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Hormone and reproductive factors and risk of systemic lupus erythematosus: a Mendelian randomized study

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with a risk associated with hormonal and reproductive factors. However, the potential causal effects between these factors and SLE remain unclear. A two-sample Mendelian randomization study was conducted using the published summary data from the genome-wide association study database. Five independent genetic variants associated with hormonal and reproductive factors were selected as instrumental variables: age at menarche, age at natural menopause, estradiol, testosterone, and follistatin. To estimate the causal relationship between these exposure factors and disease outcome, we employed the inverse-variance weighted, weighted median, and MR-Egger methods. In addition, we carried out multiple sensitivity analyses to validate model assumptions. Inverse variance weighted showed that there was a causal association between circulating follistatin and SLE risk (OR = 1.38, 95% CI 1.03 to 1.86, P = 0.033). However, no evidence was found that correlation between AAM (OR = 1.04, 95% CI 0.77 to 1.40, P = 0.798), ANM (OR = 0.99, 95% CI 0.92 to 1.06, P = 0.721), E2 (OR = 1.40, 95% CI 0.14 to 13.56, P = 0.772), T (OR = 1.25, 95% CI 0.70 to 2.28, P = 0.459), and SLE risk. Our study revealed that elevated circulating follistatin associates with an increased risk of SLE. This finding suggests that the regulatory signals mediated by circulating follistatin may provide a potential mechanism relevant to the treatment of SLE.

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Data availability

The datasets analyzed in this study can be retrieved from the public GWAS summary database (https://gwas.mrcieu.ac.uk/). Data are available upon reasonable request. Obtaining the data, you can contact the first author at changrunyu0302@163.com.

Abbreviations

SLE:

Systemic lupus erythematosus

AAM:

Age at menarche

ANM:

Age at natural menopause

E2:

Estradiol

T:

Testosterone

FST:

Follistatin

ER:

Estrogen receptors

BMI:

Body mass index

SES:

Socioeconomic status

OR:

Odds ratio

RR:

Risk ratio

CI:

Confidence interval

GWAS:

Genome-wide association study

IVs:

Instrumental variables

SNP:

Single-nucleotide polymorphism

IVW:

Inverse variance weighted

WM:

Weighted median

LD:

Linkage disequilibrium

MR:

Mendelian randomization

PRESSO:

Pleiotropy Residual Sum and Outlier

GCKR:

Glucokinase regulatory protein

GCK:

Glucokinase

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Acknowledgements

The authors express their gratitude to the participants and investigators of the ReproGen Consortium. The authors also appreciate the ReproGen Consortium and UK Biobank for releasing the GWAS summary statistics.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81973778).

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Author notes

  1. Runyu Chang, Shate Xiang and Yibo Jin contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Runyu Chang, Shate Xiang, Yibo Jin, Xiaofen Xu, Suhai Qian, Lingfeng Chen, Chao Hu & Xinghong Ding

  2. The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Yufeng Shi

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  1. Runyu Chang
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Contributions

Conceptualization: X.D. and R.C.; methodology: R.C., S.X., and X.D.; software: R.C., S.X., and Y.J.; validation: R.C. and Y.J.; formal analysis: S.X., R.C., and X.X.; investigation: Y.J.; resources: X.D.; data curation: R.C., S.X., and L.C.; writing—original draft preparation: R.C. and S.Q.; writing—review and editing: R.C., S.X., and X.D.; visualization: R.C., C.H., and Y.J.; supervision: Y.S. and X.D.; project administration: X.D.; funding acquisition: X.D. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Yufeng Shi or Xinghong Ding.

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The authors declare no competing interests.

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The aggregated statistical data used in this study are sourced from publicly available databases (https://gwas.mrcieu.ac.uk/). All original studies have obtained approval from the relevant ethical review committees. Furthermore, this study does not utilize individual-level data. Therefore, no new ethical approval is required.

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Chang, R., Xiang, S., Jin, Y. et al. Hormone and reproductive factors and risk of systemic lupus erythematosus: a Mendelian randomized study. Immunol Res (2024). https://doi.org/10.1007/s12026-024-09470-z

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