The mediating role of inflammation and nutrition metabolism in the methylmalonic acid-stroke association.

BACKGROUND

This study explored the association between Methylmalonic Acid (MMA, the primary exposure factor) and stroke, and the potential mediating roles of systemic inflammatory marker (Neutrophil-to-Lymphocyte Ratio [NLR]) and nutritional-metabolic parameters (Triglycerides [TG], Fasting Plasma Glucose [FPG]). Based on biological plausibility and evidence-based rationale, these three indicators were selected a priori and incorporated as core mediating variables in the analytical model.

METHODS

We included 9430 participants from NHANES 2011-2014, comprising 712 stroke cases and 8718 non-stroke controls; this cross-sectional study enrolled adults ≥ 20-years. Weighted Multivariable Logistic Regression (WMLR) analyzed MMA-stroke prevalence association; RCS examined their non-linearity. Subgroup/mediation analyses evaluated association heterogeneity and NLR/TG/FPG's mediating effects. In addition, the mediation effects of other inflammatory, nutritional, metabolic, and oxidative stress-related markers were also evaluated.

RESULTS

WMLR showed a significant positive association between MMA and stroke (continuous MMA: OR [95% CI]: 1.423 [1.166, 1.942]). When MMA was categorized by tertiles (T2: OR = 1.467, 95% CI: 1.067-2.129; T3: OR = 1.644, 95% CI: 1.155-2.578), the association persisted after adjusting for renal function, vitamin B₁₂, and other covariates. RCS indicated a non-linear relationship between MMA and stroke (cut-off point: ln (MMA) = 5). The association was more pronounced in participants aged < 60 years (P for interaction = 0.013). NLR, TG, and FPG exerted partial mediating effects (4.923%, 7.187%, 5.331%; all p < 0.001). By contrast, other inflammatory markers (SIRI, PLR, SII, MLR, albumin, uric acid, LDH) did not exhibit significant mediating effects, with all PM values < 1% and p > 0.05. Given the cross-sectional nature of this study, we cannot determine whether elevated MMA levels preceded stroke or were a consequence of post-stroke pathophysiology.

CONCLUSION

Serum MMA is positively associated with stroke prevalence, partially mediated by inflammatory response (NLR) and nutritional/metabolic indicators (TG and FPG).