{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:13:54Z","timestamp":1790079234672,"version":"4.0.1"},"reference-count":25,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["P3-0298"],"award-info":[{"award-number":["P3-0298"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["P1-0170"],"award-info":[{"award-number":["P1-0170"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["P3-0154"],"award-info":[{"award-number":["P3-0154"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P3-0298"],"award-info":[{"award-number":["P3-0298"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P1-0170"],"award-info":[{"award-number":["P1-0170"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P3-0154"],"award-info":[{"award-number":["P3-0154"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Krka d.d."},{"id":[{"id":"https:\/\/ror.org\/03nwfz403","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: Erectile dysfunction (ED) is a common complication of diabetes mellitus (DM), largely driven by endothelial dysfunction and impaired nitric oxide signaling. Although phosphodiesterase type 5 inhibitors (PDE5i) such as tadalafil are effective, treatment response varies considerably between individuals. Genetic variation in the folate\u2013homocysteine pathway may influence endothelial function and contribute to this variability. To investigate the association of selected polymorphisms in folate\u2013homocysteine pathway genes (MTHFR rs1801133 and rs1801131, MTR rs1805087 and MTRR rs1801394) with ED severity and response to tadalafil treatment in men with DM. Methods: In this prospective exploratory pharmacogenetic study, 78 men with DM and ED were treated with tadalafil 5 mg once daily for three months. ED was assessed using the International Index of Erectile Function (IIEF-5) questionnaire before and after treatment. The pre-specified primary endpoint was treatment response, defined as a \u22654-point increase in IIEF-5 score (based on the minimal clinically important difference for the IIEF erectile function domain). Genotyping was performed using competitive allele-specific PCR. Associations between genetic variants and treatment outcomes were evaluated using logistic regression. Results: Before treatment 24 patients (30.8%) had moderate or severe ED. No significant associations were observed between the investigated polymorphisms and baseline ED severity. IIEF-5 scores significantly increased during the three-month tadalafil treatment period, with 80.8% of patients showing improvement and 60.3% achieving a clinically relevant increase of \u22654 points in IIEF-5 score. None of the investigated polymorphisms was associated with the primary endpoint after Bonferroni correction across the three global genotype tests. In the secondary \u2018any improvement\u2019 analysis, a nominal association was observed for MTR rs1805087 in a small subgroup (n = 5 GG carriers; unadjusted OR = 0.15, 95% CI 0.02\u20130.89; p = 0.037), which was attenuated after multivariable adjustment (OR = 0.16, 95% CI 0.02\u20131.08, p = 0.060) and is regarded as hypothesis-generating only. Conclusions: Genetic variation in the folate pathway does not appear to influence baseline ED severity or tadalafil responsiveness in men with DM, although this exploratory study was not powered to exclude modest genetic effects. These preliminary findings require confirmation in larger studies that also incorporate plasma homocysteine and B-vitamin measurement.<\/jats:p>","DOI":"10.3390\/jcm15197349","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:09:35Z","timestamp":1790075375000},"page":"7349","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Folate Pathway Polymorphisms and Tadalafil Response in Men with Diabetes Mellitus and Erectile Dysfunction: An Exploratory Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1251-7161","authenticated-orcid":false,"given":"Bo\u0161tjan","family":"Hostnik","sequence":"first","affiliation":[{"name":"Division of Internal Medicine, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-5254","authenticated-orcid":false,"given":"Andrej","family":"Jane\u017e","sequence":"additional","affiliation":[{"name":"Division of Internal Medicine, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5673-4458","authenticated-orcid":false,"given":"Katja","family":"Gori\u010dar","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2104-9060","authenticated-orcid":false,"given":"Tanja","family":"Blagus","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6707-6649","authenticated-orcid":false,"given":"Vita","family":"Dol\u017ean","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3495-0165","authenticated-orcid":false,"given":"Andrej","family":"Kastrin","sequence":"additional","affiliation":[{"name":"Institute for Biostatistics and Medical 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Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1743-6109.2009.01624.x","article-title":"Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction","volume":"7","author":"Gratzke","year":"2010","journal-title":"J. Sex. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1743-6109.2005.20103.x","article-title":"Pathophysiology of Erectile Dysfunction","volume":"2","author":"Angulo","year":"2005","journal-title":"J. Sex. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1124\/pr.111.004515","article-title":"Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction","volume":"63","author":"Andersson","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/j.1745-7262.2006.00223.x","article-title":"Pathophysiology and Treatment of Diabetic Erectile Dysfunction","volume":"8","author":"Moore","year":"2006","journal-title":"Asian J. Androl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.sxmr.2020.05.005","article-title":"Effect of Genetic Polymorphism on the Response to PDE5 Inhibitors in Patients with Erectile Dysfunction: A Systematic Review and a Critical Appraisal","volume":"8","author":"Mostafa","year":"2020","journal-title":"Sex. Med. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.jsxm.2016.04.075","article-title":"PDE5A Polymorphisms Influence on Sildenafil Treatment Success","volume":"13","author":"Marchal","year":"2016","journal-title":"J. Sex. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e14234","DOI":"10.1111\/and.14234","article-title":"Association between Folic Acid, Homocysteine, Vitamin B12 and Erectile Dysfunction\u2014A Cross-sectional Study","volume":"53","author":"Xu","year":"2021","journal-title":"Andrologia"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Salvio, G., Ciarloni, A., Cutini, M., and Balercia, G. (2021). Hyperhomocysteinemia: Focus on Endothelial Damage as a Cause of Erectile Dysfunction. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010418"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1161\/01.ATV.0000110785.96039.f6","article-title":"Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease","volume":"24","author":"Alp","year":"2004","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/s41443-024-00978-4","article-title":"Association between Serum Homocysteine and Erectile Dysfunction: A Systematic Review and Meta-Analysis","volume":"37","author":"Cheng","year":"2025","journal-title":"Int. J. Impot. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng0595-111","article-title":"A Candidate Genetic Risk Factor for Vascular Disease: A Common Mutation in Methylenetetrahydrofolate Reductase","volume":"10","author":"Frosst","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_14","first-page":"101293","article-title":"MTHFR Gene Polymorphisms and Susceptibility to Myocardial Infarction: Evidence from Meta-Analysis and Trial Sequential Analysis","volume":"49","author":"Samii","year":"2023","journal-title":"Int. J. Cardiol. Heart Vasc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/(SICI)1098-2272(199911)17:4<298::AID-GEPI5>3.0.CO;2-V","article-title":"Methionine Synthase D919G Polymorphism Is a Significant but Modest Determinant of Circulating Homocysteine Concentrations","volume":"17","author":"Harmon","year":"1999","journal-title":"Genet. Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1006\/mgme.1999.2879","article-title":"A Common Variant in Methionine Synthase Reductase Combined with Low Cobalamin (Vitamin B12) Increases Risk for Spina Bifida","volume":"67","author":"Wilson","year":"1999","journal-title":"Mol. Genet. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"qdag210","DOI":"10.1093\/jsxmed\/qdag210","article-title":"PDE5A Variation Is Associated with Tadalafil Response in Men with Diabetes Mellitus and Erectile Dysfunction: A Prospective Proof-of-Concept Pharmacogenetic Study","volume":"23","author":"Hostnik","year":"2026","journal-title":"J. Sex. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.eururo.2011.07.053","article-title":"Minimal Clinically Important Differences in the Erectile Function Domain of the International Index of Erectile Function Scale","volume":"60","author":"Rosen","year":"2011","journal-title":"Eur. Urol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1002\/sim.1047","article-title":"A Solution to the Problem of Separation in Logistic Regression","volume":"21","author":"Heinze","year":"2002","journal-title":"Stat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1111\/dme.13403","article-title":"High Prevalence of Erectile Dysfunction in Diabetes: A Systematic Review and Meta-Analysis of 145 Studies","volume":"34","author":"Kouidrat","year":"2017","journal-title":"Diabet. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Adam, D.R., and Alem, M.M. (2022). Erectile Dysfunction: Pharmacological Pathways with Understudied Potentials. Biomedicines, 11.","DOI":"10.3390\/biomedicines11010046"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1080\/13685538.2017.1404022","article-title":"Folate: A Possible Role in Erectile Dysfunction?","volume":"21","author":"Sansone","year":"2018","journal-title":"Aging Male"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"41","DOI":"10.4103\/aja202335","article-title":"Association between MTHFR c","volume":"26","author":"Bai","year":"2024","journal-title":"Asian J. Androl."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ferezin, L.P., Kayzuka, C., Paiva De Alc\u00e2ntara E Silva, M., Tavares Peixeiro, C.N., Rondon-Pereira, V.C., Tanus-Santos, J.E., and Lacchini, R. (2026). Genetic Biomarkers Associated with Risk and Therapeutic Response in Erectile Dysfunction: A Systematic Review. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1771865"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1086\/429864","article-title":"A Note on Exact Tests of Hardy-Weinberg Equilibrium","volume":"76","author":"Wigginton","year":"2005","journal-title":"Am. J. Hum. Genet."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7349\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:38:47Z","timestamp":1790077127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":25,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["jcm15197349"],"URL":"https:\/\/doi.org\/10.3390\/jcm15197349","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]}}}