Plasma metabolites as mediators in inflammation-related proteins - benign prostatic hyperplasia risk: insights from Mendelian randomization

doi:10.21203/rs.3.rs-4693041/v1

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Plasma metabolites as mediators in inflammation-related proteins - benign prostatic hyperplasia risk: insights from Mendelian randomization

https://doi.org/10.21203/rs.3.rs-4693041/v1

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Benign prostatic hyperplasia (BPH) is a chronic disease that pretends to occur in elderly men. Inflammatory and metabolic factors play a key role in the pathogenesis and progression of BPH. The extent to which effects of 91 inflammation-related proteins on BPH are mediated by 1400 plasma metabolites is unclear. In our study we examined the effects of these traits using genetic evidence. We used two-sample Mendelian randomization ( two-sample MR) and Multivariable MR (MVMR) to determine:there is a genetic causal relationship between Interleukin-2 levels (IL-2)and BPH,N6,N6-dimethyllysine levels play a mediation role:higher IL-2 was associated with higher risk of BPH(β = 0.071, OR:1.074,95%CI[1.002–1.152],p = 0.045 and lower levels of N6,N6-dimethyllysine levels (β1=-0.127 p = 0.02).The N6,N6-dimethyllysine levels (β2=-0.039,p = 0.008) was negatively genetic associated with the risk of BPH.The mediation effect was 0.005,95% confidence interval(CI) [0.0004,0.012],odds-ratio (OR) :1.005,95%CI[1.000,1.012].Then,we analyzed the phenotypic co-localization of the two pairs : IL-2—BPH and N6,N6-dimethyllysine levels—BPH, which showed that IL-2 and BPH co-locate the SNP of rs145516501 on the NO. 13 chromosome. N6,N6-dimethyllysine levels, and BPH are co-located to the SNP of rs4917820 on the NO. 10 chromosome.The mediation proportion is 7.04%.The study suggested that N6,N6-dimethyllysine levels appear to mediate the causal effect of IL-2 on BPH.

Biological sciences/Genetics

Biological sciences/Immunology

Health sciences/Diseases

Health sciences/Urology

Mendelian randomization

inflammation-related proteins

plasma metabolites

BPH

mediation analysis

Colocalization

With the aging of the global population, BPH has become a global medical burden that affects the physical and mental health of middle-aged and elderly men. BPH refers to the non-cancerous enlargement of the prostate caused by interstitial and glandular epithelial hyperplasia occurring in the transitional zone of the prostate ¹.

BPH is characterized by lower urinary tract symptoms (LUTS), including obstructive symptoms (weak urinary flow, incomplete bladder emptying, hesitancy) and irritating symptoms (frequent urination, urgency, nocturia). Notably, LUTS caused by BPH increases with the advancing age. Studies have shown that BPH affects about 50% of men over the age of 50 and 90% of men over the age of 80,Almost all men will develop histological BPH before the age of 90 years ².Therefore, it is utmost significant to find out the causes and potential pathogenic mechanisms of BPH and conduct early intervention for high-risk groups.

Although the incidence of BPH is high worldwide, and more and more researchers were committed to the exploration of the cause and mechanism of BPH, However, due to the occurrence and development of BPH is a relatively complex process involving the interaction of multiple factors, there was still no definite conclusion on the etiology of BPH.However, many highly authoritative studies have focused on the possibility that BPH may be related to the immune response caused by inflammation. Inflammation can be caused by microbial, bacterial, or viral factors, hormonal changes, metabolic abnormalities, dietary factors, sedentary lifestyle ,urinary reflux, and autoimmune reactions ^3,4.

In the recent study, researchers analyzed the correlation between YAp1 expression and fibrosis in human and rat BPH model.Inflammation-triggered mechanical stiffness enhancement activates the RhoA/ROCK1/F-actin/YAp1 axis, which promotes prostate cell survival and fibrosis and accelerates BPH progression ⁵.

In recent years, with the booming development of liquid chromatograph-mass spectrometry technology, many well executed studies have shown that some plasma metabolites may be related to BPH, some of them can be a biological marker of BPH. Zeping Han's team found that serum organic acid plasma metabolites can be used as biomarkers to distinguish between prostatitis, BPH and pCa ⁶.

Many multi-center and large-sample clinical controlled trials have shown that the pathophysiology of immune-inflammatory related diseases including BPH and other diseases is the result of interactions between inflammation-related proteins and their closely related plasma metabolites ^7,8,9,10.

The etiology of BPH is ployfactorial,it is widely acknowledged that advancing age as well as androgenic hormone disturbance are the dominant contributors ¹¹. In addition, genetic susceptibility, chronic inflammation, and metabolic alterations have been identified as potential factors affecting BPH progression¹².

However, these studies above are observational studies, given the limitations of the studies themselves, the etiology of BPH cannot be accurately estimated. So this article wants to use Mendelian randomization methods to explore the cause of BPH. Mendelian randomization (MR) is the use of genetic variants associated with an exposure to estimate the causal effect of that exposure on an outcome¹³.In general in causal inference, we are interested in not only which exposure effects the outcome but also the mechanisms or pathways through which the exposure acts to affect that outcome. Mediation analysis is a field of analysis that attempts to unpick these effects and determine the causal pathways by which an exposure influences an outcome and their relative importance.

We wanted to use the Mediation MR to explore the mediator role of 1400 plasma metabolites in the causal relationship between 91 inflammation-related proteins and BPH.Meanwhile, to explore the mechanism and pathway that produces this causal relationship (Fig. 1).

The causal effect of inflammation-related proteins on BPH

Two-sample MR was used to explore the causal effect of inflammation-related proteins on BPH,the quantile-quantile plot and the Manhattan plot of the SNPs which were strongly associated with the inflammation-related proteins was showed in the Fig. 3,The inflammation-related proteins that were strongly related to BPH were identified as positive inflammation-related proteins(Supplementary Table S1 ), there are 4 inflammation-related proteins have genetic causal effect with BPH.The forest of the 4 inflammation-related protein was shown in the Fig. 4. Additionally, in order to meet the requirements of mediation MR studies, we further treated BPH as the exposure and positive inflammation-related proteins as the outcomes, conducting a reverse MR analysis :inflammation-related proteins which had reverse causal effect with BPH were excluded;After a series of sensitivity tests (included heterogeneity ,MR-PRESSO, pleiotropy-test) (Supplementary Table S2-S4) only IL-2 (OR:1.074,95%CI[1.002–1.152],p = 0.0045)(Fig. 5) and IL-5 (OR:0.929, 95%CI [0.870–0.993],p = 0.0029) left (Supplementary Fig. S1).

The causal effect of plasma metabolites on BPH

Two-sample MR was used to explore the causal effect of plasma metabolites on BPH (Supplementary Table S5,Supplementary Fig. S2), the quantile-quantile plot and the Manhattan plot of the SNPs which were strongly associated with the 1400 plasma metabolites was showed in the Fig. 6.We select the representative plasma metabolite (N6,N6-dimethyllysine levels) for display(Fig. 7).We further treated BPH as the exposure and positive plasma metabolites as outcomes, conducting a reverse MR analysis:plasma metabolites which had reverse causal effect with BPH were excluded.After sensitivity tests((included heterogeneity, MR-PRESSO, pleiotropy-test)(Supplementary Table S6-S8), there were 58 positive plasma metabolites were left which were causally related to BPH.(OR:0.893–1.089).Among them, there are 24 plasma metabolites which were positively associated with the risk of BPH genetically Supplementary Fig.S3), as well as 34 plasma metabolites were negatively associated with the risk of BPH on the genetic level(Supplementary Fig.S4).

The causal effect of positive inflammation-related proteins on positive plasma metabolites

The aim of this step is to screen out plasma metabolites that can serve as the candidate mediators.The results showed that 2 inflammation-related proteins and 5 plasma metabolites(Supplementary Table S9)had causal relationship.Among them, there were two unnamed plasma metabolites being eliminated, only Caprylate (8:0) levels. N6-methyllysine levels, N6,N6-dimethyllysine levels left(Supplementary Table S10).Then N6,N6-dimethyllysine levels were finally confirmed as the ultimate mediated metabolite by MVMR. After excluding the two candidate plasma metabolites with no significant difference(p > 0.05) or 95% confidence interval of OR value exceeded 1, only N6,N6-dimethyllysine levels was left to satisfy all conditions and become a true mediator(Supplementary Table S11).MVMR is to validate the candidate mediator and potential pathways above step through the causal stepwise test.Then the mediation effect calculated by the product of coefficients method—β 1*β 2.β 1 (β1= -0. 127;p = 0.02); β 2(β =-0.039; p = 0.008) .The mediation effect of N6,N6-dimethyllysine levels is 0.005(β = 0.005, 95%CI[0.0004–0.012;OR = 1.005, OR 95%CI[1.0004–1.012]).(Table 1).

The total effect of IL-2 on BPH is 0.071 (β = 0.071,95%CI[0.002,0.141] OR:1.074, 95%CI[1.002,1.152], p = 0.044) Accounting for 7.04% of the total effect.Therefore, IL − 2 can aggravate the occurrence and development of BPH, through the mechanisms that IL − 2 inhibits N6, N6 - dimethyllysine levels on the protective effects of BPH.

Table 1

The mediation effect of IL-2 on BPH via N6,N6-dimethyllysine
Mediator	Total effect		Mediation effect		P	Mediation proportion(%)
	β (95%CI)	OR(95%CI)	Β(95%CI)	OR(95%CI)	0.008	7.04
N6,N6-dimethylysine	0.071(0.002to 0.141)	1.074(1.002to 1.152)	0.005(0.0004to 0.012)	1.005(1.0004to1.012)

Table1: “Total effect ”indicates the effect of IL-2 on BPH,“mediation effect ”indicates the effect of IL-2 on BPH through N6,N6-dimethyllysine.Total effect was derived by IVW;mediation effect was derived by using delta method.p<0.05 was considered significant.

Colocalization analysis

After the mediation Mendelian randomization analysis above, we obtained IL−2, N6, N6 - dimethyllysine levels had causal relationship with BPH respectively,In order to validate whether the two phenotypes shared the same causal variant within a given region, we applied colocalization analysis to further demonstrate this causal relationship.IL−2 and BPH significantly correlated with the SNP of rs145516501 which located in the no. 13 chromosome,and driven by the same genetic variant:PP.H4.abf = 8.07e^− 01,PP abf for shared variant:80.7%(Supplementary Fig.S5,Supplementary Table S12-S13); N6,N6-dimethyllysine levels and BPH were significant correlated with the rs4917820 SNP which located in the no. 10 chromosome,and driven by the same genetic variant:PP.H4.abf = 9.59e^− 01,PP abf for shared variant:95.9%(Supplementary Fig.S6,Supplementary Table S14-S15).

To our knowledge ,this is the first paper to explore the extent to which plasma metabolites play the mediator roles between inflammation-related proteins and BPH.In order to obtain stable and reliable estimates of causality and mediation, as far as possible avoiding unnecessary bias,we chose particularly large sample sizes and more genetic variants, included 91 inflammation-related proteins ,1400 plasma metabolites.BPH data are huge and reliable as well,furthermore we found SNPs associated with multiple shapes through further colocalization analysis,so we had reason to be confident believedas well as safely concluded:N6,N6-dimethyllysine played an intermediary role in the causal effect between IL − 2 and BPH.After we found the significant sites through GWAS,we wanted to explore how these loci significantly affect the phenotype. We then applied colocalization analysis to explain this phenomenon: specifically, when two paired GWAS signals are detected to colocate, we would expect that the loci on the GWAS signals affect the phenotype through the altered gene expression.

Given BPH is a global public health problem that affects men over 50 years old for a long time with high economic burden, it is of great significance to find out the etiology and progression mechanism of BPH, so as to carry out effective prevention and early intervention for potential risk groups.However,sometimes it is very difficult to do in primary prevention. At this time, the importance of secondary prevention is highlighted.I think it should be the significance of our mediation Mendelian analysis.In previous observational studies, multiple logistic regression was used to assess the mediation effect of confounders.However, observational study itself has limitations,there are confounding and bias in observational studies.observational studies can only reveal the correlation between exposure and outcome,not causation.Moreover, the direction of associations between exposure and outcomes is uncertain. These traditional mediation methods have been extended to “counterfactual mediation analysis,” which uses a counterfactual framework to estimate mediation effects¹⁴.By contrast ,MR is based on genetic variation as an instrumental variable(IV), The selection of IVs must follow the following three assumptions: (1) the instrumental variables are closely related to exposure; (2) the IVs were independent confounders of exposure-outcome relationship; (3) The IVs were independent of the confounding factors.This ensures the reliability and stability of MR inference of genetic causality.Which is less affected by confounders such as environmental factors, social factors and living habits, so MR can estimate better and more stable causality estimate.furthermore,our findings provide strong support for undertaking RCTs which is the“ gold standard ”for finding a causal relationship between exposure and outcome.

BPH is a benign tumor-like hyperplasia of the internal gland of the prostate, which tends to occur in middle-aged and elderly men over 50 years old. Lower urinary tract symptoms are the main clinical manifestations.So far, the cause and pathogenesis of BPH have not been fully understood. It's clearly a complex process of multiple factors.Several well performed large clinical trials revealed that one of the causes of BPH is the immune response caused by inflammation¹⁵.

Almost all the BPH specimens in histological examination showed inflammatory infiltrates, but with the correlation of bacteria or other exogenous antigen has not yet been found ^16,17.In a mouse model of BPH, inhibition of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 did prevent the progression of BPH. This conclusion seems to be inconsistent with our study.The possible reason is that low dose IL-2 induces Treg proliferation, and Treg proliferation in the prostate induces a suppressive immune micro-environment to inhibit BPH. However, this article did not set subgroups of IL-2 concentration,nether study the effect of medium or high doses of IL-2 on BPH, which may be the reason for the discrepancy with the conclusions of our paper¹⁸.Furthermore,in another fully developed animal model of BPH,T cell-derived cytokines ifn-γ and IL-2 were 10 times higher than those in the normal prostate ^19,20,21.

Our study used MR to demonstrated that IL-2 could increase the risk of BPH.Beside,N6-N6-Dimethyl-Lysine played a mediation role.N6-N6-DimethylLysine, was known as lys(me2) or N,N-dimethyllysine, belongs to the class of organic compounds known as l-alpha-amino acids,which have the L-configuration of the alpha-carbon atom. An L-lysine derivative comprising L-lysine having two methyl substituents attached to the side-chain amino group.In a recent MR study on the causal relationship between 1400 plasma metabolites and diabetic retinopathy,N6,N6-dimethyllysine was found to be inversely associated with the risk of diabetic retinopathy ²². Through our research, N6, N6 - dimethyllysine can reduce the risk of BPH,consequently, there is the reason to believe that it would be prudent for the elder male individuals who are peculiarly prone to BPH with hormonal abnormalities, metabolic disorders and unhealthy lifestyle to closely monitor N6,N6-dimethyllysine levels,as well as prevention.It is our initial objective of mediation MR.Biological systems can do research at different levels, from the reaction of DNA to sustain life. From the most basic study of DNA structure, function, modification and utilization of genomics²³.Transcriptomics, to the study of RNA concentrations within a system, allows us to understand which cellular activities are preferentially processed or inhibited in a living system²⁴.To proteomics is the study of protein, which tell us the protein composition and location in a living system ^25,26.However,there must be limitations at any level of research.Recently, with the increasing maturity of mass spectrometry analysis technology, metabolomics, which is considered to be the closest to phenotype, has showed more and more possibilities. The concept of metabolomics is derived from the metabolome, which refers to all the low-molecular-weight plasma metabolites of a certain organism or cell in a specific physiological period. Metabolomics can be used to find potential biomarkers for complex diseases with unclear pathogenesis, and provide a new means for the diagnosis and treatment of diseases.Given metabolite samples are readily available, therefore they are considered to be a very potent and amazingly tool with great potential for clinical translation^27,28,29.There are more and more studies on BPH-related metabolites, but most of them are not mature and perfect, and there are still many problems to be solved. This paper provides some research ideas and directions for the prevention, diagnosis and treatment of BPH, we hope it will be helpful to future researchers.

Strengths and limitations

Our study has some benefits:(1) The selected exposure and mediation data are all from omics data. This ensured statistical power and the reliability of the conclusion.(2) In order to ensure the relatively complete and reliable conclusion,we used a combination of two-sample MR and MVMR analysis.MVMR is a recent extension of MR that uses genetic variants associated with multiple potentially related exposures to estimate the effect of each exposure on a single outcome³⁰.MVMR allows for equivalent analysis to mediation within the MR framework and therefore can be used to estimate mediation effects.This approach preserves the benefits of causal inference using genetic tools, such as avoiding bias due to confoundors, while allowing estimation of the different effects required for mediation analyses. (3) Another advantage of this paper is that we can not only obtain the causal relationship between IL-2 and BPH through MR analysis, but also explore the internal mechanism of the causal relationship.However, our study has some limitations. (1) The aggregated GWAS data used in the study were all from European populations, which limited the applicability of the results to non-European populations and limited the universality of the conclusions. (2) Although horizontal pleiotropy was excluded by MR-PRESSO detection, vertical pleiotropy could not be excluded; (3) The causal relationship between IL-2 and BPH mediated by N6-N6-Dimethyl-Lysineis reported for the first time and needs to be verified by further large-scale clinical studies even RCT studies.

In conclusion, our results support a causal effect of higher IL-2 on BPH risk that is, at least partially, mediated through the effect of IL-2 on N6, N6 - dimethyllysine levels. IL-2 aggravated the occurrence and progression of BPH by inhibiting the protective effect of N6,N6-dimethyllysine levels on BPH.

1.Study design and methods

We used Two sample MR And MVMR methods to study the mediation role of 1400 plasma metabolites in the genetic causal relationship between 91 inflammatory factors and BPH.Two-sample MR was used to screen positive inflammation-related proteins and positive plasma metabolites related to BPH.Then, two-sample MR was used to explore the correlation between positive inflammation-related proteins and positive plasma metabolites and screen out potential mediators. MVMR is to prove the existence of mediator through the progressive test of causation;We take inflammation-related proteins and plasma metabolites as exposure to do MVMR with BPH respectively,if both inflammation-related proteins to BPH and plasma metabolites to BPH are significant, there is no doubt the existence of mediation. First, we tested the effects of inflammation-related proteins on BPH, calculate the total effect, labeled β.Total effect can be decomposed into two parts. One part is the “direct” effect of the primary exposure on the outcome; this is the effect of the primary exposure that does not act through the mediators included in the model, represented by the arrow from inflammation-related proteins to BPH labeled β^, ; The other part is the “indirect” effect, which is the effect of the primary exposure on the outcome that only operates through the mediators³¹.We tested the causal effect value of positive inflammation-related proteins to positive plasma metabolites, labeled β1; we use MVMR to test causal effect value of plasma metabolites to BPH, labeled β 2, and then use product of coefficients method to calculate the mediation effect(β1*β 2).The proportion of the mediation effect can be calculated as the “indirect effect/total effect”.The relationship between of total effect,direct effect,indirect(mediator) effect was shown in Fig. 2.

2.Data sources

Summary-level data regarding BPH were extracted from a comprehensive European population-wide GWAS conducted within the FinnGen project in Finland ³².We selected the most recent R10 version summary data on BPH,which enrolled 32956 cases and 130139 controls.(R10_N14_PROSTHYPERLIA );The researchers performed genome-wide pQTL mapping for 91 plasma proteins measured using the Olink Target Inflammation panel in 11 cohorts totaling 14,824 European-ancestry participants.91 inflammation-related proteins data from GWAS summary data, (http://ftp.ebi.ac.uk/pub/databases/gwas/ summary_statistics) (registration number GCST90274758 to GCST90274848) to download³³. 1400 plasma metabolites data were obtained from 8299 individuals in the Canadian Longitudinal Study of Aging (CLSA) cohort study. The GWAS summary study was performed by aggregating 1,091 blood plasma metabolites and 309 metabolite ratios. Metabolite-gene and gene expression information were integrated to identify genes with significant effects on phenotypics and diseases. Genetic signatures of 109 plasma metabolites and 48 metabolite ratios were ultimately identified as effector gene³⁴.(http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics), (registration number from GCST90199621 to GCST90201020.)

3.Genetic instrumental variable:

In the analysis of inflammation-related proteins-plasma metabolites-BPH associations, we established a correlation threshold of 1×10^− 5 to identify SNPs that are significantly associated with plasma metabolites as well as inflammation-related proteins.Whereas, The threshold of reverse Mendelian randomization analysis is set at 5×e^− 8.We clumped all those genetic variants with the threshold: r² < 0.001 within 10000 kb clumping distance. The F-statistics was applied to screen for SNPs in the end. The calculation method of the F-statistics was the square of β divided by the square of the standard error, and the cut-off value was 10. When exposure ,mediation and outcome were harmonized,palindromic SNPs with intermediate allele frequencies were removed.

4. Statistical analysis

Our study mainly uses the method of inverse-variance weighting (IVW) for two-sample MR Analysis, and the overall effect estimate is obtained by weighted average of the effect estimate of each SNP site. In addition, the weighted median method, simple model method, weighted model method and MR-Egger regression method were used as supplements. Sensitivity analysis Including:the comparison of effect estimated by the five methods above ;MR-Egger method is to consider possible variables heterogeneity and provide a relatively accurate estimate of causal effects. MR-Egger regression is a modified version of IVW, which is a multi-instrumental variable MR method based on the summary data.If p < 0.05, it can be considered that it has horizontal pleiotropy and should be excluded ³⁵.MR-PRESSO identified horizontal pleiotropy through a global test, If p < 0.05, it can be considered that it has horizontal pleiotropy and should be excluded³⁶.Scatter plots : scatter plots were used to visually better examine outliers of SNP-specific causal estimates, since these variants may be pleiotropic. Each point in the scatter plot represents a genetic variant, which shows us the association of each genetic variant (SNP) with exposure and outcome ³⁷.At the same time, we adopt Cochran^, s Q to access heterogeneity,If p < 0.05, it can be considered that it has heterogeneity and should be excluded.Finally, leave-one-out was used to determine whether individual SNPs influenced primary causality.

“Two Sample MR”, “MR-PRESSO”, “Coloc”, “MendelianRandomization” R packages were used for all statistical analyses. p < 0.05 for significant statistical significance. Forest plots, scatter plots, leave-one-out plots, and funnel plots, circle hot map ,were drawn using the R package.

Data availability statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Ethics statement

Ethical consent was obtained prior to the initial GWAS studies in each country, and the current analyses were based on publicly available summary data, which did not require further approval.

Data availability statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Ethics statement

Ethical consent was obtained prior to the initial GWAS studies in each country, and the current analyses were based on publicly available summary data, which did not require further approval.

Author contributions

Yan Cui: conception and design of the work. Draft articles, draw pictures and make tables.Yuting Wang: design of the work.Hui Wang:conception and design of the work.Yan Cui:acquisition, analysis and interpretation of data. Yuting Wang:analysis data. Yan Cui: have drafted the work or substantively revised it. Hui Wang: have drafted the work or substantively revised it.All authors have approved the submitted version (and any substantially modified version that involves the author's contribution to the study,and have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Funding

The author(s) declare no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

We want to acknowledge the participants and investigators participated in this study. We are grateful to the FinnGen, Open GWAS for providing GWAS summary statistics.

Competing interest

The authors declare no competing interests.

Publisher’s note

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Supplementary material

The Supplementary Material for this article can be found in the supplementary files.

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Plasma metabolites as mediators in inflammation-related proteins - benign prostatic hyperplasia risk: insights from Mendelian randomization

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Abstract

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Introduction

Result

The causal effect of inflammation-related proteins on BPH

The causal effect of plasma metabolites on BPH

The causal effect of positive inflammation-related proteins on positive plasma metabolites

Colocalization analysis

Discussion

Strengths and limitations

Conclusion

Methods

4. Statistical analysis

Data availability statement

Ethics statement

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References

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