Abstract
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.