Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating pathways: a Mendelian randomization study
Background: Increasing evidence suggests that immunophenotypes play a crucial role in Metabolic dysfunction-associated fatty liver disease (MAFLD), but the specific immunophenotypes contributing to its pathogenesis remain unclear. Objectives: This study aimed to elucidate the causal associations bet...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2024-12-01
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| Series: | Therapeutic Advances in Chronic Disease |
| Online Access: | https://doi.org/10.1177/20406223241303649 |
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| author | Kexin Xie Ming Chen Hongjin An Jinhang Gao Chengwei Tang Zhiyin Huang |
| author_facet | Kexin Xie Ming Chen Hongjin An Jinhang Gao Chengwei Tang Zhiyin Huang |
| author_sort | Kexin Xie |
| collection | DOAJ |
| description | Background: Increasing evidence suggests that immunophenotypes play a crucial role in Metabolic dysfunction-associated fatty liver disease (MAFLD), but the specific immunophenotypes contributing to its pathogenesis remain unclear. Objectives: This study aimed to elucidate the causal associations between immunophenotypes and MAFLD and identify the underlying mediation pathways involved. Design: Mendelian randomization (MR) study. Methods: This study is a quasi-causal inference analysis using univariable and multivariable MR (UVMR and MVMR). Five MAFLD genome-wide association studies (GWASs) and the largest immunophenotype GWAS were analyzed to assess their causal associations. Two-step MR identified potential mediators and quantified their mediation proportions. Comprehensive MR methods, multiple sensitivity analyses, meta-analyses, and false discovery rate (FDR) further enhanced the robustness of our findings. Results: Pooled inverse-variance weighted (IVW) estimates in UVMR identified 47 immunophenotypes having a suggestive causal association with MAFLD. After adjusting for FDR, three lymphocyte phenotypes remained significant: CD20 on IgD − CD24 − B cells (OR: 1.035, p fdr : 0.006), terminally differentiated CD8 + T cells %T cells (OR: 1.052, p fdr : 0.006), and CD4 on CD39 + secreting CD4 + regulatory T cells (OR: 1.036, p fdr : 0.046). Meta-analysis of IVW MVMR estimates with confounders adjustment confirmed that CD20 on IgD − CD24 − B cells and terminally differentiated CD8 + T cells %T cells had significant direct causal associations on MAFLD ( p fdr < 0.05). Additionally, two-step MR analysis identified the waist-to-hip ratio as a mediator, accounting for 42.64% of the causal association between CD20 on IgD − CD24 − B cells and MAFLD. Conclusion: The causal associations of three lymphocyte phenotypes with increased MAFLD risk were identified in this study. CD20 on IgD − CD24 − B cells may both directly and indirectly elevate MAFLD risk, while terminally differentiated CD8 + T cells have a direct causal relationship with MAFLD. These findings suggest new possibilities for targeted therapies and underscore the potential for personalized immunotherapy in managing MAFLD. |
| format | Article |
| id | doaj-art-4fbf4c803b8140ee9c072d434debef21 |
| institution | Kabale University |
| issn | 2040-6231 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Therapeutic Advances in Chronic Disease |
| spelling | doaj-art-4fbf4c803b8140ee9c072d434debef212024-12-12T08:03:31ZengSAGE PublishingTherapeutic Advances in Chronic Disease2040-62312024-12-011510.1177/20406223241303649Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating pathways: a Mendelian randomization studyKexin XieMing ChenHongjin AnJinhang GaoChengwei TangZhiyin HuangBackground: Increasing evidence suggests that immunophenotypes play a crucial role in Metabolic dysfunction-associated fatty liver disease (MAFLD), but the specific immunophenotypes contributing to its pathogenesis remain unclear. Objectives: This study aimed to elucidate the causal associations between immunophenotypes and MAFLD and identify the underlying mediation pathways involved. Design: Mendelian randomization (MR) study. Methods: This study is a quasi-causal inference analysis using univariable and multivariable MR (UVMR and MVMR). Five MAFLD genome-wide association studies (GWASs) and the largest immunophenotype GWAS were analyzed to assess their causal associations. Two-step MR identified potential mediators and quantified their mediation proportions. Comprehensive MR methods, multiple sensitivity analyses, meta-analyses, and false discovery rate (FDR) further enhanced the robustness of our findings. Results: Pooled inverse-variance weighted (IVW) estimates in UVMR identified 47 immunophenotypes having a suggestive causal association with MAFLD. After adjusting for FDR, three lymphocyte phenotypes remained significant: CD20 on IgD − CD24 − B cells (OR: 1.035, p fdr : 0.006), terminally differentiated CD8 + T cells %T cells (OR: 1.052, p fdr : 0.006), and CD4 on CD39 + secreting CD4 + regulatory T cells (OR: 1.036, p fdr : 0.046). Meta-analysis of IVW MVMR estimates with confounders adjustment confirmed that CD20 on IgD − CD24 − B cells and terminally differentiated CD8 + T cells %T cells had significant direct causal associations on MAFLD ( p fdr < 0.05). Additionally, two-step MR analysis identified the waist-to-hip ratio as a mediator, accounting for 42.64% of the causal association between CD20 on IgD − CD24 − B cells and MAFLD. Conclusion: The causal associations of three lymphocyte phenotypes with increased MAFLD risk were identified in this study. CD20 on IgD − CD24 − B cells may both directly and indirectly elevate MAFLD risk, while terminally differentiated CD8 + T cells have a direct causal relationship with MAFLD. These findings suggest new possibilities for targeted therapies and underscore the potential for personalized immunotherapy in managing MAFLD.https://doi.org/10.1177/20406223241303649 |
| spellingShingle | Kexin Xie Ming Chen Hongjin An Jinhang Gao Chengwei Tang Zhiyin Huang Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating pathways: a Mendelian randomization study Therapeutic Advances in Chronic Disease |
| title | Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating pathways: a Mendelian randomization study |
| title_full | Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating pathways: a Mendelian randomization study |
| title_fullStr | Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating pathways: a Mendelian randomization study |
| title_full_unstemmed | Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating pathways: a Mendelian randomization study |
| title_short | Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating pathways: a Mendelian randomization study |
| title_sort | causal associations of immunophenotypes with metabolic dysfunction associated fatty liver disease and mediating pathways a mendelian randomization study |
| url | https://doi.org/10.1177/20406223241303649 |
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