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The association of immune-related genes and the potential role of IL10 with biliary atresia

Pediatric Research volume 94, pages 1659–1666 (2023)Cite this article

Abstract

Background

Biliary atresia (BA) is a severe immune-related disease that is characterized by biliary obstruction and cholestasis. The etiology of BA is unclear, our aim was to explore the relationship between biliary tract inflammation and immune-related genes.

Methods

We selected 14 SNPs in 13 immune-related genes and investigated their associations with BA by using a large case‒control cohort with a total of 503 cases and 1473 controls from southern China.

Results

SNP rs1518111 in interleukin10 (IL10) was identified as associated with BA (P = 5.79E-03; OR: 0.80; 95% CI: 0.68–0.94). The epistatic effects of the following pairwise interactions among these SNPs were associated with BA: signal transducer and activator of transcription 4 (STAT4) and chemokine (C-X-C motif) ligand 3 (CXCL3); STAT4 and damage-regulated autophagy modulator1 (DRAM1); CXCL3 and RAD51 paralog B (RAD51B); and interferon gamma (IFNG) and interleukin26 (IL26). Furthermore, we explored the potential role of IL-10 in the pathogenesis of the neonatal mouse model of BA. IL-10 effectively prevented biliary epithelial cell injury and biliary obstruction in murine BA as well as inhibit the activation of BA-related immune cells.

Conclusions

In conclusion, this study provided strong evidence implicating IL10 as a susceptibility gene for BA in the southern Chinese population.

Impact

  • This study provided strong evidence implicating IL10 as a susceptibility gene for BA in the southern Chinese population.

  • This study could infer that IL-10 may play a protective role in BA mouse model.

  • We found that four SNPs (rs7574865, rs352038, rs4622329, and rs4902562) have genetic interactions.

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Fig. 1: Forest plot of the odds ratios for the SNPs stratified by genetic inheritance patterns following genotypic, dominant and recessive models.
Fig. 2: The relative expression levels of IL10 for different genotypes of SNP rs1518111.
Fig. 3: Effect of IL-10 inhibition or activation on the BA mouse model.
Fig. 4: Inhibition and activation of IL-10 altered pathology and immune cell status.

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Data availability

Data included in this manuscript are available upon request by contacting with the corresponding author and will be freely available to any researcher wishing to use them for non-commercial purposes, without breaching participant confidentiality.

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Acknowledgements

The authors would like to thank the Clinical Biological Resource Bank of Guangzhou Women and Children’s Medical Center for providing the clinical samples.

Funding

This study was supported by grant from the Medical Scientific Research Foundation of Guangdong Province grant A2017406 (L.L.), the Science and Technology Project of Guangzhou grant 202102020196 (Z.L.), 202201020616 (Z.L.), and the National Natural Science Foundation of China grant 82101808 (Z.L.).

Author information

Author notes

  1. These authors contributed equally: Zefeng Lin, Yan Tian, Chengwei Chai.

Authors and Affiliations

  1. Provincial Key Laboratory of Research in Structure Birth Defect Disease and Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China

    Zefeng Lin, Chengwei Chai, Ming Fu, Qi Wu, Ledong Tan, Le Li, Xisi Guan, Zhe Wang, Jinglu Zhao, Hezhen Wang, Yanlu Tong, Yan Zhang & Ruizhong Zhang

  2. Department of Anesthesiology, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, China

    Yan Tian

  3. Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Ruizhong Zhang

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  1. Zefeng Lin
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Contributions

Z.L., Y.T.(Yan Tian), and C.C. participated in analyzing data and wrote the manuscript. L.T., L.L., X.G., Z.W., and H.W., collected clinical samples and information. M.F., J.Z., and Q.W., revised the manuscript for important intellectual content. R.Z., and Y.Z., coordinated the study over the entire time. All authors reviewed the final manuscript.

Corresponding author

Correspondence to Ruizhong Zhang.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Medical Ethics Committee of Guangzhou Women and Children’s Medical Center (NO. 2018030327). And all animal experimental protocols were approved by the Institutional Animal Care and Use Committee of Guangzhou Forevergen Biosciences Medical Laboratory Animal Center (SYXK (yue) 2018-0186). Consent was provided by parents or legal guardians (carers) of all patients via written, informed consent ahead of study initiation. Within this informed consent, they agreed to allow analysis of the research data and publication of the paper.

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Lin, Z., Tian, Y., Chai, C. et al. The association of immune-related genes and the potential role of IL10 with biliary atresia. Pediatr Res 94, 1659–1666 (2023). https://doi.org/10.1038/s41390-023-02626-x

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