TY - JOUR
T1 - Causal relationship between key genes and metabolic dysfunction-associated fatty liver disease risk mediated by immune cells
T2 - A Mendelian randomization and mediation analysis
AU - Feng, Gong
AU - He, Na
AU - Gao, Jing
AU - Li, Xiao Cheng
AU - Zhang, Fen Na
AU - Liu, Cheng Cheng
AU - Targher, Giovanni
AU - Byrne, Christopher D.
AU - Mi, Man
AU - Zheng, Ming Hua
AU - Ye, Feng
N1 - Publisher Copyright:
© 2024 John Wiley & Sons Ltd.
PY - 2024/12
Y1 - 2024/12
N2 - Aim: Non-invasive diagnostics for metabolic dysfunction–associated fatty liver disease (MAFLD) remain challenging. We aimed to identify novel key genes as non-invasive biomarkers for MAFLD, elucidate causal relationships between biomarkers and MAFLD and determine the role of immune cells as potential mediators. Materials and Methods: Utilizing published transcriptome data of patients with biopsy-proven MAFLD, we applied linear models for microarray data, least absolute shrinkage and selector operation (LASSO) regressions and receiver operating characteristic (ROC) curve analyses to identify and validate biomarkers for MAFLD. Using the expression quantitative trait loci database and a cohort of 778 614 Europeans, we used Mendelian randomization to analyse the causal relationships between key biomarkers and MAFLD. Additionally, mediation analysis was performed to examine the involvement of 731 immunophenotypes in these relationships. Results: We identified 31 differentially expressed genes, and LASSO regression showed three hub genes, IGFBP2, PEG10, and P4HA1, with area under the receiver operating characteristic (AUROC) curve of 0.807, 0.772 and 0.791, respectively, for identifying MAFLD. The model of these three genes had an AUROC of 0.959 and 0.800 in the development and validation data sets, respectively. This model was also validated using serum-based enzyme-linked immunosorbent assay data from MAFLD patients and control subjects (AUROC: 0.819, 95% confidence interval: 0.736–0.902). PEG10 was associated with an increased MAFLD risk (odds ratio = 1.106, p = 0.032) via inverse variance–weighted analysis, and about 30% of this risk was mediated by the percentage of CD11c + CD62L– monocytes. Conclusions: The MAFLD panels have good diagnostic accuracy, and the causal link between PEG10 and MAFLD was mediated by the percentage of CD11c + CD62L– monocytes.
AB - Aim: Non-invasive diagnostics for metabolic dysfunction–associated fatty liver disease (MAFLD) remain challenging. We aimed to identify novel key genes as non-invasive biomarkers for MAFLD, elucidate causal relationships between biomarkers and MAFLD and determine the role of immune cells as potential mediators. Materials and Methods: Utilizing published transcriptome data of patients with biopsy-proven MAFLD, we applied linear models for microarray data, least absolute shrinkage and selector operation (LASSO) regressions and receiver operating characteristic (ROC) curve analyses to identify and validate biomarkers for MAFLD. Using the expression quantitative trait loci database and a cohort of 778 614 Europeans, we used Mendelian randomization to analyse the causal relationships between key biomarkers and MAFLD. Additionally, mediation analysis was performed to examine the involvement of 731 immunophenotypes in these relationships. Results: We identified 31 differentially expressed genes, and LASSO regression showed three hub genes, IGFBP2, PEG10, and P4HA1, with area under the receiver operating characteristic (AUROC) curve of 0.807, 0.772 and 0.791, respectively, for identifying MAFLD. The model of these three genes had an AUROC of 0.959 and 0.800 in the development and validation data sets, respectively. This model was also validated using serum-based enzyme-linked immunosorbent assay data from MAFLD patients and control subjects (AUROC: 0.819, 95% confidence interval: 0.736–0.902). PEG10 was associated with an increased MAFLD risk (odds ratio = 1.106, p = 0.032) via inverse variance–weighted analysis, and about 30% of this risk was mediated by the percentage of CD11c + CD62L– monocytes. Conclusions: The MAFLD panels have good diagnostic accuracy, and the causal link between PEG10 and MAFLD was mediated by the percentage of CD11c + CD62L– monocytes.
KW - Mendelian randomization
KW - diagnostic markers
KW - mediation analysis
KW - metabolic dysfunction–associated fatty liver disease
UR - https://www.scopus.com/pages/publications/85203119252
U2 - 10.1111/dom.15925
DO - 10.1111/dom.15925
M3 - 文章
C2 - 39228284
AN - SCOPUS:85203119252
SN - 1462-8902
VL - 26
SP - 5590
EP - 5599
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 12
ER -
