Whole-exome sequencing reveals novel variants associated with abnormal uterine bleeding caused by copper intrauterine device

Abstract

Aim: This study aimed to explore the genetic risk factors and validate variants of abnormal uterine bleeding after copper intrauterine device insertion. Methods: Whole-exome sequencing was performed and several variants were validated by Sequenom MassARRAY. Results: Eight variants showed potential clinical damage according to American College of Medical Genetics and Genomics criteria. By combined analysis of screening and validation, NFASCRS2802808C>G p.Ile971Met (P_allele = 0.009 and P_genotype = 0.027) and PIGRRS2275531C>T p.Gly365Ser (P_allele = 0.009 and P_genotype = 0.013) variants were identified as significantly associated with abnormal uterine bleeding with a false discovery rate <0.05. NFASC and PIGR may play a role in abnormal uterine bleeding by regulating coagulation fibrinolysis and endometrial epithelium inflammation functions. Conclusion: These findings provide a genetic basis for clinical individualization and precision of intrauterine device implantation.

Plain language summary

Abnormal uterine bleeding (AUB) after Cu intrauterine device (Cu-IUD) insertion is the most common side effect of Cu-IUD use. AUB is a multifactorial process that relates to endometrial-related genetic factors, ovulatory function-related genetic factors, coagulation, the fibrinolytic system, contraction of the uterine arteries and endometritis inflammatory factor. This is the first study to explore the underlying genetic mechanisms of AUB related to the use of Cu-IUDs by whole-exome sequencing in the Chinese Han population. The authors found that variants of NFASC and PIGR genes were significantly associated with AUB in women using Cu-IUDs. NFASC and PIGR may be involved in coagulation fibrinolysis and endometrial epithelium inflammation functions, indicating its potential functions in AUB. This study could provide a genetic basis for studies on the individualization and precision of IUD use in the future.

Tweetable abstract

This study found the underlying genetic mechanism of abnormal uterine bleeding in Chinese Han Cu-intrauterine devices users. By using sequencing techniques, NFASC and PIGR gene variants may lead to bleeding by regulating coagulation fibrinolysis and endometrial epithelium inflammation functions.

Keywords::

• abnormal uterine bleeding
• Cu intrauterine devices
• genetic
• SNVs
• whole-exome sequencing

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/pme-2022-0060

Author contributions

Y Shen was responsible for the acquisition of data, analysis and interpretation of data, drafting of the article and critical revision for important intellectual content. X Liu, L Xu, W Zhu, Z Zhang, J Liu, L Jiang, Y Mao, J Xu, X Yan, J Sun, F Liu, X Xiong and X Chen contributed to the acquisition of data. W Zhu and J Liu contributed to the drawing of several figures. J Du and Y Che were responsible for conception and design of the study, critical revision of the manuscript for important intellectual content and final approval of the version to be submitted.

Acknowledgments

The authors thank the many women who participated in the study.

Financial & competing interests disclosure

This work was supported by the Innovation-Oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2017-03). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

Ethical approval was obtained from the medical ethical committee, Shanghai Institute of Planned Parenthood Research (PJ2017-03).

Availability of data & materials

The authors declare that the data supporting the findings of this study are available within the article and on request from the corresponding authors. The whole-exome sequencing data have been submitted to the Sequence Read Archive (PRJNA719775).

Additional information

Funding

This work was supported by the Innovation-Oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2017-03). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.