Methylenetetrahydrofolate reductase (MTHFR) polymorphism increases the risk of cervical intraepithelial neoplasia

Although cervical cancer is a common female cancer; little attention has be en given to genetic susceptibility factors. The present case-cona ol study was under taken to examine MTHFR polymorphism as a potential molecular mark er of cervical intraepithelial neoplasia (CIN) susceptibility and to I elat e the findings to smoking, HPV infection, ethnicity, parity and oral contra ceptive we, which are known risk factors for cervical cancer A base change from C to T at the nucleotide position 677 of the MTHFR gene results in sub stitution of valine (GTC) for alanine (GCC). The homozygous normal (Ala/Ala ), homozygous mutant (Val/Val), and heterozygous mutant (Ala/Val) genotypes for the MTHFR gene were determined in cervical tissues of 64 cases of CIN lesions and 31 cona ols. The genotype frequencies of both Val/Val (17%) and Ala/Val (56%) were significantly higher in subjects with CIN lesions compa red to controls with Val/Val (10%) and Ala/Val (39%), (trend p = 0.03). The results suggested a significantly increased CIN risk with an alanine to va line substitution at amino acid 223 of MTHFR with an odds ratio of 2.9 (95% confidence interval: 1.2-79, p = 0.02). Age, ethnicity, smoking and oral c ontraceptive use were weakly and nonsignificantly associated with CIN risk. HPV infection was associated with a statistically nonsignificant threefold increase in CIN risk. Parity and MTHFR genotype displayed a strong interac tion. Neither nulliparous women with MTHFR polymorphism nor parous women wi thout the polymorphism were at higher risk than women who did not have chil dren and were MTHFR homozygous normal (the reference category). Women with mutant MTHFR genotype who had children, however; showed a significantly hig her risk of GIN, with an odds ratio of 23 (95% confidence interval: 2.3-225 ) as compared to the reference category. No other factors displayed such a strong pattern of interaction. Since MTHFR polymorphism and pregnancy incre ases folate requirements and can impair folate status, this association cou ld reflect an inadequate response of mutant MTHFR genotype carriers to the increased demand for folate imposed by pregnancy. Tissue folate deficiency, in turn, could increase the risk of CIN in the affected women.