Potential Causal Association between Plasma Metabolites, Immunophenotypes, and Female Reproductive Disorders: A Two-Sample Mendelian Randomization Analysis

Author:

Shen Hui-Hui1,Zhang Yang-Yang12ORCID,Wang Xuan-Yu3,Wang Cheng-Jie4,Wang Ying5,Ye Jiang-Feng6,Li Ming-Qing127ORCID

Affiliation:

1. Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China

2. Shanghai Medical College, Fudan University, Shanghai 200032, China

3. College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 10, Poyang Lake Road, Tuanpo Xinchengxi District, Jinghai District, Tianjin 301617, China

4. Department of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China

5. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Ji’nan 250012, China

6. Institute for Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138632, Singapore

7. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China

Abstract

Background: While extensive research highlighted the involvement of metabolism and immune cells in female reproductive diseases, causality remains unestablished. Methods: Instrumental variables for 486 circulating metabolites (N = 7824) and 731 immunophenotypes (N = 3757) were derived from a genome-wide association study (GWAS) meta-analysis. FinnGen contributed data on 14 female reproductive disorders. A bidirectional two-sample Mendelian randomization study was performed to determine the relationships between exposures and outcomes. The robustness of results, potential heterogeneity, and horizontal pleiotropy were examined through sensitivity analysis. Results: High levels of mannose were found to be causally associated with increased risks of gestational diabetes (GDM) (OR [95% CI], 6.02 [2.85–12.73], p = 2.55 × 10−6). A genetically predicted elevation in the relative count of circulating CD28−CD25++CD8+ T cells was causally related to increased female infertility risk (OR [95% CI], 1.26 [1.14–1.40], p = 1.07 × 10−5), whereas a high absolute count of NKT cells reduced the risk of ectopic pregnancy (OR [95% CI], 0.87 [0.82–0.93], p = 5.94 × 10−6). These results remained consistent in sensitivity analyses. Conclusions: Our study supports mannose as a promising GDM biomarker and intervention target by integrating metabolomics and genomics.

Funder

National Key Research and Development Program of China

Major Research Program of National Natural Science Foundation of China

Shanghai Natural Science Foundation

Program for Zhuoxue of Fudan University

Publisher

MDPI AG

Subject

Molecular Biology,Biochemistry

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