血清代谢物与人类间质性肺病的因果关系：一项孟德尔随机化研究。
Causal relationship between serum metabolites and interstitial lung disease in humans: A mendelian randomization study.
机构信息
Department of Respiratory and Critical Care Medicine, Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Wenzhou Medical University, Zhuji, Zhejiang, China.
Department of Neurology, Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Wenzhou Medical University, Zhuji, Zhejiang, China.
出版信息
Technol Health Care. 2024;32(5):3485-3496. doi: 10.3233/THC-240285.
BACKGROUND
A significant proportion of interstitial lung disease (ILD) patients experience two or more comorbidities, leading to an increasing burden of disease, frequent hospitalizations, and premature death.
OBJECTIVE
To investigate the causal relationship between serum metabolites and ILD in humans using Mendelian randomization.
METHODS
Genetic loci closely related to human serum metabolites were selected as instrumental variables (IVs), with the inverse-variance weighted method (IVW) as the primary method and the weighted median method (WME) and MR-Egger regression as auxiliary methods for Mendelian randomization analysis of the data. Meanwhile, the causal relationship between human serum metabolites and ILD was evaluated by OR, along with the assessment of the stability and reliability of the results via 3 methods, i.e., heterogeneity testing, gene pleiotropy testing, and sensitivity analysis.
RESULTS
8,234 single nucleotide polymorphism (SNP) loci were included as IV, among which 23 SNP loci were selected as IV. Specifically, IVW estimated that the risk of ILD in the anti-Jo-1 antibody-positive population was 4.122 times higher than that in the negative population (95% CI: 2.311-5.954, P< 0.001). IVW also supported a causal effect between anti-SSA antibody positivity and ILD (OR = 2.781, 95% CI: 1.413-4.350, P< 0.001). At the same time, MR-Egger fitted a linear relationship between erythrocyte sedimentation rate (ESR) (95% CI: 1.257-5.894, P= 0.002), C-reactive protein (CRP) (95% CI: 2.433-6.935, P= 0.001), and ILD. Additionally, heterogeneity testing with IVW and MR-Egger regression indicated no heterogeneity, and MR-Egger regression intercept and MR-PRESSO testing suggested minimal influence of gene pleiotropy on the results, without non-specific SNPs identified in the leave-one-out analysis.
CONCLUSION
A positive causal relationship may exist between anti-Jo-1 antibody positivity, anti-SSA antibody positivity, elevated ESR, elevated CRP, and ILD.
背景
相当一部分间质性肺疾病（ILD）患者存在两种或两种以上合并症，导致疾病负担增加、频繁住院和过早死亡。
目的
使用孟德尔随机化研究血清代谢物与人类 ILD 之间的因果关系。
方法
选择与人类血清代谢物密切相关的遗传位点作为工具变量（IV），采用逆方差加权法（IVW）作为主要方法，加权中位数法（WME）和 MR-Egger 回归作为 Mendelian 随机化分析的辅助方法。同时，通过 OR 评估血清代谢物与 ILD 之间的因果关系，并通过 3 种方法评估结果的稳定性和可靠性，即异质性检验、基因多效性检验和敏感性分析。
结果
纳入 8234 个单核苷酸多态性（SNP）位点作为 IV，其中选择 23 个 SNP 位点作为 IV。具体而言，IVW 估计抗 Jo-1 抗体阳性人群患 ILD 的风险是阴性人群的 4.122 倍（95%CI：2.311-5.954，P<0.001）。IVW 还支持抗 SSA 抗体阳性与 ILD 之间存在因果关系（OR=2.781，95%CI：1.413-4.350，P<0.001）。同时，MR-Egger 拟合了红细胞沉降率（ESR）（95%CI：1.257-5.894，P=0.002）、C 反应蛋白（CRP）（95%CI：2.433-6.935，P=0.001）和 ILD 之间的线性关系。此外，IVW 和 MR-Egger 回归的异质性检验表明没有异质性，MR-Egger 回归截距和 MR-PRESSO 检验表明基因多效性对结果的影响很小，在逐一剔除分析中未发现非特异性 SNP。
结论
抗 Jo-1 抗体阳性、抗 SSA 抗体阳性、ESR 升高、CRP 升高与 ILD 之间可能存在正因果关系。
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