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. 2024 Jun 28:15:1398600.
doi: 10.3389/fendo.2024.1398600. eCollection 2024.

Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization

Zilong Tan  1 , Jianwu Shen  1   2 , Yuxiao Huang  3 , Junru Li  4 , Mengdi Ding  1 , Aochuan Sun  5 , Jing Hong  6 , Yan Yang  7 , Sheng He  8 , Xueying Zhu  3 , Ran Luo  3
Affiliations

Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization

Zilong Tan et al. Front Endocrinol (Lausanne). .

Abstract

Background: Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain.

Objective: This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations.

Methods: We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality.

Results: We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (β=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (β=-0.127), showed an indirect effect on infertility mediated by SUA (β=-0.0187; 95% CI, -0.041 to -0.003; P=0.046).

Conclusion: Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.

Keywords: European; endocrinology; female infertility; genome wide association; mediated Mendelian randomization; metabolism.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Genetic instrument selection of single-variable Mendelian randomization study.
Figure 2
Figure 2
Schematic diagram of the study design. SUA was used as an exposure factor, sex hormone-related phenotypes was used as the mediators, and female infertility was used as an outcome factor; IV, instrument variable.
Figure 3
Figure 3
Schematic diagram of the study design. sex hormone-related phenotypes were used as the exposure factors, SUA was used as the mediator, and female infertility was used as an outcome factor; IV, instrument variable.
Figure 4
Figure 4
The relationship between different phenotypes was analyzed by bidirectional two-sample and mediated Mendelian randomization; IVW, inverse-variance weighting.
See this image and copyright information in PMC

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