Folate Pathway Polymorphisms and Tadalafil Response in Men with Diabetes Mellitus and Erectile Dysfunction: An Exploratory Study.
5 affiliations
- 1Division of Internal Medicine, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
- 2Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
- 3Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
- 4Institute for Biostatistics and Medical Informatics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
- 5Division of Surgery, Department of Abdominal Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
Abstract
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-homocysteine pathway may influence endothelial function and contribute to this variability. To investigate the association of selected polymorphisms in folate-homocysteine 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 ≥4-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 ≥4 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 'any improvement' analysis, a nominal association was observed for MTR rs1805087 in a small subgroup (n = 5 GG carriers; unadjusted OR = 0.15, 95% CI 0.02-0.89; p = 0.037), which was attenuated after multivariable adjustment (OR = 0.16, 95% CI 0.02-1.08, 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.
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BibTeX
@article{hostnik2026folate,
title = {{Folate Pathway Polymorphisms and Tadalafil Response in Men with Diabetes Mellitus and Erectile Dysfunction: An Exploratory Study.}},
author = {Boštjan Hostnik and Andrej Janež and Katja Goričar and Tanja Blagus and Vita Dolžan and Andrej Kastrin and Jasna Klen},
journal = {Journal of clinical medicine},
year = {2026},
month = sep,
doi = {10.3390/jcm15197349},
url = {https://europepmc.org/article/MED/42881810},
note = {CC BY},
}
RIS
TY - JOUR
TI - Folate Pathway Polymorphisms and Tadalafil Response in Men with Diabetes Mellitus and Erectile Dysfunction: An Exploratory Study.
AU - Boštjan Hostnik
AU - Andrej Janež
AU - Katja Goričar
AU - Tanja Blagus
AU - Vita Dolžan
AU - Andrej Kastrin
AU - Jasna Klen
PY - 2026
DA - 2026/09/22
JO - Journal of clinical medicine
DO - 10.3390/jcm15197349
UR - https://europepmc.org/article/MED/42881810
AB - 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-homocysteine pathway may influence endothelial function and contribute to this variability. To investigate the association of selected polymorphisms in folate-homocysteine 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 ≥4-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 ≥4 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 'any improvement' analysis, a nominal association was observed for MTR rs1805087 in a small subgroup (n = 5 GG carriers; unadjusted OR = 0.15, 95% CI 0.02-0.89; p = 0.037), which was attenuated after multivariable adjustment (OR = 0.16, 95% CI 0.02-1.08, 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.
SN - 2077-0383
ER -