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Polymorphisms in genes involved in folate metabolism modify the association of dietary and circulating folate and vitamin B-6 with cervical neoplasia


High folate intake has been suggested as an important factor for cancer prevention; however, previous studies on the relationship between folate intake, serum folate and plasma homocysteine are controversial. We conducted a hospital-based, case-control study in Brazil investigating associations between dietary and circulating vitamins B-6, B-12 and folate, homocysteine, genotypes of folate-metabolizing enzyme methylenetetrahydrofolate reductase [MTHFR C677T, A1298C], 5-methyltetrahydrofolate-homocysteine methyltransferase [MTR A2756G], methionine synthase reductase [MTRR A66G], reduced folate carrier [RFC1 G80A] and risk of cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3. The study was composed by 453 controls, 140 CIN1, 126 CIN2, and 231 CIN3. We investigated the joint effects of genetic variants of folate-related genes using genetic risk scores (GRS) by summing the number of risk alleles for CIN1 and CIN2+ (CIN2 + CIN3 cases). The OR (95% CI) for CIN1 and CIN2+ per each risk allele were, respectively, 1.29 (1.01, 1.65) and 1.22 (1.01, 1.46). An association between folate intake and CIN2+ was only observed after stratification according to GRS: crude OR (95% CI) for lower folate intake and GRS e 4 was 1.67 (0.92, 3.04) (P-trend< 0.001) when compared with higher folate intake (above the median) and GRS d 3. The CIN2+ risk for lower serum vitamin B-6 and GRS e 4 was 2.14 (0.92, 5.02) (P-trend = 0.05) and lower serum folate (below the median) and GRS e 4 was 0.49 (0.20, 1.17) (P-trend = 0.05), after adjustment for confounding variables and HPV infection. Our data suggest that polymorphisms in genes related to folate metabolism modify the association of dietary and circulating folate and vitamin-B6 with cervical neoplasia. (AU)

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