - Zhang, Meifen

AU - Chi, Wei

AU - Liu, Xiaoli

AU - Wang, Yuqin

AU - Chen, Ling

AU - Meguro, Akira

AU - Takeuchi, Masaki

AU - Mizuki, Nobuhisa

AU - Ohno, Shigeaki

AU - Zuo, Xianbo

AU - Kijlstra, Aize

AU - Yang, Peizeng

PY - 2022/4

Y1 - 2022/4

N2 - OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD).METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

AB - OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD).METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

KW - BINDING

KW - EXPRESSION

KW - GENETICS

KW - IL10

KW - IL23R-IL12RB2

KW - INSIGHTS

KW - MHC CLASS-I

KW - SUSCEPTIBILITY

KW - T-CELLS

U2 - 10.1002/art.41998

DO - 10.1002/art.41998

M3 - Article

C2 - 34652073

SN - 2326-5191

VL - 74

SP - 671

EP - 681

JO - Arthritis & Rheumatology

JF - Arthritis & Rheumatology

IS - 4

M1 - 41998

ER -