Abstract
<title>Abstract</title> <p> Background Nasopharyngeal carcinoma is a multifactorial malignancy influenced by genetic, environmental, and viral factors, particularly Epstein-Barr Virus. Alterations in folate metabolism genes may impair DNA synthesis and methylation, promoting carcinogenesis. This study aimed to investigate the association between common polymorphisms in <italic>MTHFR</italic> (C677T and A1298C), <italic>MTRR</italic> (A66G), and <italic>MTR</italic> (A2756G) genes and nasopharyngeal carcinoma risk in a Tunisian cohort. Methods Between May 2020 and August 2023, 36 patients diagnosed with NPC and 41 healthy controls were enrolled. Genotyping was performed using TaqMan® Real-Time PCR assays. Allelic and genotypic distributions were compared using chi-square and Fisher’s exact tests, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results A significant association was observed between the <italic>MTHFR</italic> A1298C polymorphism and NPC susceptibility. The C allele was associated with an increased risk of NPC (OR = 4.07; 95% CI: 1.47–11.24; p = 0.0068), and the CC genotype was detected exclusively among cases. No significant associations were found for <italic>MTHFR</italic> C677T, <italic>MTRR</italic> A66G, or <italic>MTR</italic> A2756G variants. Conclusion Our findings provide preliminary evidence that the <italic>MTHFR A1298C</italic> polymorphism may contribute to genetic susceptibility to NPC in the Tunisian population. Although confirmation in larger cohorts is required, these results support the growing evidence that alterations in folate metabolism could modulate NPC risk through interactions with environmental and viral factors. </p>