Exploring the causal relationship between ankylosing spondylitis and common andrological diseases based on Mendelian randomization

doi:10.21203/rs.3.rs-3456511/v1

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Exploring the causal relationship between ankylosing spondylitis and common andrological diseases based on Mendelian randomization

https://doi.org/10.21203/rs.3.rs-3456511/v1

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Objective: This study was designed to analyze the causal relationship between ankylosing spondylitis and common male diseases (male infertility, prostatic hyperplasia, prostatitis, erectile dysfunction, orchitis and epididymitis, sexual dysfunction and sperm cyst) using Mendelian randomization and to provide suggestions for clinical prevention and treatment.

Methods and materials: A summary dataset of genome-wide association studies was used for the method study. Mendelian randomization was performed using inverse variance weighting, weighted median, and MR‒Egger regression analysis to assess the causal relationship between ankylosing spondylitis and common andrological diseases. Heterogeneity was tested using the Cochran Q method, pleiotropic properties were tested using the MR‒Egger and MR-PRESSO methods, and sensitivity was tested using the leave-one-out method.

Results: The results showed that the risk of male infertility in patients with ankylosing spondylitis was 2.389 times that in patients Non-ankylosing spondylitis (OR=2.389, 95% CL: 1.334–4.278, P=0.034), and the risk of prostatic hyperplasia was correspondingly increased (OR=1.260, 95% CL: 1.057–1.501, P=0.009), without a significant causal relationship with other common male diseases. The results of the MR‒Egger analysis and the weighted median method were not significant. The results from the Cochran Q method showed no heterogeneity of the included SNPs. The results from the MR‒Egger and MR-PRESSO methods indicated that there was no horizontal pleiotropic effect between exposure and outcome variables. The results of the sensitivity analysis with the one-stay method were stable, and no strong impact of SNP sites in instrumental variables on the results was detected.

Limitations: Additional research is imperative.

Conclusion: There is a positive causal relationship between ankylosing spondylitis and male infertility, and benign prostate hyperplasia. Suffering from ankylosing spondylitis will increase the risk of male infertility and BPH.

Mendelian randomization

Ankylosing spondylitis

Male infertility

Prostatic hyperplasia

Ankylosing spondylitis (AS) is a rheumatic disease mainly characterized by chronic inflammation of the medial axis joints. It belongs to the category of chronic inflammatory diseases, with the main symptoms of pain and stiffness in the axial spine joint and sacroiliac joint. Along with the gradual aggravation of the disease, it will evolve into joint stiffness and deformity. Epidemiological studies show^[1] that the population with concentrated AS was under 30 years old and mainly male. The incidence rate in China is approximately 0.22%, and the number of people suffering from this disease is more than 4 million. Common andrological diseases include male infertility, benign prostatic hyperplasia, prostatitis and many other diseases, which are caused by long-term bad habits, and most of them are chronic diseases, which have been reported in some articles^[2]. The incidence of male diseases increases by 3% every year, and male fertility declines every year. Therefore, how to improve the quality of male fertility problems needs to be solved. As one of the main hormones that maintains male secondary sexual characteristics, testosterone can promote the improvement of male sperm quality and density^[3]. Male sex hormones, especially testosterone, are the key factors for common andrological diseases. Gonadal degeneration due to changes in testosterone levels is one of the most common causes of common male disease problems^[4]. In recent years, studies have shown that bone loss in patients with AS may be related to an intermediate product in testosterone biosynthesis^[5]. It has also been reported that men with hypogonadism have a much higher incidence of rheumatism/autoimmune diseases than normal men^[6]. Combined with this research, it can be concluded that there may be an association between ankylosing spondylitis and common male diseases, but whether there is a causal relationship remains controversial.

The lack of random allocation in observational studies results in lower reliability of results, while randomized controlled trials have certain limitations due to various clinical limiting factors. Mendelian randomization (MR) is an analytical method using instrumental variables (IVs) to assess the causal relationship between exposure and outcome^[7] and can effectively reduce the influence of potential confounding factors and eliminate the interference of reverse causality, making the results more reliable and accurate^[8]. In recent years, an increasing amount of data containing information on genetic variation related to exposure and disease has been summarized and published, and these data can be used as instrumental variables for MR analysis^[9]. Therefore, the causal relationship between exposure and disease can be estimated more accurately, and a more reliable scientific basis is provided for disease prevention and treatment. Therefore, the Mendelian randomization method was adopted in this study as the basis for exploring the relationship between ankylosing spondylitis and common male diseases.

2.1 Research design

In this study, ankylosing spondylitis was used as the exposure factor, and single nucleotide polymorphisms (SNPs) with significant correlations were used as IVs. Common male diseases (male infertility, prostatic hyperplasia, prostatitis, erectile dysfunction, orchitis and epididymitis, sexual dysfunction and sperm cysts) were selected as outcome variables. Causal association analysis was performed using the TwoSampleMR package in R, and sensitivity analysis was performed to verify the reliability of the results.

2.2 Data sources

Data on ankylosing spondylitis were derived from pooled data from independent European populations in the British Biological Sample Bank database. Data on male infertility, benign prostatic hyperplasia, prostatitis, erectile dysfunction, orchitis and epididymitis, sexual dysfunction and sperm cysts were obtained from pooled data from independent European populations in the Finnish database. Relevant data information is shown in Table 1.

Table 1

Summary Information of Study Data
variable	ID	Sample size(person)		race	age
ankylosing spondylitis	ebi-a-GCST005529	22647	99962	Europeans	2017
Male infertility	finn-b-N14_MALEINFERT	73479	16377329	Europeans	2021
hyperplasia of prostate	finn-b-N14_PROSTHYPERPLA	42439	16377460	Europeans	2021
prostatitis	finn-b-N14_PROSTATITIS	74658	16377460	Europeans	2021
Erectile dysfunction	ebi-a-GCST006956	223805	9310196	Europeans	2018
Orchitis and epididymitis	finn-b-N14_ORHCEPINDIDYMITIS	74096	16377371	Europeans	2021
sexual dysfunction	finn-b-F5_SEXDYSSEXDYS	213986	16380450	Europeans	2021
spermatocele	finn-b-N14_SPERMATOCELE	73860	16377353	Europeans	2021

2.3 Screening of instrumental variables

To avoid losing the strong correlation between SNPs and common male diseases, instrumental variables were obtained on the website using R software, i.e., the strong linkage disequilibrium (LD) between SNPs might cause analysis bias. We used genome-wide association research (GWAS) to find SNPs significantly associated with common male diseases by comparing the genomic sequences of patients with common male diseases with those of healthy control groups. (P < 5 × 10 − 8, R2 < 0.001, genetic distance M = 10000 kB). The heterogeneity test was performed to eliminate the significantly heterogeneous SNPs, and finally, the tool variable of significantly associated SNPs of common male diseases was obtained.

2.4 MR analysis

In this study, three analytical methods, including random effect inverse variance addition (IVW), MR‒Egger regression and weight median estimator (WME), were used to infer the causal relationship between ankylosing spondylitis and common male diseases. IVW is a widely used method for calculating the weighted average of the effect values of instrumental variables, which shows extremely high reliability in MR analysis. The weighted average method assigns different weights to each index according to the importance degree and then uses the weighted median method to calculate the regression equation and obtain the estimation coefficient through the test^[10].MR-Egger is a tool that can perform MR analysis and pleiotropic evaluation simultaneously., and it uses the reciprocal of outcome variance as the weight to fit, thereby achieving more accurate results. The weighted median method used a combination of statistical tests and hypothesis testing to make judgments about the subject data^[11]. The advantage of WME is that even when the effective tool variable length is at least half, effective results can still be obtained by MR analysis^[12]. These three methods allow visualization of the results obtained for sensitivity analysis.

2.5 Sensitivity analysis

The heterogeneity test, MR‒Egger regression, MR-PRESSO analysis and leave-one-out are the main components of the sensitivity analysis. Heterogeneity was assessed by the P value from the Cochran Q-test; P values less than 0.05 indicated differences between IVs; otherwise, there was no heterogeneity. Since different methods are used for trial design in clinical studies, corresponding statistical models need to be established to estimate the relationship between each variable.

The presence of pleiotropy in this study was examined using MR‒Egger regression and MR-PRESSO. The intercept term P > 0.05 for MR‒Egger regression indicates no horizontal pleiotropy, if P < 0.05, and then the lack of confidence in the results of the MR analysis. The larger the calculation result of MR-PRESSO indicated that pleiotropy was more significant^[13]. In this case, the abnormal SNPs will be excluded, and the corrected result will be estimated using the MR-PRESSO method. Then, the difference between the pre- and post-corrected results will be examined to reduce the impact of gene pleiotropy on the result.

The rationale behind leave-one-out is to phase out the results after a single SNP to clarify the impact of a single SNP on the results so that its stability can be assessed^[14].

3.1 Instrumental variables

As shown in Table 2, in this study, we selected AS as the exposure factor and used R software to identify genome-wide SNP sites by screening criteria, then tested and removed palindromes and incompatible SNPs, and finally obtained the corresponding SNPs as instrumental variables to be studied.

Table 2

Mendelian randomization analysis results of ankylosing spondylitis on male sterile and prostatic hyperplasia
Outcome	Method	Nsnp	b	OR(95%CI)	P value
Male infertility	Inverse variance weighted	24	0.871	2.389(1.334～ 4.278)	0.003
	MR Egger	24	0.688	1.690(0.613～ 4.657)	0.321
	Weighted median	24	2.878	1.990(0.999～ 3.962)	0.0501
hyperplasia of prostate	Inverse variance weighted	24	0.231	1.260(1.057～ 1.501)	0.009
	MR Egger	24	0.346	1.413(1.043～ 1.916)	0.363
	Weighted median	24	0.272	1.313(1.078～ 1.599)	0.007

3.2 Mendelian randomization analysis of ankylosing spondylitis on common male diseases

The IVW, MR‒Egger regression, and WME analyses in the Two SampleMR package showed that the risk of male infertility with ankylosing spondylitis was 2.389 times higher in patients with Non-ankylosing spondylitis (OR = 2.389, 95% CL: 1.334–4.278, p = 0.034). The results of the MR-Egger analysis (P = 0.321) were not significant concerning the weighted median (P = 0.0501). The risk of BPH in ankylosing spondylitis patients was 1.260 times that in Non-ankylosing spondylitis patients (OR = 1.260, 95% CL: 1.057–1.501, P = 0.009). The results of the MR-Egger analysis (P = 0.363) were not significant with respect to the weighted median (P = 0.007). The specific conditions are shown in Table 2.The results of the causal analysis of ankylosing spondylitis and other diseases were not statistically significant, so the next analysis was only performed on male infertility and ankylosing spondylitis. The specific conditions are shown in Table 3.

Table 3

Results of Mendelian Randomization Analysis of Ankylosing Spondylitis on Other Common Male Diseases
Outcome	Method	Nsnp	b	P value
prostatitis	Inverse variance weighted	25	-0.0004	0.998
	MR Egger	25	0.151	0.627
	Weighted median	25	-0.023	0.915
Erectile dysfunction	Inverse variance weighted	25	-0.027	0.749
	MR Egger	25	-0.099	0.499
	Weighted median	25	-0.053	0.634
Orchitis and epididymitis	Inverse variance weighted	24	-0.023	0.902
	MR Egger	24	-0.061	0.850
	Weighted median	24	-0.168	0.528
sexual dysfunction	Inverse variance weighted	24	0.407	0.422
	MR Egger	24	-0.290	0.743
	Weighted median	24	-0.073	0.916
spermatocele	Inverse variance weighted	24	0.060	0.777
	MR Egger	24	0.487	0.187
	Weighted median	24	0.183	0.509

3.3 Sensitivity analysis

3.3.1 Heterogeneity test

Both the IVW method and MR‒Egger tests showed p-values above 0.05, indicating that there was no heterogeneity in the SNPs included in the study and that heterogeneity played a negligible role in the estimation of causal effects. The specific conditions are shown in Table 4.

Table 4

Heterogeneity test results
Name	Method	Q	P value
Male infertility	MR Egger	26.705	0.144
Male infertility	Inverse variance weighted	27.295	0.161
hyperplasia of prostate	MR Egger	33.576	0.054
hyperplasia of prostate	Inverse variance weighted	34.841	0.054

3.3.2 pleiotropy test

Based on the results of the analysis, the intercept term for MR‒Egger was 0.022 (P = 0.421) for male infertility, P was 0.213 for the MR-PRESSO method, the intercept term for MR‒Egger for prostatic hyperplasia was − 0.007 (P = 0.372), and P was 0.071 for the MR-PRESSO method. The results were all greater than 0.05, indicating that gene pleiotropy had little effect on the results, and there was no horizontal pleiotropy between exposure factors and outcome variables, so the results were more stable and reliable. The specific conditions are shown in Table 5.

Table 5

Results of the pleiotropic test
Outcome	MR egger interpreter	MRegger interpreter Pvalue	MR-PRESSO Pvalue
Male infertility	0.22	0.421	0.213
hyperplasia of prostate	-0.007	0.372	0.071

3.3.3 Leave-one-out

The leave-one-out method was used to analyze causal sensitivity and to stepwise eliminate individual SNPs. At the same time, the results analyzed by the IVW method were consistent with the results after the integration of all SNPs, and no SNP sites with a strong influence on the results were found in the instrumental variables. The results of the sensitivity analysis of some SNPs are shown in Figs. 1–2.

Mendelian randomization is a commonly used causal inference method with some obvious advantages. First, it can provide more reliable and accurate causal inferences than traditional observational studies^[7]. Mendelian randomization can eliminate potential confounding factors, reverse causal effects and reduce the misleading results commonly seen in observational studies by taking advantage of the random natural allocation of genes.^[15] Second, Mendelian randomized analysis can effectively avoid selection bias in the study. In traditional observational studies, due to the voluntary connection between exposure and outcome, individual selective behavior may lead to a correlation between outcome and exposure, thus generating bias. Mendelian randomization can eliminate this bias and provide more reliable results^[16]. In this study, we used this approach to explore the causal relationship between ankylosing spondylitis and common andrological conditions using a pooled data set from genome-wide association studies. The risk of male infertility in patients with AS is 2.389 times higher than that in the normal population, and the risk of prostatic hyperplasia is correspondingly increased.

The results from the MR‒Egger and weighted median methods were not significant. The values of IVW and MR‒Egger Q_P for heterogeneity analysis were greater than 0.05, indicating that there was no significant heterogeneity for the included SNPs, and the result p for pleiotropic analysis was greater than 0.05, indicating that there was no horizontal pleiotropic effect for exposure factors and outcome variables. The sensitivity analysis was performed using the leave-one-out method, and no significant effect of SNP loci in any tool variable was found on the results, indicating that the results were highly reliable.

Ankylosing spondylitis is generally occult; at present, the cause of the disease is not completely clear and mainly includes genetic factors, inflammation and some infection factors (common infection lesions in ankylosing spondylitis patients are mainly in the upper respiratory tract, gastrointestinal tract, and genitourinary tract, and ankylosing spondylitis-related common pathogenic bacteria are Klebsiella pneumoniae, mycoplasma, chlamydia, etc.)、 endocrine factors (the occurrence of ankylosing spondylitis is closely related to internal environment disorders caused by the sex hormone immune response and abnormal metabolites). and immune factors, etc^[17–20]. Pathogenesis mainly includes abnormal expression or misfolding of HLA-B27, joint peptide hypothesis, primary abnormality of ERAP pruning function, intestinal immunity, and other factors^[21]. Progression of ankylosing spondylitis should be prevented. Nonsteroidal anti-inflammatory drugs are the first-line therapy, and tumor necrosis factor-α antagonists can be applied for treatment if the disease is aggravated^[22]. At the same time, they can be combined with acupuncture treatment with a significant effect. Infection prevention is also needed in daily life.

Male infertility is usually caused by one or more causes or diseases and is therefore complex. It includes primary infertility and secondary infertility^[23]. Male infertility is related to many factors. According to the survey, we believe that the most likely cause of male infertility is mainly endogenous (such as oxidative stress and sperm chromatin damage) and exogenous (such as environmental pollution, male reproductive tract infection, urinary system diseases, some inflammation, electromagnetic radiation and automobile exhaust). Some idiopathic causes include idiopathic abnormal semen parameters, idiospermia, etc^[24–30]. The treatment principles for male infertility include the age of the spouse, multi-experience treatment, and the technique of using drugs first and test-tube baby second. There is currently a lack of systematic medication plans for the medical treatment of male infertility. It mainly includes hormone drugs, anti-infection treatment, levocarnitine treatment, antioxidant treatment, treatment to improve reproductive system microcirculation, and Chinese medicine treatment^{[31, 32]}.

Benign prostatic hyperplasia (BPH) is a common disease of the urinary system and is common in middle-aged and elderly people. The clinical manifestations of BPH include frequent micturition, urgent urination, strenuous urination, nocturia and dribbling urine^[33]. The pathogenesis of BPH is caused by a variety of factors. Age and testis function are clear factors for the occurrence and development of BPH. Metabolic disorders caused by MS also play an aggravating role in the development of BPH. In addition, the occurrence of the disease is closely related to residents' increasingly poor lifestyle, dysfunctional diet (such as smoking, drinking, exercising, animal protein intake is less or high and intake of fat is too high), and no sexual activity^{[34, 35]}. If BPH does not cause more obvious obstruction, usually no treatment is needed. Medication is available for patients with minor obstruction or surgical intolerance; surgical treatment can be performed in patients with severe urination obstruction and residual urine volume exceeding 50 mL or in patients who induce complications for which pharmacological treatment is not effective. Common drug therapies mainly include α1-AR antagonists, 5α-reductase inhibitors, phosphodiesterase 5 inhibitors, and plant preparations. Surgical treatments include transurethral resection of the prostate with bipolar plasma vaporization, transurethral incision of the prostate, and transurethral enucleation of the prostate^[36].

Patients with AS are generally at risk for decreased sperm motility and increased incidence of sperm aneuploidy^{[37, 38]}. Chatzimeletiou et al.^[39] Semen analysis of patients with AS by light, electron and fluorescence microscopy revealed a high incidence of sperm head, neck and tail abnormalities, with low aneuploidy levels for all chromosomes tested. At the same time, combined with previous studies, he concluded that inflammation in patients with AS seemed to be related to impaired testicular function. Javier et al^[6] observed that in untreated male patients with hypogonadism, hypogonadism itself and very low serum testosterone levels are associated with an increase in AS frequency. As shown in the experimental results by a handful of scholars, testosterone or its metabolites regulate the balance of immune function by affecting the inhibition of NK cell proliferation, T-cell count and CD8 + activity. Low testosterone levels may lead to abnormal immune function, thus increasing the probability of ankylosing spondylitis. Therefore, in consideration of the above aspects, there may be a potential mechanism by which the serum-free testosterone level can be used as an index for predicting the immune ability status of the body.

However, there are also scholars whose results are quite different. Gordon et al^[40]. Thirty-three patients with AS were evaluated and found to have lost fertility in only one patient. Nukumizu et al^[41]. Minimal sperm abnormalities were observed in 20 patients with AS, and effects on male fertility are considered to be empirically substantiated. Almeida et al^[42] found that there was no significant difference in the levels of sex hormones and semen analysis between the 20 patients with AS and the 24 healthy control groups. Therefore, determining the association between the two needs further experimental verification.

However, there were some potential biases and limitations in this study that need to be noted. First, the Mendelian randomization method assumes that gene variation is completely random for exposure, which may not be true in some cases. For example, the results may be affected if genetic variation is associated with other potential confounding factors. Second, the European population is the subject of the GWAS data study, and therefore, there are differences at the gene level, and it is uncertain whether this result applies to other populations. Third, the GWAS data extracted in this study lacked hierarchical analysis on age, disease course, and other aspects, so an in-depth study of specific information was not possible. Last, the data on male infertility and BPH used in this paper are insufficient for further analysis of outcome variables due to a lack of clinical data.

In summary, in this study, ankylosing spondylitis was used as the exposure factor, and significantly related SNPs were selected as the instrumental variables. IVW, Mr. Egger 's regression and WME were used for analysis. Sensitivity analysis did not find pleiotropicity or heterogeneity. The results showed that patients with ankylosing spondylitis had an increased risk of male infertility and prostatic hyperplasia, and it was suggested that patients with ankylosing spondylitis should pay attention to the prevention and treatment of male infertility and prostatic hyperplasia. At the same time, scholars can expand the research and improve the direction on this basis, expecting to find new causal mechanisms related to male infertility and BPH and providing new treatment perspectives for clinicians and new ideas for the prevention and treatment of male infertility and BPH.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors have explicitly declared that they do not possess any possible conflicts of interest pertaining to the research, writing, and/or publishing of this paper.

Funding

The National Natural Science Foundation of China (No. 82174377), China Postdoctoral Science Foundation (No.2023T160201 and No.2022M721068) Natural Science Foundation of Henan Province (No.222300420485), Science and Technology Program of Henan Province (No.192102310159, No.232102311199), the Special Scientific Research Project of National TCM Clinical Research Base (No.2021JDZX2056) and Creative Education initiative for University students in Henan Province (No. 202210471022, 202310471011) provided funding for this project.

Author contributions

The process, management of the project, and the initial draft of the writing were performed by Wenbang, Liu and Chenming ,Zhang. Formal analysis: Sicheng, Ma. Data curation: Jing, Hu. Validation: Xiaohui, Hao. Resources: Wenlin, Yu. Visualization: Ruimin , Ma and Lishuo, Zhang.Conceptualization, Writing- Reviewing & Editing: Hehe, Cui. The work underwent a thorough review process and received unanimous approval from all contributing authors.

Acknowledgements

We are grateful for the contributions made by all the researchers whose articles were incorporated into this study.

ORCID iDs

Chenming Zhang https://orcid.org/0000-0003-1426-0092

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No competing interests reported.

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Exploring the causal relationship between ankylosing spondylitis and common andrological diseases based on Mendelian randomization

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Abstract

Figures

1. Introduction

2. Material and methods

2.1 Research design

2.2 Data sources

2.3 Screening of instrumental variables

2.4 MR analysis

2.5 Sensitivity analysis

3. Results

3.1 Instrumental variables

3.2 Mendelian randomization analysis of ankylosing spondylitis on common male diseases

3.3 Sensitivity analysis

3.3.1 Heterogeneity test

3.3.2 pleiotropy test

3.3.3 Leave-one-out

4. Discussion

Declarations

References

Additional Declarations

Status:

Version 1