Liu Shaowen, Musha Jiayinaxi, Wang Zhiru, Wang Xueting, Li Tengfei, Zhan Jianghua
Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China.
Department of General Surgery, Tianjin Children's Hospital, Tianjin, China.
World J Pediatr Surg. 2024 May 8;7(2):e000754. doi: 10.1136/wjps-2023-000754. eCollection 2024.
In recent years, Mendelian randomization (MR) has been widely used to infer causality of related disease risk exposures. However, this strategy has not been applied to biliary atresia (BA).
Genome-wide association studies (GWAS) data of 41 inflammatory cytokines, 731 immune cell traits, and 1400 metabolites were obtained from public databases as exposure factors. The outcome information was obtained from a GWAS meta-analysis of 499 children with BA and 1928 normal controls. Inverse variance weighting was the primary causality analysis. Cochran Q-test, MR-Egger intercept, MR pleiotropy residual sum and outlier, and 'leave-one-out' analyses were used for sensitivity analysis. Reverse MR, MR-Steiger, and Linkage Disequilibrium Score were used to exclude the effects of reverse causality, genetic association, and linkage disequilibrium.
MR results showed that a total of seven traits had potential causal relationships with BA, including three inflammatory cytokines: eotaxin (odds ratio (OR)=1.45, 95% confidence interval (CI): 1.08 to 1.95, =0.18), G-CSF (OR=4.21, 95% CI: 1.75 to 10.13, =0.05) and MCP-1/MCAF (OR=1.53, 95% CI: 1.12 to 2.10, =0.14); three immune cell traits: CD8dim NKT/T cells ratio (OR=0.59, 95% CI: 0.45 to 0.77, =0.06), CD8dim NKT counts (OR=0.58, 95% CI: 0.43 to 0.78, =0.06), CD8dim NKT/lymphocyte ratio (OR=0.63, 95% CI: 0.49 to 0.81, =0.06); one metabolite: X-12261 levels (OR=2.86, 95% CI: 1.73 to 4.74, =0.06).
In this study, eotaxin, G-CSF, MCP-1/MCAF, and X-12261 levels were shown to be risk factors for BA. However, CD8dim NKT/T cells ratio, CD8dim NKT counts, and CD8dim NKT/lymphocyte ratio were protective factors for BA. These findings provided a promising genetic basis for the etiology, diagnosis, and treatment of BA.
近年来，孟德尔随机化（MR）已被广泛用于推断相关疾病风险暴露的因果关系。然而，该策略尚未应用于胆道闭锁（BA）。
从公共数据库中获取41种炎性细胞因子、731种免疫细胞特征和1400种代谢物的全基因组关联研究（GWAS）数据作为暴露因素。结局信息来自对499例BA患儿和1928例正常对照的GWAS荟萃分析。逆方差加权是主要的因果关系分析方法。采用Cochran Q检验、MR-Egger截距、MR多效性残差和离群值分析以及“留一法”分析进行敏感性分析。采用反向MR、MR-Steiger和连锁不平衡评分来排除反向因果关系、基因关联和连锁不平衡的影响。
MR结果显示，共有7个特征与BA存在潜在因果关系，包括3种炎性细胞因子：嗜酸性粒细胞趋化因子（优势比（OR）=1.45，95%置信区间（CI）：1.08至1.95，P=0.18）、粒细胞集落刺激因子（G-CSF）（OR=4.21，95%CI：1.75至10.13，P=0.05）和单核细胞趋化蛋白-1/巨噬细胞炎性蛋白-1α（MCP-1/MCAF）（OR=1.53，95%CI：1.12至2.10，P=0.14）；3种免疫细胞特征：CD8dim自然杀伤T（NKT）/T细胞比值（OR=0.59，95%CI：0.45至0.77，P=0.06）、CD8dim NKT计数（OR=0.58，95%CI：0.43至0.78，P=0.06）、CD8dim NKT/淋巴细胞比值（OR=0.63，95%CI：0.49至0.81，P=0.06）；1种代谢物：X-12261水平（OR=2.86，95%CI：1.73至4.74，P=0.06）。
在本研究中，嗜酸性粒细胞趋化因子、G-CSF、MCP-1/MCAF和X-12261水平被证明是BA的危险因素。然而，CD8dim NKT/T细胞比值、CD8dim NKT计数和CD8dim NKT/淋巴细胞比值是BA的保护因素。这些发现为BA的病因学研究、诊断和治疗提供了有前景的遗传学依据。
