Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Molecular Genetics and Biology of Complex Diseases and Department of Clinical and Molecular Hepatology, Institute of Medical Research, University of Buenos Aires-National Scientific and Technical Research Council, Ciudad Autonoma de Buenos Aires, Argentina.
Hepatology. 2022 Nov;76(5):1482-1494. doi: 10.1002/hep.32491. Epub 2022 Apr 21.
It is unclear whether rs738409 (p.I148M) missense variant in patatin-like phospholipase domain-containing 3 rs738409 promotes fibrosis development by triggering specific fibrogenic pathways or by creating an unfavorable microenvironment by promoting steatosis, inflammation, and ultimately fibrosis. We tested the hypothesis that intermediate histologic traits, including steatosis, lobular and portal inflammation, and ballooning may determine the effect of rs738409 on liver fibrosis among individuals with biopsy-proven NAFLD.
Causal mediation models including multiple mediators in parallel or sequentially were performed to examine the effect of rs738409, by decomposing its total effect on fibrosis severity into direct and indirect effects, mediated by histology traits in 1153 non-Hispanic White patients. Total effect of rs738409 on fibrosis was β = 0.19 (95% CI: 0.09-0.29). The direct effect of rs738409 on fibrosis after removing mediators' effects was β = 0.09 (95% CI: 0.01-0.17) and the indirect effect of rs738409 on fibrosis through all mediators' effects were β = 0.010 (95% CI: 0.04-0.15). Among all mediators, the greatest estimated effect size was displayed by portal inflammation (β = 0.09, 95% CI: 0.05-0.12). Among different sequential combinations of histology traits, the path including lobular inflammation followed by ballooning degeneration displayed the most significant indirect effect (β = 0.023, 95% CI: 0.011-0.037). Mediation analysis in a separate group of 404 individuals with biopsy-proven NAFLD from other races and ethnicity showed similar results.
In NAFLD, nearly half of the total effect of the rs738409 G allele on fibrosis severity could be explained by a direct pathway, suggesting that rs738409 may promote fibrosis development by activating specific fibrogenic pathways. A large proportion of the indirect effect of rs738409 on fibrosis severity is mediated through portal inflammation.
尚不清楚 patatin 样磷脂酶结构域包含蛋白 3（PNPLA3）rs738409（p.I148M）错义变体是否通过触发特定的纤维生成途径，或者通过促进脂肪变性、炎症和最终纤维化来创造不利的微环境，从而促进纤维化的发展。我们检验了这样一个假设，即中间组织学特征，包括脂肪变性、汇管区和门管区炎症以及气球样变，可能会决定 rs738409 在经活检证实的非酒精性脂肪性肝病（NAFLD）个体中对肝纤维化的影响。
我们在 1153 名非西班牙裔白种人群中，并行或依次进行了多个中介物的因果中介模型分析，以检验 rs738409 对纤维化严重程度的总效应，该总效应通过组织学特征来进行分解，以确定其对纤维化严重程度的直接和间接影响。rs738409 对纤维化的总效应为 β=0.19（95%CI：0.09-0.29）。在消除中介物作用后的 rs738409 对纤维化的直接效应为 β=0.09（95%CI：0.01-0.17），而 rs738409 通过所有中介物对纤维化的间接效应为 β=0.010（95%CI：0.04-0.15）。在所有中介物中，门静脉炎症的估计效应最大（β=0.09，95%CI：0.05-0.12）。在组织学特征的不同顺序组合中，包括汇管区炎症继以气球样变性的路径显示出最显著的间接效应（β=0.023，95%CI：0.011-0.037）。在另一组来自其他种族和民族的经活检证实的 NAFLD 患者（404 例）中进行的中介分析显示出了相似的结果。
在 NAFLD 中，rs738409 G 等位基因对纤维化严重程度的总效应的近一半可以通过直接途径来解释，这表明 rs738409 可能通过激活特定的纤维生成途径来促进纤维化的发展。rs738409 对纤维化严重程度的间接效应的很大一部分是通过门静脉炎症来介导的。
