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.
- systemic lupus erythematosus
- autoimmune diseases
- gene polymorphism
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Y-FW, YZ and ZZ contributed equally.
Handling editor Josef S Smolen
Contributors WY, YLL, YZ, YS and Y-FW designed the association study. Y-FW and YZ wrote the manuscript. WY and JJS revised the manuscript. YZ selected SNPs for validation. YZ, ZZ, YS, HZ, H-FP, JY, SY, D-QY, XZ and YC designed and performed replication studies. Y-FW designed and performed fine-mapping studies. Y-FW and T-YW designed and performed the study of drug repositioning. DLM and TJV shared systemic lupus erythematosus association data in European populations.
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).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster and Institutional Ethical Committee of the first affiliated hospital of Anhui Medical University.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data request should be sent to firstname.lastname@example.org.
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