Association of methylmalonic acid with erectile dysfunction and the mediating role of endothelial activation: a population-based study of NHANES 2001-2004.

Background: Oxidative stress, mitochondrial dysfunction, and endothelial injury are important mechanisms in erectile dysfunction (ED). Methylmalonic acid (MMA) is related to vitamin B12 metabolism, mitochondrial dysfunction, and oxidative stress, but its relationship with ED and endothelial activation remains unclear. Aim: To investigate the associations of MMA and Endothelial Activation and Stress Index (EASIX) with ED and to evaluate whether EASIX mediates the association between MMA and ED. Methods: This cross-sectional study analyzed data from 2 National Health and Nutrition Examination Survey cycles (2001-2002 and 2003-2004; overall period, 2001-2004). A total of 3306 men aged 20 years or older were included. Survey-weighted logistic regression models were used to examine the associations of continuous MMA and EASIX with ED; exploratory categorical analyses based on data-derived cutoffs were treated as sensitivity analyses. The mediating effect of EASIX on the association between MMA and ED was assessed using the distribution-of-product method. Outcomes: The primary outcome was ED, defined using NHANES item KIQ400. The primary exposures were serum MMA and EASIX, both analyzed primarily as continuous variables. Results: Higher MMA was associated with greater odds of ED after adjustment for confounding factors (OR 1.031, 95% CI, 1.008-1.056). Higher EASIX was also associated with increased odds of ED (OR 2.284, 95% CI, 1.278-4.080). In the primary continuous-variable mediation analysis, EASIX significantly mediated the association between MMA and ED, with an indirect-effect OR of 1.0022 (95% CI, 1.0004-1.0049), and the proportion mediated was 7.18%. Exploratory categorical analyses based on restricted cubic spline-derived cutoffs showed similar directions of association. Clinical Implications: Methylmalonic acid and EASIX may serve as population-level markers associated with ED risk and may help inform future studies on metabolic-endothelial pathways in male sexual dysfunction. Strengths and Limitations: Strengths of this study include the use of a nationally representative sample and survey-weighted analyses. Limitations include the cross-sectional design, self-reported assessment of ED, and the historical nature of the NHANES cycles used. Conclusion: Higher MMA and higher EASIX were associated with increased odds of ED, and EASIX partly mediated the association in continuous-variable primary analyses. These findings should be interpreted as hypothesis-generating because of the cross-sectional design.