Mitochondrial DNA Copy Number and Risk of Gestational Metabolic Disorders: A Two-Sample Mendelian Randomization Study

IF 2.4 3区医学 Q3 IMMUNOLOGY

American Journal of Reproductive Immunology Pub Date : 2025-08-20 DOI:10.1111/aji.70144

Feng Zhan, Huijuan Yang, Xuemei Li, Yina Guo, Jianbo Wu, Lidan He

{"title":"Mitochondrial DNA Copy Number and Risk of Gestational Metabolic Disorders: A Two-Sample Mendelian Randomization Study","authors":"Feng Zhan, Huijuan Yang, Xuemei Li, Yina Guo, Jianbo Wu, Lidan He","doi":"10.1111/aji.70144","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Mitochondrial DNA copy number (mtDNA-CN) has been implicated in gestational metabolic disorders (GMD), yet their causal relationships remain unclear. This study employed genetic approaches to investigate potential causal associations between mtDNA-CN and various GMDs.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We conducted a two-sample Mendelian randomization (MR) analysis utilizing genome-wide association study (GWAS) summary statistics from large-scale populations: mtDNA-CN (<i>n</i> = 395 718), preeclampsia (PE) (<i>n</i> = 267 242), gestational diabetes mellitus (GDM) (<i>n</i> = 123 579), gestational hypertension (GH) (<i>n</i> = 118 990), hyperlipidemia (<i>n</i> = 9714), and obesity (<i>n</i> = 463 010). Independent single-nucleotide polymorphisms (SNPs) were rigorously selected as instrumental variables (IVs) following stringent criteria. The primary analysis employed the fixed-effects inverse variance weighted (IVW) method. Multiple sensitivity analyses, including leave-one-out analysis, Cochran's Q test, and MR-Egger regression, were conducted to assess the robustness of our findings.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The IVW analysis revealed a significant protective association between increased mtDNA-CN and PE risk (OR = 0.6262, 95% CI: 0.4201–0.9335, <i>p </i>= 0.0283). However, no significant associations were observed between mtDNA-CN and other GMDs (all <i>p </i>> 0.05). Sensitivity analyses, including MR-Egger regression, showed no evidence of horizontal pleiotropy (all <i>p</i> > 0.05), supporting the robustness of our findings.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>This genetic investigation provides compelling evidence for a potentially protective effect of higher mtDNA-CN against PE development. These findings not only suggest mtDNA-CN as a promising biomarker for PE risk assessment but also offer novel insights into the biological mechanisms underlying PE, potentially informing future preventive strategies and therapeutic interventions.</p>\n </section>\n </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 2","pages":""},"PeriodicalIF":2.4000,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Reproductive Immunology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/aji.70144","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Mitochondrial DNA copy number (mtDNA-CN) has been implicated in gestational metabolic disorders (GMD), yet their causal relationships remain unclear. This study employed genetic approaches to investigate potential causal associations between mtDNA-CN and various GMDs.

Methods

We conducted a two-sample Mendelian randomization (MR) analysis utilizing genome-wide association study (GWAS) summary statistics from large-scale populations: mtDNA-CN (n = 395 718), preeclampsia (PE) (n = 267 242), gestational diabetes mellitus (GDM) (n = 123 579), gestational hypertension (GH) (n = 118 990), hyperlipidemia (n = 9714), and obesity (n = 463 010). Independent single-nucleotide polymorphisms (SNPs) were rigorously selected as instrumental variables (IVs) following stringent criteria. The primary analysis employed the fixed-effects inverse variance weighted (IVW) method. Multiple sensitivity analyses, including leave-one-out analysis, Cochran's Q test, and MR-Egger regression, were conducted to assess the robustness of our findings.

Results

The IVW analysis revealed a significant protective association between increased mtDNA-CN and PE risk (OR = 0.6262, 95% CI: 0.4201–0.9335, p = 0.0283). However, no significant associations were observed between mtDNA-CN and other GMDs (all p > 0.05). Sensitivity analyses, including MR-Egger regression, showed no evidence of horizontal pleiotropy (all p > 0.05), supporting the robustness of our findings.

Conclusion

This genetic investigation provides compelling evidence for a potentially protective effect of higher mtDNA-CN against PE development. These findings not only suggest mtDNA-CN as a promising biomarker for PE risk assessment but also offer novel insights into the biological mechanisms underlying PE, potentially informing future preventive strategies and therapeutic interventions.

查看原文本刊更多论文

线粒体DNA拷贝数和妊娠代谢障碍的风险：一项双样本孟德尔随机研究

线粒体DNA拷贝数（mtDNA-CN）与妊娠代谢障碍（GMD）有关，但其因果关系尚不清楚。本研究采用遗传方法调查mtDNA-CN与各种GMDs之间的潜在因果关系。方法利用全基因组关联研究（GWAS）的汇总统计数据，对大型人群进行两样本孟德尔随机化（MR）分析：mtDNA-CN （n = 395 718）、先兆子痫（n = 267 242）、妊娠糖尿病（n = 123 579）、妊娠高血压（n = 118 990）、高脂血症（n = 9714）和肥胖（n = 463010）。独立的单核苷酸多态性（snp）按照严格的标准被严格选择为工具变量（IVs）。初步分析采用固定效应反方差加权（IVW）方法。我们进行了多重敏感性分析，包括留一分析、科克伦Q检验和egger回归，以评估我们研究结果的稳健性。结果IVW分析显示mtDNA-CN增加与PE风险之间存在显著的保护性关联（OR = 0.6262, 95% CI: 0.4201-0.9335, p = 0.0283）。然而，mtDNA-CN与其他GMDs之间没有显著相关性（均p >； 0.05）。敏感性分析，包括MR-Egger回归，没有显示水平多效性的证据（均p >； 0.05），支持我们研究结果的稳健性。结论本遗传学研究为高mtDNA-CN对PE发育的潜在保护作用提供了强有力的证据。这些发现不仅表明mtDNA-CN是一种有前景的PE风险评估生物标志物，而且为PE的生物学机制提供了新的见解，可能为未来的预防策略和治疗干预提供信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

American Journal of Reproductive Immunology 医学-免疫学

CiteScore

6.20

自引率

5.60%

发文量

314

审稿时长

2 months

期刊介绍： The American Journal of Reproductive Immunology is an international journal devoted to the presentation of current information in all areas relating to Reproductive Immunology. The journal is directed toward both the basic scientist and the clinician, covering the whole process of reproduction as affected by immunological processes. The journal covers a variety of subspecialty topics, including fertility immunology, pregnancy immunology, immunogenetics, mucosal immunology, immunocontraception, endometriosis, abortion, tumor immunology of the reproductive tract, autoantibodies, infectious disease of the reproductive tract, and technical news.