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Assessing the causal relationship between immune traits and systemic lupus erythematosus by bi-directional Mendelian randomization analysis

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Abstract

Previous studies have observed relationships between immune cells and systemic lupus erythematosus (SLE), but their causal links remain undetermined. Based on the public available genome-wide association studies (GWAS) summary statistics, we conducted two-sample Mendelian randomization (MR) to evaluate the associations between 731 immune phenotypes and SLE pairs. Pairwise pleiotropy analysis was performed to identify pleiotropic genes for significant immunophenotype–SLE pairs. A comprehensive gene function analysis was undertaken to explore the mechanisms of immune cells in SLE. By using the instrumental variables extracted from GWAS data, we observed that increased levels of five immune phenotypes were causally associated with SLE risk (FDR < 0.05), that were CD20 on IgD+ CD38− naïve, BAFF-R on IgD+ CD38dim, CD39+ secreting Treg AC, CD14− CD16+ monocyte AC, and HLA DR on CD14+ monocyte. Pairwise gene-based analyses identified a total of 38 pleiotropic genes for 5 significant pairs identified and gene set enrichment analysis revealed the involvement of the identified pleiotropic genes in complex pathways (i.e., systemic lupus erythematosus, an integral component of luminal side of endoplasmic reticulum membrane, C-type lectin receptor signaling pathway and regulation of hormone secretion). This study demonstrates that the immune response influences the progression of SLE in a complex pattern. These findings greatly improve our understanding of the interaction between immune response and SLE risk and also aid in the design of therapeutic strategies from an immunological perspective.

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Data availability

Data are available in a public, open access repository. Data URLs: GWAS summary statistics for 731 immune traits could be download form GWAS Catalog (Study accession: GCST90001001 ~ GCST90002000, https://www.ebi.ac.uk/gwas/home); GWAS summary statistics for SLE could be available form http://mygeneticswebsite.s3-website.eu-west-2.amazonaws.com/insidegen-LUPUS-data.html. All codes used in the research are available from the corresponding authors.

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Acknowledgements

We thank all the consortiums for making the summary association statistics data publicly available, and we are grateful to the participants and many researchers involved in proteome GWAS studies.

Funding

This work was supported by National Natural Science Foundation of China (82273733) to Lihong Huang.

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Author notes

  1. Jie Gu, Guan-Min Yan have contributed equally to the present work.

Authors and Affiliations

  1. Department of Outpatient and Emergency, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China

    Jie Gu, Guan-Min Yan, Xiao-Lin Kong, Yin-Ying Zhang & Hui-Min Lu

  2. Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China

    Li-Hong Huang

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  1. Jie Gu
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Contributions

HL, and JG conceived the design of the study; HL, YZ and JG obtained the data; HL and GY cleared up the datasets; HL, XK, LH and GY mainly performed the data analyses; HL, GY, JG and LH drafted and revised the manuscript, and all authors approved the manuscript and provided relevant suggestions.

Corresponding authors

Correspondence to Li-Hong Huang or Hui-Min Lu.

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Conflict of interest

Guan-min Yan, Jie Gu, Xiao-Lin Kong, Yin-Ying Zhang, Li-Hong Huang, Hui-Min Lu declare that they have no conflicts of interest.

Web resources

MAGMA, https://ctg.cncr.nl/software/magma; FUMA, https://fuma.ctglab.nl; Metascape, https://metascape.org; PLINK, https://www.cog-genomics.org; R, https://www.r-project.org.

Additional information

Communicated by Shuhua Xu.

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438_2023_2071_MOESM1_ESM.xlsx

Table S1. Instrusmental variables for five identified immune cells. Table S2. Sensitive analysis for causal associations of all immune cells on SLE risk. Table S3. MR-PRESSO analysis for effects of identified immune cells on SLE risk. Table S4. Causal associations of all immune cells on SLE risk after removing IVs associated with other immune cells. Table S5. Identified pleiotropic genes

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Gu, J., Yan, GM., Kong, XL. et al. Assessing the causal relationship between immune traits and systemic lupus erythematosus by bi-directional Mendelian randomization analysis. Mol Genet Genomics 298, 1493–1503 (2023). https://doi.org/10.1007/s00438-023-02071-9

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