MTHFR rs1801131 GG Genotype Combined with Serum LDH Level Predicts Lung Adenocarcinoma Susceptibility and Poor Prognosis in Guangxi Zhuang Population

IntroductionMethylenetetrahydrofolate reductase (MTHFR) polymorphisms modulate folate metabolism and carcinogenesis, yet their role in lung adenocarcinoma (LUAD) susceptibility and prognosis, particularly in underrepresented populations, remains unclear.MethodsWe conducted a retrospective case-control study of 306 lung cancer (LC) patients (predominantly LUAD) and 156 healthy controls of Guangxi Zhuang ethnicity, with prognostic follow-up of the cases. Genotyping (rs1801131/rs1801133), serum lactate dehydrogenase (LDH) levels, and tumor MTHFR protein expression were analyzed. Associations with susceptibility (logistic regression), survival (Cox models/Kaplan-Meier), and molecular mechanisms were evaluated.ResultsThe MTHFR rs1801131 GG genotype conferred increased LUAD susceptibility (adjusted OR = 2.14, 95% CI: 0.99-4.65, P = 0.054) and predicted poor overall survival (OS, P = 0.043) and progression-free interval (PFI, P = 0.023). Among all LC subtypes, the GG genotype was also associated with worse prognosis (P = 0.033). Patients with both GG genotype and elevated LDH (eLDH) had higher mortality OS risk than those with TT or GG genotype with eLDH in the LC and LUAD cohorts (P = 0.034 and 0.042). Mechanistically, the GG genotype reduced tumor MTHFR protein expression (P < 0.05). The GG (rs1801131-G/rs1801133-G) haplotype elevated LUAD risk by 1.53-fold (P = 0.022).ConclusionIn the Guangxi Zhuang cohort, the MTHFR rs1801131 GG genotype may represent a population-specific marker associated with LUAD susceptibility and poorer prognosis. Its combination with elevated LDH may provide supplementary information for risk stratification, although further validation in larger multicenter and multi-ethnic cohorts is required.