ArticleClinics (Sao Paulo, Brazil)2026
The mediating role of inflammation and nutrition metabolism in the methylmalonic acid-stroke association.
Article in Clinics (Sao Paulo, Brazil), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThis 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.
methodsWe 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.
resultsWMLR 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.
conclusionSerum MMA is positively associated with stroke prevalence, partially mediated by inflammatory response (NLR) and nutritional/metabolic indicators (TG and FPG).
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