Integrated Analysis of WES and scRNA-Seq Data Reveals the Genetic Basis of Immune Dysregulation in Unexplained Recurrent Pregnancy Loss

IF 2.6 4区医学 Q2 MEDICAL LABORATORY TECHNOLOGY

Journal of Clinical Laboratory Analysis Pub Date : 2025-03-11 DOI:10.1002/jcla.70011

Zhao-Jing Lin, Lei Zhu, Yi Dong, Jiao Yun, Ya-Nan Zhi, Wei Zhang, Yan-Mei Sun, Yu-Jie Jiang, Shu Liu, Liang-Liang Fan, Ya-Li Li, Shuai Guo

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引用次数: 0

Abstract

Objective

This study aimed to identify genetic variants and their functional consequences underlying Unexplained Recurrent Pregnancy Loss (uRPL) through comprehensive genomic and transcriptomic analyses.

Methods

We recruited 13 Chinese uRPL patients and performed Whole Exome Sequencing (WES) on chorionic villi samples from miscarriage tissues. Additionally, we conducted an integrative analysis using single-cell RNA sequencing data from decidual immune cells to examine expression patterns.

Results

WES analysis pinpointed variants in the four MUC genes (MUC4, MUC6, MUC16, and MUC17), six lipid metabolism genes in immune cells (ABCA4, ABCA7, ABCB5, ABCC8, ADGRV1, and ANK3), and two structural genes (PIEZO1 and PKD1), whose variants impair mucosal barriers and lipid homeostasis, thereby leading to immune dysregulation and contributing to uRPL. To delve deeper into the effects of these genetic variants on cellular expression patterns, we undertook an integrative analysis using a single-cell dataset from decidual immune cells in uRPL cases. We observed significant dysregulation of lipid metabolism within immune cells, reduced heat shock protein expression, and enhanced chemokine signaling in uRPL samples, indicating a pro-inflammatory state.

Conclusions

In summary, our study reveals a complex interplay between genetic variants and immune cell dysfunctions in uRPL, emphasizing the role of identified genetic variants in driving pro-inflammatory states. These findings provide a comprehensive view of the molecular mechanisms underlying uRPL, opening paths for novel therapeutic interventions and improved clinical management.

Abstract Image

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WES和scRNA-Seq数据的综合分析揭示了不明原因复发性妊娠丢失免疫失调的遗传基础。

目的：本研究旨在通过全面的基因组和转录组学分析，确定不明原因复发性妊娠丢失（uRPL）的遗传变异及其功能后果。方法：我们招募了13例中国uRPL患者，对流产组织的绒毛膜绒毛样本进行了全外显子组测序（WES）。此外，我们使用来自个体免疫细胞的单细胞RNA测序数据进行了综合分析，以检查表达模式。结果：WES分析确定了4个MUC基因（MUC4、MUC6、MUC16和MUC17）、免疫细胞中6个脂质代谢基因（ABCA4、ABCA7、ABCB5、ABCC8、ADGRV1和ANK3）和2个结构基因（PIEZO1和PKD1）的变异，这些变异破坏了粘膜屏障和脂质稳态，从而导致免疫失调并导致uRPL。为了更深入地研究这些遗传变异对细胞表达模式的影响，我们使用来自uRPL病例中个体免疫细胞的单细胞数据集进行了综合分析。我们观察到免疫细胞内脂质代谢明显失调，热休克蛋白表达减少，uRPL样品中趋化因子信号传导增强，表明促炎状态。结论：总之，我们的研究揭示了uRPL中遗传变异与免疫细胞功能障碍之间的复杂相互作用，强调了已鉴定的遗传变异在驱动促炎状态中的作用。这些发现为uRPL的分子机制提供了一个全面的视角，为新的治疗干预和改进的临床管理开辟了道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Clinical Laboratory Analysis 医学-医学实验技术

CiteScore

5.60

自引率

7.40%

发文量

584

审稿时长

6-12 weeks

期刊介绍： Journal of Clinical Laboratory Analysis publishes original articles on newly developing modes of technology and laboratory assays, with emphasis on their application in current and future clinical laboratory testing. This includes reports from the following fields: immunochemistry and toxicology, hematology and hematopathology, immunopathology, molecular diagnostics, microbiology, genetic testing, immunohematology, and clinical chemistry.