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Shared genetic study gives insights into the shared and distinct pathogenic immunity components of IgA nephropathy and SLE

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Abstract

An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r2 ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.

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Funding

This study was funded by National Natural Science Foundation of China (grant number 81800636 and 82070733), Clinical Medicine Plus X—Young Scholars Project of Peking University (grant number PKU2021LCXQ017), the Fundamental Research Funds for the Central Universities, and CAMS Innovation Fund for Medical Sciences (grant number 2019-I2M-5–046).

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Authors and Affiliations

  1. Renal Division, Department of Medicine, Peking University First Hospital, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, China

    Yue-miao Zhang, Xu-jie Zhou, Yan-Na Wang, Xing-zi Liu & Hong Zhang

  2. Institute of Nephrology, Peking University, Beijing, China

    Yue-miao Zhang, Xu-jie Zhou, Yan-Na Wang, Xing-zi Liu & Hong Zhang

  3. Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China

    Yue-miao Zhang, Xu-jie Zhou, Yan-Na Wang, Xing-zi Liu & Hong Zhang

  4. Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China

    Yue-miao Zhang, Xu-jie Zhou, Yan-Na Wang, Xing-zi Liu & Hong Zhang

  5. Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, the University of Hong Kong, 21 Sassoon Road, Hong Kong, China

    Yong-Fei Wang, Yu-lung Lau & Wan-ling Yang

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  1. Yue-miao Zhang
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  2. Xu-jie Zhou
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  8. Hong Zhang
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Correspondence to Hong Zhang.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Communicated by Stefan Hohmann.

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Zhang, Ym., Zhou, Xj., Wang, YN. et al. Shared genetic study gives insights into the shared and distinct pathogenic immunity components of IgA nephropathy and SLE. Mol Genet Genomics 296, 1017–1026 (2021). https://doi.org/10.1007/s00438-021-01798-7

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  • DOI: https://doi.org/10.1007/s00438-021-01798-7

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