MTHFR Polymorphisms and Opisthorchis viverrini Infection: a Relationship with Increased Susceptibility to Cholangiocarcinoma in Thailand

Opisthorchis viverrini (OV) infection is the major risk factor for cholangiocarcinoma (CCA).Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism. Change in MTHFRactivity may influence both DNA methylation and synthesis, crucial steps in carcinogenesis. This study aimed toinvestigate the association between MTHFR polymorphisms and OV infection with CCA risk in a high-incidencearea of Thailand. A nested case-control study within cohort study was carried out: 219 subjects with primaryCCA were matched with two non-cancer controls from the same cohort on sex, age at recruitment and presence/absence of OV eggs in stool. At the time of recruitment information on consumption of foodstuffs potentiallycontaminated by OV was obtained by questionnaire. MTHFR polymorphisms were analyzed using PCR withhigh resolution melting analysis. Associations between variables and the risk of CCA were assessed usingconditional logistic regression. Risk of CCA was related to consumption of a dish of raw freshwater fish (Koi-Pla) with clear dose-response effects, and there were joint effects on CCA risk between MTHFR polymorphismsand consumption of dishes containing raw- and/or semi-raw freshwater fish. This study provides evidence tosupport a relationship of increased susceptibility to CCA in individuals with MTHFR variants, especially forthose individuals who have OV infection or consume semi-raw freshwater fish (acting either as a source of OVor of pre-formed nitrosamine). Folate may play an important role in OV-related cholangiocarcinogenesis byupsetting the balance between DNA methylation and synthesis in the folate pathway.