Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

Yong Fei Wang; Yan Zhang; Zhengwei Zhu; Ting You Wang; David L. Morris; Jiangshan Jane Shen; Huoru Zhang; Hai Feng Pan; Jing Yang; Sen Yang; Dong Qing Ye; Timothy J. Vyse; Yong Cui; Xuejun Zhang; Yujun Sheng; Yu Lung Lau; Wanling Yang

doi:10.1136/annrheumdis-2018-213093

Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

Yong Fei Wang, Yan Zhang, Zhengwei Zhu, Ting You Wang, David L. Morris, Jiangshan Jane Shen, Huoru Zhang, Hai Feng Pan, Jing Yang, Sen Yang, Dong Qing Ye, Timothy J. Vyse, Yong Cui, Xuejun Zhang, Yujun Sheng, Yu Lung Lau, Wanling Yang

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

29 Scopus citations

Abstract

Objectives Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. this study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. Methods We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. Results We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, p_meta=4.40E-08), MFHAS1 (rs2428, p_meta=1.17E-08) and CSNK2A2 (rs2731783, p_meta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, p_meta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in b-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (or=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. Conclusion this study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

Original language	English (US)
Pages (from-to)	1078-1084
Number of pages	7
Journal	Annals of the Rheumatic Diseases
Volume	77
Issue number	7
DOIs	https://doi.org/10.1136/annrheumdis-2018-213093
State	Published - Jul 2018
Externally published	Yes

Bibliographical note

Funding Information:
WY, YS and Y-FW received grant support from national Key research and development program of China (2017YFC0909001). WY and YLL received support from research Grant Council of Hong Kong (GrF 17146616, 17125114, HKU783813M). YZ received grant support from national natural Science Foundation of China (Grant no. 81601423). YS, xZ and YC received grant support from national Key basic research program of China (2014Cb541901) and national natural Science Foundation of China (Grant no.81402590).

Funding Information:
Funding WY, YS and Y-FW received grant support from national Key research and development program of China (2017YFC0909001). WY and YLL received support from research Grant Council of Hong Kong (GrF 17146616, 17125114, HKU783813M). YZ received grant support from national natural Science Foundation of China (Grant no. 81601423). YS, xZ and YC received grant support from national Key basic research program of China (2014Cb541901) and national natural Science Foundation of China (Grant no.81402590).

Funding Information:
Acknowledgements the authors thank Hong Kong phd fellowship scheme (HKpF), HKU postgraduate Scholarships and the Edward & Yolanda Wong Fund for supporting postgraduate students who participated in this work.

Publisher Copyright:
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved.

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10.1136/annrheumdis-2018-213093

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Wang, Y. F., Zhang, Y., Zhu, Z., Wang, T. Y., Morris, D. L., Shen, J. J., Zhang, H., Pan, H. F., Yang, J., Yang, S., Ye, D. Q., Vyse, T. J., Cui, Y., Zhang, X., Sheng, Y., Lau, Y. L., & Yang, W. (2018). Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning. Annals of the Rheumatic Diseases, 77(7), 1078-1084. https://doi.org/10.1136/annrheumdis-2018-213093

Wang, YF, Zhang, Y, Zhu, Z, Wang, TY, Morris, DL, Shen, JJ, Zhang, H, Pan, HF, Yang, J, Yang, S, Ye, DQ, Vyse, TJ, Cui, Y, Zhang, X, Sheng, Y, Lau, YL & Yang, W 2018, 'Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning', Annals of the Rheumatic Diseases, vol. 77, no. 7, pp. 1078-1084. https://doi.org/10.1136/annrheumdis-2018-213093

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title = "Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning",

abstract = "Objectives Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. this study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. Methods We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. Results We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in b-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (or=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. Conclusion this study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.",

author = "Wang, {Yong Fei} and Yan Zhang and Zhengwei Zhu and Wang, {Ting You} and Morris, {David L.} and Shen, {Jiangshan Jane} and Huoru Zhang and Pan, {Hai Feng} and Jing Yang and Sen Yang and Ye, {Dong Qing} and Vyse, {Timothy J.} and Yong Cui and Xuejun Zhang and Yujun Sheng and Lau, {Yu Lung} and Wanling Yang",

note = "Funding Information: WY, YS and Y-FW received grant support from national Key research and development program of China (2017YFC0909001). WY and YLL received support from research Grant Council of Hong Kong (GrF 17146616, 17125114, HKU783813M). YZ received grant support from national natural Science Foundation of China (Grant no. 81601423). YS, xZ and YC received grant support from national Key basic research program of China (2014Cb541901) and national natural Science Foundation of China (Grant no.81402590). Funding Information: Funding WY, YS and Y-FW received grant support from national Key research and development program of China (2017YFC0909001). WY and YLL received support from research Grant Council of Hong Kong (GrF 17146616, 17125114, HKU783813M). YZ received grant support from national natural Science Foundation of China (Grant no. 81601423). YS, xZ and YC received grant support from national Key basic research program of China (2014Cb541901) and national natural Science Foundation of China (Grant no.81402590). Funding Information: Acknowledgements the authors thank Hong Kong phd fellowship scheme (HKpF), HKU postgraduate Scholarships and the Edward & Yolanda Wong Fund for supporting postgraduate students who participated in this work. Publisher Copyright: {\textcopyright} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved.",

year = "2018",

month = jul,

doi = "10.1136/annrheumdis-2018-213093",

language = "English (US)",

volume = "77",

pages = "1078--1084",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

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number = "7",

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TY - JOUR

T1 - Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

AU - Wang, Yong Fei

AU - Zhang, Yan

AU - Zhu, Zhengwei

AU - Wang, Ting You

AU - Morris, David L.

AU - Shen, Jiangshan Jane

AU - Zhang, Huoru

AU - Pan, Hai Feng

AU - Yang, Jing

AU - Yang, Sen

AU - Ye, Dong Qing

AU - Vyse, Timothy J.

AU - Cui, Yong

AU - Zhang, Xuejun

AU - Sheng, Yujun

AU - Lau, Yu Lung

AU - Yang, Wanling

N1 - Funding Information: WY, YS and Y-FW received grant support from national Key research and development program of China (2017YFC0909001). WY and YLL received support from research Grant Council of Hong Kong (GrF 17146616, 17125114, HKU783813M). YZ received grant support from national natural Science Foundation of China (Grant no. 81601423). YS, xZ and YC received grant support from national Key basic research program of China (2014Cb541901) and national natural Science Foundation of China (Grant no.81402590). Funding Information: Funding WY, YS and Y-FW received grant support from national Key research and development program of China (2017YFC0909001). WY and YLL received support from research Grant Council of Hong Kong (GrF 17146616, 17125114, HKU783813M). YZ received grant support from national natural Science Foundation of China (Grant no. 81601423). YS, xZ and YC received grant support from national Key basic research program of China (2014Cb541901) and national natural Science Foundation of China (Grant no.81402590). Funding Information: Acknowledgements the authors thank Hong Kong phd fellowship scheme (HKpF), HKU postgraduate Scholarships and the Edward & Yolanda Wong Fund for supporting postgraduate students who participated in this work. Publisher Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved.

PY - 2018/7

Y1 - 2018/7

N2 - Objectives Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. this study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. Methods We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. Results We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in b-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (or=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. Conclusion this study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

AB - Objectives Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. this study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. Methods We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. Results We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in b-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (or=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. Conclusion this study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

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Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

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