Causal analysis of uterine artery pulsatility index-related proteins and the risk of precocious puberty in girls: a Mendelian randomization study

Yi Gao; Fengfeng Qi

doi:10.1515/jpem-2025-0073

Article

Causal analysis of uterine artery pulsatility index-related proteins and the risk of precocious puberty in girls: a Mendelian randomization study

Yi Gao and Fengfeng Qi

Published/Copyright: September 26, 2025

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 38 Issue 11

Abstract

Objectives

Precocious puberty in girls is a condition marked by the early onset of secondary sexual characteristics, with vascular factors like uterine artery pulsatility index having been suggested as potential indicators.

Methods

We performed Mendelian randomization (MR) analysis using genetic instruments from large-scale genome-wide association studies (GWAS) datasets, including ebi-a-GCST008403, ukb-a-250, and ukb-b-11971, to evaluate the relationship between arterial stiffness and precocious puberty. Exposure and outcome data were sourced from the GWAS Catalog, eQTLGen, and the R11_E4_PREPUB dataset. The TwoSampleMR package was employed to assess causal relationships, with several MR methods applied, including inverse variance weighted, MR Egger, weighted median, and mode-based methods.

Results

Our analysis of arterial stiffness using ebi-a-GCST008403, ukb-a-250, and ukb-b-11971 datasets did not show a statistically significant causal relationship with precocious puberty. The IVW method showed an OR of 0.707 (p=0.885) for arterial stiffness, indicating no reliable association. The investigation into MMP2 also yielded non-significant results across all methods, with an OR of 0.778 (p=0.330) from the IVW method. However, the analysis of MMP9 revealed a significant association with precocious puberty, showing an OR of 3.89 (p=0.004) using the IVW method, and an OR of 3.96 (p=0.027) from the Weighted Median method, indicating a strong positive effect of MMP9 on precocious puberty risk.

Conclusions

Our findings suggest that while arterial stiffness and other MMPs do not have a significant causal role, MMP9 may significantly increase the risk of precocious puberty in girls.

Keywords: precocious puberty; Mendelian randomization; arterial stiffness; MMP9; CD40; uterine artery pulsatility index

Corresponding author: Fengfeng Qi, Department of Pediatrics, Huzhou Maternity & Child Health Care Hospital, No. 2 East Street, Wuxing District, Huzhou City, 313000, Zhejiang, China, E-mail: qiff2006@126.com

Acknowledgments

This study was supported by a public welfare research project (Application of Uterine Arterial Pulsatility Index in Diagnosis and Treatment Monitoring of Early Precocious Puberty in Spring Girls), with the project number of 20223 GY 03.

Research ethics: The study was approved by the Ethics Committee of Huzhou Maternity and Child Care Hospital Zhejiang.
Informed consent: Not applicable.
Author contributions: YG and FFQ were involved in the conception and design, or analysis and interpretation of the data; YG the drafting of the paper, revising it critically for intellectual content; FFQ the final approval of the version to be published; and that all authors agree to be accountable for all aspects of the work. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: None declared.
Data availability: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2025-02-14

Accepted: 2025-05-13

Published Online: 2025-09-26

Published in Print: 2025-11-25

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https://doi.org/10.1515/jpem-2025-0073

Keywords for this article

precocious puberty; Mendelian randomization; arterial stiffness; MMP9; CD40; uterine artery pulsatility index