子痫前期和胎儿生长受限中免疫失调和炎症生物标志物复杂相互作用的新见解:两步孟德尔随机分析法

IF 4.7 Q2 IMMUNOLOGY
Chumei Zeng , Huiying Liu , Zilian Wang , Jingting Li
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引用次数: 0

摘要

背景遗传性免疫失调与子痫前期(PE)或子痫伴胎儿生长受限(PE with FGR)的发生之间的关系得出了不一致的研究结果,而这种关联的潜在中介因素仍然难以捉摸。我们的目的是探讨遗传性免疫失调对子痫或子痫合并 FGR 风险的因果影响,并阐明特定转录组在介导这种关系中的作用。方法进行了两步孟德尔随机化(MR)分析,以探讨免疫失调与子痫或子痫合并 FGR 之间的联系,并确定作为介导因素的潜在炎症生物标志物。结果的 GWAS 总结数据来自 FinnGen 数据集。分析包括五种全身性免疫相关疾病、四种慢性生殖器炎症疾病和 31 种炎症生物标志物。结果主要的单变量分析显示,系统性红斑狼疮(SLE)、1 型糖尿病(T1D)、2 型糖尿病(T2D)和类风湿性关节炎(RA)与 PE 或 PE 伴 FGR 的风险之间存在显著的正相关。令人惊讶的是,一个反直觉的发现表明,盆腔腹膜子宫内膜异位症(EMoP)与妊娠合并胎儿畸形的风险呈显著负相关。没有一个炎症因素与 PE 或 PE 合并绒毛膜促性腺激素有因果关系。然而,淋巴细胞计数与妊娠合并先天性子宫发育不良的风险有明显关系。在淋巴细胞亚群中,自然杀伤(NK)细胞的比例和幼稚CD4+T细胞的绝对计数对妊娠合并FGR的风险都有显著影响。两步 MR 分析强调了基因预测的淋巴细胞数量是 T1D 和胎儿绒毛膜促性腺激素性肝炎之间的重要中介因素。此外,SMR 分析表明 SH2B3 可能参与了妊娠合并绒毛膜促性腺激素增多症的发生。结论我们的研究结果提供了大量证据,证明免疫失调与妊娠合并绒毛膜促性腺激素增多症或妊娠合并绒毛膜促性腺激素增多症之间存在潜在的因果关系,其中一些疾病被证明会加速免疫细胞失调,进而导致妊娠合并绒毛膜促性腺激素增多症或妊娠合并绒毛膜促性腺激素增多症的发病风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Novel insights into the complex interplay of immune dysregulation and inflammatory biomarkers in preeclampsia and fetal growth restriction: A two-step Mendelian randomization analysis

Background

The relationship between genetic immune dysregulation and the occurrence of preeclampsia (PE) or PE with fetal growth restriction (PE with FGR) has yielded inconsistent findings, and the underlying mediators of this association remain elusive. We aimed to explore the causal impact of genetic immune dysregulation on the risk of PE or PE with FGR and to elucidate the role of specific transcriptomes in mediating this relationship.

Methods

A two-step Mendelian randomization (MR) analysis was performed to explore the link between immune dysregulation and PE or PE with FGR, as well as to identify potential inflammatory biomarkers that act as mediators. GWAS summary data for outcomes were obtained from the FinnGen dataset. The analyses encompassed five systemic immune-associated diseases, four chronic genital inflammatory diseases, and thirty-one inflammatory biomarkers. Summary-data-based MR (SMR) and HEIDI analysis were conducted to test whether the effect size of single nucleotide polymorphisms (SNPs) on outcomes was mediated by the expression of immune-associated genes.

Results

The primary univariable analysis revealed a significant positive correlation between systemic lupus erythematosus (SLE), type 1 diabetes (T1D), type 2 diabetes (T2D), and rheumatoid arthritis (RA) with the risk of PE or PE with FGR. Surprisingly, a counterintuitive finding showed a significant negative association between endometriosis of pelvic peritoneum (EMoP) and the risk of PE with FGR. None of the inflammatory factors had a causal relationship with PE or PE with FGR. However, there was a significant association between lymphocyte count and the risk of PE with FGR. Within the lymphocyte subset, both the proportion of Natural Killer (NK) cells and absolute counts of naïve CD4+ T cells demonstrated significant effects on the risk of PE with FGR. Two-step MR analysis underscored the genetically predicted lymphocyte count as a significant mediator between T1D and PE with FGR. Additionally, SMR analysis indicated the potential involvement of SH2B3 in the occurrence of PE with FGR.

Conclusions

Our findings provided substantial evidence of the underlying causal relationship between immune dysregulation and PE or PE with FGR and some of these diseases proved to accelerate immune cells disorders and then contribute to the risk of incident PE or PE with FGR.

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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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