Genetic factors play a critical role in autoimmune hepatitis (AIH), and numerous studies have been conducted to identify variants associated with the risk of AIH. However, our knowledge of these genetic risk factors is still limited. In this study, we aim to provide a comprehensive synopsis of the genetic architecture of this disease. A systematic search was conducted to identify published studies on the associations between genetic variants and the risk of AIH. Meta-analyses were conducted to calculate the pooled odds ratio (OR) and 95% confidence interval (CI). Then, the cumulative evidence was evaluated for significant associations according to the Venice criteria and false-positive report probability. Finally, functional annotations and pathway analyses were conducted to identify potential pathogenic loci and related pathways. In total, 62 studies involving 11,068 cases and 45,482 controls were included to assess the association between 75 genetic variants and the risk of AIH. Among them, 24 variants were associated with the risk of AIH, and there is strong cumulative evidence supporting these associations. Importantly, HLA DRB1*0301 (OR: 3.023, 95% CI: 2.443 - 1.678, P = 2.81 × 10?24) and DRB3*0101 (OR: 3.667, 95% CI: 2.649 - 5.075, P = 4.69 × 10?15) are newly identified genome-wide significant risk loci. In addition, the rs3184504 variant (OR: 1.305, 95% CI: 1.122 - 1.516, P = 0.001) in the SH2B3 gene is a potential functional mutation. GO pathway analysis suggests that these genes are enriched in antigen processing and presentation, response to interferon-gamma, and immune response-regulating signaling pathways. This study comprehensively summarizes the genetic architecture of AIH and provides cumulative evidence. We have identified two new loci that exceed genome-wide significance. The findings from this study will offer new insights into the pathogenesis of AIH.
References
[1]
Muratori, L., Lohse, A.W. and Lenzi, M. (2023) Diagnosis and Management of Autoimmune Hepatitis. BMJ, 380, e070201. https://doi.org/10.1136/bmj-2022-070201
Lv, T., Li, M., Zeng, N., Zhang, J., Li, S., Chen, S., et al. (2019) Systematic Review and Meta-Analysis on the Incidence and Prevalence of Autoimmune Hepatitis in Asian, European, and American Population. Journal of Gastroenterology and Hepatology, 34, 1676-1684. https://doi.org/10.1111/jgh.14746
[4]
Li, Y., Sun, Y., Liu, Y., Wang, B., Li, J., Wang, H., et al. (2022) Genome-Wide Meta-Analysis Identifies Susceptibility Loci for Autoimmune Hepatitis Type 1. Hepatology, 76, 564-575. https://doi.org/10.1002/hep.32417
[5]
Ahuja, N., Singh, J., Minz, R.W., Anand, S., Das, A. and Taneja, S. (2023) HLA and Non-HLA Gene Polymorphisms in Autoimmune Hepatitis Patients of North Indian Adults. Frontiers in Immunology, 13, Article 984083.
https://doi.org/10.3389/fimmu.2022.984083
[6]
Ma, Y., Su, H., Yuksel, M., Longhi, M.S., McPhail, M.J., Wang, P., et al. (2021) Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry. Hepatology, 74, 2032-2046.
https://doi.org/10.1002/hep.31893
[7]
Yousefi, A., Najafi, M., Motamed, F., Mahmoudi, E., Bidoki, A.Z., Sadr, M., et al. (2018) Association of Interleukin-6 and Interleukin-1 Family Gene Polymorphisms in Autoimmune Hepatitis. Annals of Hepatology, 17, 1021-1025.
https://doi.org/10.5604/01.3001.0012.7202
[8]
Liberati, A. (2009) The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration. Annals of Internal Medicine, 151, W65-94.
https://doi.org/10.7326/0003-4819-151-4-200908180-00136
[9]
Sagoo, G.S., Little, J. and Higgins, J.P.T. (2009) Systematic Reviews of Genetic Association Studies. PLOS Medicine, 6, e1000028.
https://doi.org/10.1371/journal.pmed.1000028
[10]
Moher, D., Liberati, A., Tetzlaff, J. and Altman, D.G. (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. BMJ, 339, b2535. https://doi.org/10.1136/bmj.b2535
[11]
Lau, J. (1997) Quantitative Synthesis in Systematic Reviews. Annals of Internal Medicine, 127, 820-826. https://doi.org/10.7326/0003-4819-127-9-199711010-00008
[12]
Begg, C.B. and Mazumdar, M. (1994) Operating Characteristics of a Rank Correlation Test for Publication Bias. Biometrics, 50, 1088-1101. https://doi.org/10.2307/2533446
[13]
Egger, M., Smith, G.D., Schneider, M. and Minder, C. (1997) Bias in Meta-Analysis Detected by a Simple, Graphical Test. BMJ, 315, 629-634.
https://doi.org/10.1136/bmj.315.7109.629
[14]
Zhang, M., Tang, M., Fang, Y., Cui, H., Chen, S., Li, J., et al. (2017) Cumulative Evidence for Relationships between Multiple Variants in the VTI1A and TCF7L2 Genes and Cancer Incidence. International Journal of Cancer, 142, 498-513.
https://doi.org/10.1002/ijc.31074
[15]
Wacholder, S., Chanock, S., Garcia-Closas, M., El ghormli, L. and Rothman, N. (2004) Assessing the Probability That a Positive Report Is False: An Approach for Molecular Epidemiology Studies. JNCI: Journal of the National Cancer Institute, 96, 434-442. https://doi.org/10.1093/jnci/djh075
[16]
Ward, L.D. and Kellis, M. (2011) HaploReg: A Resource for Exploring Chromatin States, Conservation, and Regulatory Motif Alterations within Sets of Genetically Linked Variants. Nucleic Acids Research, 40, D930-D934.
https://doi.org/10.1093/nar/gkr917
[17]
Watanabe, K., Taskesen, E., van Bochoven, A. and Posthuma, D. (2017) Functional Mapping and Annotation of Genetic Associations with FUMA. Nature Communications, 8, Article No. 1826. https://doi.org/10.1038/s41467-017-01261-5
[18]
Zhang, B., Kirov, S. and Snoddy, J. (2005) WebGestalt: An Integrated System for Exploring Gene Sets in Various Biological Contexts. Nucleic Acids Research, 33, W741-W748. https://doi.org/10.1093/nar/gki475
[19]
Liu, J.Z., Hov, J.R., Folseraas, T., Ellinghaus, E., Rushbrook, S.M., Doncheva, N.T., et al. (2013) Dense Genotyping of Immune-Related Disease Regions Identifies Nine New Risk Loci for Primary Sclerosing Cholangitis. Nature Genetics, 45, 670-675.
https://doi.org/10.1038/ng.2616
[20]
Doherty, D.G., Donaldson, P.T., Underhill, J.A., Farrant, M.J., Duthie, A., Mieli-Vergani, G., et al. (1994) Allelic Sequence Variation in the HLA Class II Genes and Proteins in Patients with Autoimmune Hepatitis. Hepatology, 19, 609-615.
https://doi.org/10.1002/hep.1840190311
[21]
Wang, C., Zheng, X., Tang, R., Han, C., Jiang, Y., Wu, J., et al. (2020) Fine Mapping of the MHC Region Identifies Major Inde-pendent Variants Associated with Han Chinese Primary Biliary Cholangitis. Journal of Autoimmunity, 107, Article ID: 102372. https://doi.org/10.1016/j.jaut.2019.102372
[22]
Okada, Y., Eyre, S., Suzuki, A., Kochi, Y. and Yamamoto, K. (2018) Genetics of Rheumatoid Arthritis: 2018 Status. Annals of the Rheumatic Diseases, 78, 446-453.
https://doi.org/10.1136/annrheumdis-2018-213678
[23]
International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium, Sawcer, S., et al. (2011) Genetic Risk and a Primary Role for Cell-Mediated Immune Mechanisms in Multiple Sclerosis. Nature, 476, 214-219.
https://doi.org/10.1038/nature10251
[24]
Strippel, C., Herrera-Rivero, M., Wendorff, M., Tietz, A.K., Degenhardt, F., Witten, A., et al. (2022) A Genome-Wide Association Study in Autoimmune Neurological Syndromes with Anti-GAD65 Autoantibodies. Brain, 146, 977-990.
https://doi.org/10.1093/brain/awac119
[25]
Ji, S., Juran, B.D., Mucha, S., Folseraas, T., Jostins, L., Melum, E., et al. (2016) Genome-wide Association Study of Primary Sclerosing Cholangitis Identifies New Risk Loci and Quantifies the Genetic Relationship with Inflammatory Bowel Disease. Nature Genetics, 49, 269-273. https://doi.org/10.1038/ng.3745
[26]
Stahl, E.A., Raychaudhuri, S., Remmers, E.F., Xie, G., Eyre, S., Thomson, B.P., et al. (2010) Genome-wide Association Study Meta-Analysis Identifies Seven New Rheumatoid Arthritis Risk Loci. Nature Genetics, 42, 508-514. https://doi.org/10.1038/ng.582
[27]
Hunt, K.A., Zhernakova, A., Turner, G., Heap, G.A.R., Franke, L., Bruinenberg, M., et al. (2008) Newly Identified Genetic Risk Variants for Celiac Disease Related to the Immune Response. Nature Genetics, 40, 395-402. https://doi.org/10.1038/ng.102
[28]
de Boer, Y.S., van Gerven, N.M.F., Zwiers, A., Verwer, B.J., van Hoek, B., van Erpecum, K.J., et al. (2014) Genome-wide Association Study Identifies Variants Associated with Autoimmune Hepatitis Type 1. Gastroenterology, 147, 443-452.e5.
https://doi.org/10.1053/j.gastro.2014.04.022
[29]
Westra, H., Peters, M.J., Esko, T., Yaghootkar, H., Schurmann, C., Kettunen, J., et al. (2013) Systematic Identification of Trans eQTLs as Putative Drivers of Known Disease Associations. Nature Genetics, 45, 1238-1243. https://doi.org/10.1038/ng.2756
[30]
Mack, C.L., Adams, D., Assis, D.N., Kerkar, N., Manns, M.P., Mayo, M.J., et al. (2020) Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines from the American Association for the Study of Liver Diseases. Hepatology, 72, 671-722. https://doi.org/10.1002/hep.31065
