Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Exploring the causal association between serum metabolites and erectile dysfunction: a bidirectional Mendelian randomisation study

Abstract

Erectile dysfunction is a common sexual disorder in men. Some studies have found a strong association between some serum metabolites and erectile dysfunction. To investigate this association further, we used bidirectional Mendelian randomisation to investigate causality and possible biological mechanisms.Firstly, this study screened the statistics of genome-wide association studies of serum metabolites and erectile dysfunction to obtain instrumental variables. Inverse variance weighting was used as the primary method for causal effect analysis of instrumental variables in forward or reverse Mendelian randomisation, and the results obtained by MR-Egger regression and the weighted median method were used as references. Subsequently, the metabolites causally associated with erectile dysfunction were subjected to replication analyses and meta-analyses, and the results of the meta-analyses were analysed by pathway analyses to find influential pathways. In this process, Mendelian randomisation results need to be assessed for stability and reliability using sensitivity analysis.It was found that a total of six serum metabolites were causally associated with erectile dysfunction in a forward Mendelian randomisation study. 1,3,7-trimethyluraten (0.85 (0.73–0.99), P = 0.0368), ergothioneine (0.65 (0.45–0.94), P = 0.0226) and gamma-glutamylglutamate (0.63 (0.46–0.88), P = 0.0059) were protective against the development of erectile dysfunction, whereas 2-hydroxyhippurate (1.10 (1.02–1.19), P = 0.0152), N2,N2-dimethylguanosine (1.57 (1.02–2.40), P = 0.0395) and octanoylcarnitine (1.38 (1.06–1.82), P = 0.0183) were able to induce the development of erectile dysfunction. In addition, metabolic pathway analysis showed that 1,3,7-trimethylurate was able to influence the development of erectile dysfunction via the caffeine metabolism pathway (P = 0.0454). On the other hand, reverse Mendelian randomisation analysis showed that erectile dysfunction reduced serum homocitrulline levels (0.99 (0.97–1.00), P = 0.0360). Sensitivity analyses, including heterogeneity tests and pleiotropy tests, confirmed the reliability of the results.In conclusion, this study demonstrated a bidirectional causal relationship between serum metabolites and erectile dysfunction using bidirectional Mendelian randomisation analysis and replication meta-analysis. On this basis, this study provides a new direction of thinking and strong evidence for the therapeutic application and adjunctive diagnosis of serum metabolites in erectile dysfunction, and provides a certain reference value for subsequent related studies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The overall flowchart of the study.
Fig. 2: Forest plot of the causal effects of metabolites on the risk of ED derived from the IVW method.
Fig. 3: Forest plot for forward MR replication analysis.
Fig. 4: Forest plots of the meta-analysis of each of the 10 metabolites in the forward MR.
Fig. 5: Forest plot of the causal effects of ED on the risk of metabolites derived from the IVW method.
Fig. 6: Forest plots for reverse MR replication analysis. (MR: Mendelian randomisation.
Fig. 7: Forest plots of the meta-analysis of each of the 6 metabolites in the reverse MR.

Similar content being viewed by others

Data availability

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article.

References

  1. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA. 1993;270:83–90.

    Article  Google Scholar 

  2. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994;151:54–61.

    Article  CAS  PubMed  Google Scholar 

  3. Corona G, Lee DM, Forti G, O’Connor DB, Maggi M, O’Neill TW, et al. Age-related changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS). J Sex Med. 2010;7:1362–80.

    Article  PubMed  Google Scholar 

  4. Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb S, et al. Erectile dysfunction. Nat Rev Dis Primers. 2016;2:16003.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hatzimouratidis K, Salonia A, Adaikan G, Buvat J, Carrier S, El-Meliegy A, et al. Pharmacotherapy for Erectile Dysfunction: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med. 2016;13:465–88.

    Article  PubMed  Google Scholar 

  6. Corona G, Rastrelli G, Burri A, Jannini EA, Maggi M. The safety and efficacy of Avanafil, a new 2(nd) generation PDE5i: comprehensive review and meta-analysis. Expert Opin Drug Saf. 2016;15:237–47.

    Article  CAS  PubMed  Google Scholar 

  7. Goldsmith P, Fenton H, Morris-Stiff G, Ahmad N, Fisher J, Prasad KR. Metabonomics: a useful tool for the future surgeon. J Surg Res. 2010;160:122–32.

    Article  CAS  PubMed  Google Scholar 

  8. Lopez DS, Advani S, Tsilidis KK, Wang R, Baillargeon J, Dobs A, et al. Association of Urinary Phthalate Metabolites With Erectile Dysfunction in Racial and Ethnic Groups in the National Health and Nutrition Examination Survey 2001-2004. Am J Mens Health. 2017;11:576–84.

    Article  PubMed  Google Scholar 

  9. Katsimardou A, Patoulias D, Zografou I, Siskos F, Stavropoulos K, Imprialos K, et al. The Impact of Metabolic Syndrome Components on Erectile Function in Patients with Type 2 Diabetes. Metabolites. 2023;13:617.

  10. Rocca MS, Vignoli A, Tenori L, Ghezzi M, De Rocco Ponce M, Vatsellas G, et al. Evaluation of Serum/Urine Genomic and Metabolomic Profiles to Improve the Adherence to Sildenafil Therapy in Patients with Erectile Dysfunction. Front Pharmacol. 2020;11:602369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27:1133–63.

    Article  PubMed  Google Scholar 

  13. Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: A review. Res Synth Methods. 2019;10:486–96.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wichmann HE, Gieger C, Illig T. KORA-gen-resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen. 2005;67:S26–30. Suppl 1

    Article  PubMed  Google Scholar 

  15. Moayyeri A, Hammond CJ, Hart DJ, Spector TD. The UK Adult Twin Registry (TwinsUK Resource). Twin Res Hum Genet. 2013;16:144–9.

    Article  PubMed  Google Scholar 

  16. Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J, et al. An atlas of genetic influences on human blood metabolites. Nat Genet. 2014;46:543–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. 2012;40:D109–14.

    Article  CAS  PubMed  Google Scholar 

  18. Bovijn J, Jackson L, Censin J, Chen CY, Laisk T, Laber S, et al. GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology. Am J Hum Genet. 2019;104:157–63.

    Article  CAS  PubMed  Google Scholar 

  19. Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40:755–64.

    Article  PubMed  Google Scholar 

  20. Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2011;40:740–52.

    Article  PubMed  Google Scholar 

  21. Emdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA. 2017;318:1925–6.

    Article  PubMed  Google Scholar 

  22. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37:658–65.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40:304–14.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32:377–89.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cohen JF, Chalumeau M, Cohen R, Korevaar DA, Khoshnood B, Bossuyt PM. Cochran’s Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy. J Clin Epidemiol. 2015;68:299–306.

    Article  PubMed  Google Scholar 

  26. Greco MF, Minelli C, Sheehan NA, Thompson JR. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med. 2015;34:2926–40.

    Article  Google Scholar 

  27. Wan B, Ma N, Lu W. Mendelian randomization investigation identified the causal relationship between body fat indexes and the risk of bladder cancer. PeerJ. 2023;11:e14739.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018;27:R195–r208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11:193–206.

    Article  PubMed  Google Scholar 

  30. Viechtbauer W. Hypothesis tests for population heterogeneity in meta-analysis. Br J Math Stat Psychol. 2007;60:29–60.

    Article  PubMed  Google Scholar 

  31. Jewison T, Su Y, Disfany FM, Liang Y, Knox C, Maciejewski A, et al. SMPDB 2.0: big improvements to the Small Molecule Pathway Database. Nucleic Acids Res. 2014;42:D478–84. Database issue

    Article  CAS  PubMed  Google Scholar 

  32. Kot M, Daniel WA. Caffeine as a marker substrate for testing cytochrome P450 activity in human and rat. Pharmacol Rep. 2008;60:789–97.

    CAS  PubMed  Google Scholar 

  33. Daniel WA, Kot M, Wójcikowski J. Effects of classic and newer antidepressants on the oxidation pathways of caffeine in rat liver. In vitro study. Pol J Pharmacol. 2003;55:1045–53.

    CAS  PubMed  Google Scholar 

  34. Lopez DS, Wang R, Tsilidis KK, Zhu H, Daniel CR, Sinha A, et al. Role of Caffeine Intake on Erectile Dysfunction in US Men: Results from NHANES 2001-2004. PLoS One. 2014;10:e0123547.

    Article  PubMed  Google Scholar 

  35. Allen MS, Walter EE. Health-Related Lifestyle Factors and Sexual Dysfunction: A Meta-Analysis of Population-Based Research. J Sex Med. 2018;15:458–75.

    Article  PubMed  Google Scholar 

  36. Yang R, Wang J, Chen Y, Sun Z, Wang R, Dai Y. Effect of caffeine on erectile function via up-regulating cavernous cyclic guanosine monophosphate in diabetic rats. J Androl. 2008;29:586–91.

    Article  CAS  PubMed  Google Scholar 

  37. Gołembiowska K, Dziubina A, Kowalska M, Kamińska K. Paradoxical effects of adenosine receptor ligands on hydroxyl radical generation by L-DOPA in the rat striatum. Pharmacol Rep. 2008;60:319–30.

    PubMed  Google Scholar 

  38. Lee C. Antioxidant ability of caffeine and its metabolites based on the study of oxygen radical absorbing capacity and inhibition of LDL peroxidation. Clin Chim Acta. 2000;295:141–54.

    Article  CAS  PubMed  Google Scholar 

  39. Salisbury D, Bronas U. Reactive oxygen and nitrogen species: impact on endothelial dysfunction. Nurs Res. 2015;64:53–66.

    Article  PubMed  Google Scholar 

  40. Zheng D, Liu J, Piao H, Zhu Z, Wei R, Liu K. ROS-triggered endothelial cell death mechanisms: Focus on pyroptosis, parthanatos, and ferroptosis. Front Immunol. 2022;13:1039241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Terentes-Printzios D, Ioakeimidis N, Rokkas K, Vlachopoulos C. Interactions between erectile dysfunction, cardiovascular disease and cardiovascular drugs. Nat Rev Cardiol. 2022;19:59–74.

    Article  PubMed  Google Scholar 

  42. Burnett AL. Nitric oxide in the penis-science and therapeutic implications from erectile dysfunction to priapism. J Sex Med. 2006;3:578–82.

    Article  CAS  PubMed  Google Scholar 

  43. Suzuki T, Yamamoto H, Pfleiderer W. Nitrosation of N-methyl derivatives of uric acid and their transnitrosation ability to N-acetylcysteine. Chem Pharm Bull. 2010;58:1271–5.

    Article  CAS  Google Scholar 

  44. Gründemann D, Harlfinger S, Golz S, Geerts A, Lazar A, Berkels R, et al. Discovery of the ergothioneine transporter. Proc Natl Acad Sci USA. 2005;102:5256–61.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Cheah IK, Halliwell B. Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim Biophys Acta. 2012;1822:784–93.

    Article  CAS  PubMed  Google Scholar 

  46. Paul BD, Snyder SH. The unusual amino acid L-ergothioneine is a physiologic cytoprotectant. Cell Death Differ. 2010;17:1134–40.

    Article  CAS  PubMed  Google Scholar 

  47. Borodina I, Kenny LC, McCarthy CM, Paramasivan K, Pretorius E, Roberts TJ, et al. The biology of ergothioneine, an antioxidant nutraceutical. Nutr Res Rev. 2020;33:190–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Paul BD. Ergothioneine: A Stress Vitamin with Antiaging, Vascular, and Neuroprotective Roles? Antioxid Redox Signal. 2022;36:1306–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Koh SS, Ooi SC, Lui NM, Qiong C, Ho LT, Cheah IK, et al. Effect of Ergothioneine on 7-Ketocholesterol-Induced Endothelial Injury. Neuromolecular Med. 2021;23:184–98.

    Article  CAS  PubMed  Google Scholar 

  50. Li RW, Yang C, Sit AS, Kwan YW, Lee SM, Hoi MP, et al. Uptake and protective effects of ergothioneine in human endothelial cells. J Pharmacol Exp Ther. 2014;350:691–700.

    Article  PubMed  Google Scholar 

  51. Liu Q, Zhang Y, Wang J, Li S, Cheng Y, Guo J, et al. Erectile Dysfunction and Depression: A Systematic Review and Meta-Analysis. J Sex Med. 2018;15:1073–82.

    Article  PubMed  Google Scholar 

  52. Nakamichi N, Nakayama K, Ishimoto T, Masuo Y, Wakayama T, Sekiguchi H, et al. Food-derived hydrophilic antioxidant ergothioneine is distributed to the brain and exerts antidepressant effect in mice. Brain Behav. 2016;6:e00477.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Matsuda Y, Ozawa N, Shinozaki T, Wakabayashi KI, Suzuki K, Kawano Y, et al. Ergothioneine, a metabolite of the gut bacterium Lactobacillus reuteri, protects against stress-induced sleep disturbances. Transl Psychiatry. 2020;10:170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vangipurapu J, Fernandes Silva L, Kuulasmaa T, Smith U, Laakso M. Microbiota-Related Metabolites and the Risk of Type 2 Diabetes. Diabetes Care. 2020;43:1319–25.

    Article  CAS  PubMed  Google Scholar 

  55. Hidalgo-Tamola J, Chitaley K. Review type 2 diabetes mellitus and erectile dysfunction. J Sex Med. 2009;6:916–26.

    Article  CAS  PubMed  Google Scholar 

  56. Pallan PS, Kreutz C, Bosio S, Micura R, Egli M. Effects of N2,N2-dimethylguanosine on RNA structure and stability: crystal structure of an RNA duplex with tandem m2 2G:A pairs. RNA. 2008;14:2125–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tormey DC, Waalkes TP, Gehrke CW. Biological markers in breast carcinoma-clinical correlations with pseudouridine, N2,N2-dimethylguanosine, and 1-methylinosine. J Surg Oncol. 1980;14:267–73.

    Article  CAS  PubMed  Google Scholar 

  58. Woo KB, Waalkes TP, Ahmann DL, Tormey DC, Gehrke CW, Oliverio VT. A quantitative approach to determining disease response during therapy using multiple biologic markers: application to carcinoma of the breast. Cancer. 1978;41:1685–703.

    Article  CAS  PubMed  Google Scholar 

  59. Ottosson F, Smith E, Gallo W, Fernandez C, Melander O. Purine Metabolites and Carnitine Biosynthesis Intermediates Are Biomarkers for Incident Type 2 Diabetes. J Clin Endocrinol Metab. 2019;104:4921–30.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the participants and investigators of the IEU consortium, FinnGen consortium and Metabolomics GWAS.

Funding

This work was supported the Young/Middle aged Talent Cultivation Project that was funded by the Fujian Provincial Health and Family Planning Commission and Xiamen Health and Family Planning Commission (No. 2021GGB028).

Author information

Authors and Affiliations

Authors

Contributions

RX and XW designed the study, contributed to the data analysis, and wrote the manuscript. SL, LL and YB contributed to the data analysis and data interpretation. PB and GL contributed to manuscript writing and revision of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xin-jun Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, R., Liu, S., Li, Ly. et al. Exploring the causal association between serum metabolites and erectile dysfunction: a bidirectional Mendelian randomisation study. Int J Impot Res (2024). https://doi.org/10.1038/s41443-024-00926-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41443-024-00926-2

Search

Quick links