TITLE:
Cumulative Evidence on Associations between Genetic Variants and Autoimmune Hepatitis
AUTHORS:
Dongqing Gu, Yizhou Wang, Liang Ge, Min Zhang
KEYWORDS:
Autoimmune Hepatitis, Genetic Architecture, Cumulative Evidence, Functional Annotations, HLA
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.12 No.12,
December
31,
2024
ABSTRACT: 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.