Causal relationship between sex hormone-binding globulin, 25-hydroxyvitamin D and polycystic ovary syndrome: a two-sample bidirectional Mendelian randomization study

doi:10.21203/rs.3.rs-5032941/v1

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Causal relationship between sex hormone-binding globulin, 25-hydroxyvitamin D and polycystic ovary syndrome: a two-sample bidirectional Mendelian randomization study

https://doi.org/10.21203/rs.3.rs-5032941/v1

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Many studies have reported that sex hormone-binding globulin (SHBG) and 25-hydroxyvitamin D (25(OH)D) are important factors affecting polycystic ovary syndrome (PCOS), but their interrelationship remains controversial. Our study employed bidirectional Mendelian randomization analysis to elucidate the causal relationships between SHBG, 25(OH)D, and PCOS. The genetic loci closely related to SHBG, 25(OH) D and PCOS were extracted from large-sample GWAS data as instrumental variables. Five algorithms, namely, MR‒Egger regression, weighted median, inverse variance weighting (IVW), simple mode and weighted mode, were used for bidirectional Mendelian randomization analysis. In addition, the Cochran Q test was used to evaluate heterogeneity, the MR‒Egger intercept plot and the funnel plot were used to test horizontal pleiotropy, and sensitivity analysis was performed with the leave-one-out method to evaluate whether there was a correlation between SHBG, 25(OH)D and PCOS. We found that a decrease in SHBG and 25(OH) D levels is a genetic susceptibility factor for PCOS, whereas PCOS does not lead to a change in SHBG and 25(OH) D levels. In addition, a positive causal relationship was found between SHBG and 25(OH) D, with a decrease in SHBG leading to a corresponding decrease in 25(OH) D, whereas the change in SHBG was independent of 25(OH) D.

Sex hormone-binding globulin

25-hydroxyvitamin D

Polycystic ovary syndrome

Mendelian randomization

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy, with a global prevalence ranging from 11–13%. The disease affects mainly women of reproductive age and is the main cause of female infertility¹. The main manifestations of this disease are hyperandrogenaemia, persistent anovulation and polycystic ovarian changes, which are often accompanied by metabolic disorders, such as type 2 diabetes and cardiovascular disease^2–4. PCOS has strong genetic and epigenetic susceptibility, but its pathogenesis remains unclear^5,6. It has been suggested that decreased sex hormone-binding globulin (SHBG) levels increase the bioavailability of androgens, which can lead to ovarian lesions, cause ovarian anovulation, and promote the progression of PCOS phenotypic characteristics⁷. In addition, 25(OH) D was found to be positively correlated with SHBG in a clinical cohort study of PCOS patients. Moreover, 25-hydroxyvitamin D (25(OH)D) was found to be positively correlated with SHBG in a clinical cohort of PCOS patients⁸.

Epidemiological studies on the relationship between SHBG and PCOS have shown that a single nonfasting measurement of SHBG has excellent accuracy in diagnosing PCOS⁹ and that SHBG can be used as an early biomarker for the diagnosis of PCOS^10,11. However, other studies have shown that, compared with that in the control group, the serum SHBG level in the PCOS group was lower, but the difference was not significant (p = 0.936)¹². A genetic case‒control association study suggested that SHBG was a candidate gene for PCOS¹³ and that PCOS was significantly associated with the (TAAAA)n polymorphism of the SHBG gene promoter¹⁴. However, another meta-analysis revealed no association between the (TAAAA)n repeat polymorphism and PCOS risk¹⁵. It is still controversial whether SHBG polymorphisms are related to the incidence of PCOS.

In studies related to 25(OH)D, it has been reported that the majority of PCOS patients have insufficient or deficient levels of vitamin D¹⁶. Supplementation with vitamin D can improve serum 25(OH)D levels in women with PCOS, and high-dose vitamin D (4000 IU) has been shown to have beneficial effects on SHBG^17,18. However, studies have suggested that supplementation with vitamin D does not affect SHBG levels in PCOS patients^19,20,21.

However, studies have revealed that there is a correlation between SHBG, 25(OH)D and PCOS. However, neither the direction nor the causal chain is fully understood. Therefore, by utilizing inherent genetic variation, Mendelian randomization can be used as a robust statistical method to evaluate the causal relationships among SHBG, 25(OH)D, and PCOS. Mendelian randomization is superior to traditional observation methods in controlling the potential bias of confounders and reverse causality and can provide more reliable evidence for establishing the causal relationships among SHBG, 25(OH)D and PCOS. Our study aims to investigate the causal relationship between SHBG, 25(OH)D, and PCOS through a two-sample bidirectional Mendelian randomization analysis. This will provide valuable insights for the diagnosis and treatment of PCOS, particularly in terms of dietary and nutritional supplement recommendations.

2.1 Data sources and summary

The genome-wide association study (GWAS) data for SHBG, 25(OH)D, and PCOS are sourced from the IEU Open GWAS database. The polycystic ovary syndrome (PCOS) data (ebi-a-GCST90044902) were derived from 141,355 cases, covering 229,81890 single nucleotide polymorphisms (SNPs). The sex hormone binding globulin (SHBG) data (ieu-b-4870) were obtained from 214,989 cases and encompassed 12,321875 SNPs. The serum 25-hydroxyvitamin D (25(OH)D) level data (ebi-a-GCST90000617) originated from 417580 patients and included 8,401108 SNPs. This study was conducted using publicly published shared data that had received ethical approval and informed consent. No additional ethical approval is needed.

2.2 Study design

The design flow chart of this two-sample bidirectional Mendelian randomization study is shown in Fig. 1. The instrumental variable (IV) in Mendelian randomization analysis must simultaneously satisfy the following core assumptions: ① close correlation between the IV and exposure factor; ② independence of the IV from confounding factors; ③ exclusive influence of the IV on outcomes through the exposure factor. In this Mendelian randomization analysis, a significance threshold for SNPs was set at p < 5 × 10^− 8, and SNPs with low linkage disequilibrium (r² < 0.001, kb = 10000) were excluded. Additionally, SNPs significantly associated with outcomes were removed, and proxy SNPs were not utilized. In forward Mendelian randomization analysis, the exposure factors were SHBG and 25(OH)D, and the outcome was PCOS. In the reverse Mendelian randomization analysis, the exposure factor was PCOS, and the outcome was SHBG, 25(OH)D. In addition, the relationship between SHBG and 25(OH)D was analyzed bidirectionally by Mendelian randomization. The F statistic of each SNP was evaluated (F = β²_exposure/SE²_exposure), and SNPs with F < 10 were deleted to ensure the reliability of the method.

2.3 Statistical analysis

In this study, five algorithms, namely, MR‒Egger regression, weighted median, inverse variance weighting (IVW), simple mode and weighted mode, are used to carry out Mendelian randomization analysis, with IVW as the main analysis method. The Cochran Q test was used to evaluate heterogeneity, the MR‒Egger intercept plot and funnel plot were used to test horizontal pleiotropy, and one method was used for sensitivity analysis to determine the reliability of the Mendelian randomization results. All the analyses were performed in R (version 4.0.3), and the R package TwoSampleMR (version 0.5.5) was used for all the statistical analyses.

3.1 Causal relationship of forward Mendelian randomization between SHBG and 25(OH)D with the risk of PCOS

After filtering, 155 independent SNPs of SHBG were identified as IV (Supplement Table 1), and 93 independent SNPs of 25(OH) D were identified as IV (Supplement Table 2). The forward Mendelian randomization results revealed causal relationships between SHBG and PCOS (p = 9.923E-06) and between 25(OH) D and PCOS (p = 0.031) (Table 1). According to the IVW method, SHBG (OR = 0.738, 95% CI = 0.645 ~ 0.844) and 25(OH) D (OR = 0.764, 95% CI = 0.599 ~ 0.975) were identified as protective factors for PCOS. The scatter plot shows that confounding factors have little effect on the confidence of the forward Mendelian randomization analysis due to the negligible intercept, and the slope based on the IVW method is negative, indicating that SHBG and 25(OH)D are protective factors for PCOS. Forest maps were created to evaluate the diagnostic efficiency of each SNP of SHBG and 25(OH)D for the treatment of PCOS. SNPs of SHBG and 25(OH) D were significantly skewed to the left in the total MR‒Egger and total IVW models, suggesting that SHBG and 25(OH) D were potential favorable factors for PCOS. In addition, the funnel plot results show that the results of the forward Mendelian randomization analysis of the effects of SHBG and 25(OH)D on the causality of PCOS conforms to the second law of Mendelian randomization (Fig. 2).

Table 1

Forward Mendelian randomization results of SHBG and 25(OH)D on the risk of PCOS
Exposure	Outcome	nSnp	pval	OR	OR_lci95	OR_uci95
SHBG
MR Egger	PCOS	155	0.352	0.893	0.705	1.132
Weighted median	PCOS	155	0.008	0.733	0.584	0.922
Inverse-variance weighted	PCOS	155	9.923E-06	0.738	0.645	0.844
Simple mode	PCOS	155	0.050	0.597	0.358	0.996
Weighted mode	PCOS	155	0.011	0.687	0.516	0.915
25(OH)D
MR Egger	PCOS	93	0.350	0.828	0.559	1.227
Weighted median	PCOS	93	0.370	0.835	0.562	1.239
Inverse-variance weighted	PCOS	93	0.031	0.764	0.599	0.975
Simple mode	PCOS	93	0.399	0.761	0.404	1.432
Weighted mode	PCOS	93	0.303	0.827	0.578	1.184

3.2 Causal relationship of forward Mendelian randomization between SHBG and 25(OH)D

After filtering, 176 individual SNPs of SHBG were identified as IVs (supplemental Table 3). The forward Mendelian randomization results revealed a causal relationship between SHBG and 25(OH)D (p = 0.004) (Table 2). According to the IVW method, SHBG (OR = 1.040, 95% CI = 1.013 ~ 1.068) was identified as a positive correlation factor for 25(OH) D. The slope of the scatter plot is positive, and the forest plot shows that the SNP of SHBG skews significantly to the right in the total MR‒Egger and total IVW models. The funnel plot results show that the forward Mendelian randomization analysis of the causal effect of SHBG on 25(OH)D conforms to the Mendelian second law of randomization (Fig. 3).

Table 2

Forward Mendelian randomization results of SHBG and 25(OH)D
Exposure	Outcome	nSnp	pval	OR	OR_lci95	OR_uci95
SHBG
MR Egger	25(OH)D	176	0.228	1.032	0.980	1.087
Weighted median	25(OH)D	176	0.004	1.033	1.010	1.056
Inverse-variance weighted	25(OH)D	176	0.004	1.040	1.013	1.068
Simple mode	25(OH)D	176	0.097	1.057	0.990	1.128
Weighted mode	25(OH)D	176	0.072	1.029	0.998	1.062

3.3 Verification of the reliability of the forward Mendelian randomization results via sensitivity analysis

Sensitivity analysis of forward Mendelian randomization results revealed that SHBG (Q_pval = 0.405) and 25(OH) D (Q_pval = 0.736) had no significant heterogeneity in the incidence of PCOS. Although there was heterogeneity between SHBG and 25(OH) D (Q_pval = 8.170E-136), it had no effect on the IVW results, so the conclusions of the Mendelian randomization analysis were reliable (Table 3). Moreover, there was no evidence that SHBG (p = 0.058) and 25(OH) D (p = 0.610) were associated with the onset of PCOS, and SHBG was associated with 25(OH) D (p = 0.732) in horizontal polymorphisms (Table 4). The LOO method was used to evaluate the influence of each SNP on the Mendelian randomization results, and the results revealed no serious bias (Fig. 4). Therefore, the forward Mendelian randomization results have proven reliable.

Table 3

Sensitivity analysis based on the heterogeneity test
Exposure	Outcome	Q	Q_df	Q_pval
SHBG
MR Egger	PCOS	153.9	153	0.464
Inverse-variance weighted	PCOS	157.6	154	0.405
25(OH)D
MR Egger	PCOS	82.83	91	0.717
Inverse-variance weighted	PCOS	83.09	92	0.736
SHBG
MR Egger	25(OH)D	1110	174	4.434E-136
Inverse-variance weighted	25(OH)D	1111	175	8.170E-136

Table 4

Sensitivity analysis based on the horizontal pleiotropy test
Exposure	Outcome	Egger_intercept	se	pval
SHBG	PCOS	-0.0085	0.0045	0.058
25(OH)D	PCOS	-0.0027	0.0053	0.610
SHBG	25(OH)D	0.00031	9E-04	0.732

3.4 Reverse Mendelian randomization analysis revealed that PCOS had no causal relationship with SHBG or 25(OH) D and that 25(OH) D had no causal relationship with SHBG

For reverse Mendelian randomization analysis, in the Mendelian randomization analysis of PCOS and SHBG, 4 independent SNPs were selected as IVs after filtering (supplementary Table 4). In the Mendelian randomization analysis of PCOS and 25(OH) D, 2 independent SNPs were selected as IVs after filtering (supplementary Table 5). In the Mendelian randomization analysis of 25(OH) D and SHBG, 106 independent SNPs were selected as IVs after filtering (supplementary Table 6). The results of reverse Mendelian randomization revealed that the p values between PCOS and SHBG (p = 0.504), PCOS and 25(OH) D (p = 0.738), and 25(OH) D and SHBG (P = 0.224) were not statistically significant (Table 5). This finding indicates that there is no causal relationship between PCOS as an exposure factor and SHBG, 25(OH) D as a result, and 25(OH) D as an exposure factor and SHBG as a result.

Table 5

Reverse Mendelian randomization results of the effects of PCOS on the risk of SHBG/25(OH)D and 25(OH)D in the SHBG
Exposure	Outcome	nSnp	pval	OR	OR_lci95	OR_uci95
PCOS
MR Egger	SHBG	4	0.233	0.943	0.880	1.010
Weighted median	SHBG	4	0.491	0.992	0.971	1.014
Inverse-variance weighted	SHBG	4	0.504	0.994	0.975	1.012
Simple mode	SHBG	4	0.390	0.982	0.947	1.018
Weighted mode	SHBG	4	0.398	0.981	0.945	1.019
PCOS
Inverse-variance weighted	25(OH)D	2	0.738	1.004	0.980	1.029
25(OH)D
MR Egger	SHBG	106	0.868	0.982	0.797	1.210
Weighted median	SHBG	106	0.103	1.039	0.992	1.088
Inverse-variance weighted	SHBG	106	0.224	1.086	0.951	1.242
Simple mode	SHBG	106	0.567	1.025	0.942	1.115
Weighted mode	SHBG	106	0.022	1.051	1.008	1.096

Our two-sample bidirectional Mendelian randomization study provides new evidence for the causal relationship between SHBG, 25(OH)D and PCOS. We found that a decrease in SHBG and 25(OH) D levels is a genetic susceptibility factor for PCOS, whereas PCOS does not lead to a change in SHBG and 25(OH) D levels. In addition, a positive causal relationship was found between SHBG and 25(OH) D, with a decrease in SHBG leading to a corresponding decrease in 25(OH) D, whereas the change in SHBG was independent of 25(OH) D.

One cross-sectional study of women with PCOS revealed that low serum 25(OH)D levels were common in women with PCOS²², and another study reported that both SHBG and serum 25(OH)D levels were reduced in women with PCOS²³. In a study of 1,000 women with PCOS from 21 research centers in China, SHBG showed predictive power for ovulation, conception, pregnancy, and live birth, and higher baseline SHBG levels were associated with increased ovulation²⁴. However, other studies have reached different conclusions. A study on two different PCOS subtypes revealed that the SHBG levels of different subtypes were different, among which the SHBG level of the "reproductive" group was greater, whereas the SHBG level of the "metabolic" group was lower²⁵. Our findings support the role of reduced SHBG and 25(OH)D levels in promoting the pathogenesis of PCOS, but due to the lack of data on specific PCOS subtypes in the GWAS database, further analysis of differences between subgroups is currently not possible.

In terms of the pathogenesis of PCOS promoted by 25(OH) D and SHBG, oxidative stress inhibits the expression and secretion of SHBG by downregulating HNF-4α in vitro, which may be an important factor in promoting hyperandrogenaemia in patients with PCOS²⁶. In addition, the AMPK signaling pathway can affect SHBG synthesis by regulating HNF-4α expression²⁷. Some studies have shown that 25(OH) D levels and SHBG levels in PCOS patients can be regulated by medication. Pioglitazone can increase SHBG levels in PCOS patients by upregulating HNF-4α²⁸. Vitamin D supplementation can restore physiological serum 25(OH)D levels in women with PCOS and significantly reduce hirsute scores and androgen levels in women with PCOS²⁹. Our study demonstrated the role of decreased SHBG and 25(OH)D levels in promoting the pathogenesis of PCOS, but the specific mechanism leading to the pathogenesis of PCOS and the impact of drug intervention need further clinical and experimental studies.

In addition, most studies on 25(OH) D and SHBG have focused on clinical observations of the changes in the levels of these two indicators, and few studies have investigated the interaction between 25(OH) D and SHBG, especially the specific mechanism of action between 25(OH) D and SHBG in PCOS patients. Our reverse Mendelian randomization analysis revealed that a decrease in SHBG leads to a corresponding decrease in 25(OH) D, whereas a change in SHBG is independent of 25(OH) D, providing more robust preliminary evidence of an association.

However, our study has several limitations. The exact biological mechanism of SHBG and 25(OH)D in the pathogenesis of PCOS cannot be determined on the basis of the analysis of Mendelian randomization. In this study, the PCOS data in this study were mainly for the European population, so whether the results can be extended to other groups remains to be confirmed. In addition, owing to the lack of individual PCOS subtype data, it is not possible to analyze the causal relationship between SHBG and 25(OH) D and the risk of developing different subtypes of PCOS. With the emergence of larger sample GWAS data and improvements in data on different subtypes of PCOS, the above problems may be improved in the future. The next step is to clarify the potential mechanism of SHBG and 25(OH)D in the pathogenesis of PCOS and the interaction between SHBG and 25(OH)D through large-scale randomized controlled trials and animal experiments.

In summary, our study confirms that genetic susceptibility to PCOS is associated with decreased SHBG and 25(OH) D and that decreased SHBG leads to a corresponding decrease in 25(OH) D. Therefore, SHBG and 25(OH) D can be identified as protective factors for PCOS, and the influence of SHBG on 25(OH) D should be considered.

AUTHOR CONTRIBUTIONS

Yan Ou and Yan Li designed the study. Yan Ou and Xi Zhang analyzed the data. Yan Ou, Xiao Liu, Qi Wang, Xiaomin Wen and Yong Liang interpreted the results and drafted the manuscript. All the authors revised the manuscript and approved the final version.

ACKNOWLEDGMENTS

We thank all the participants, researchers and staff of the open GWAS database who made this study possible.

FUNDING INFORMATION

This study was funded by Wang Qi Guizhou Famous Traditional Chinese Medicine Inheritance Studio Sinan Ethnic Chinese Medicine Hospital Workstation (Qian Traditional Chinese Medicine Letter [2024]39)

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no competing interests.

DATA AVAILABILITY STATEMENT

The genome-wide association study (GWAS) summary data on SHBG, 25(OH)D and PCOS were retrieved from the Integrative Epidemiology Unit OpenGWAS database (https://gwas.mrcieu.ac.uk/).

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Causal relationship between sex hormone-binding globulin, 25-hydroxyvitamin D and polycystic ovary syndrome: a two-sample bidirectional Mendelian randomization study

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Abstract

Figures

1 INTRODUCTION

2 METHODS

2.1 Data sources and summary

2.2 Study design

2.3 Statistical analysis

3 RESULTS

3.1 Causal relationship of forward Mendelian randomization between SHBG and 25(OH)D with the risk of PCOS

3.2 Causal relationship of forward Mendelian randomization between SHBG and 25(OH)D

3.3 Verification of the reliability of the forward Mendelian randomization results via sensitivity analysis

4 DISCUSSION

5 CONCLUSION

Declarations

References

Additional Declarations

Supplementary Files

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