Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele.
BACKGROUND
Folate is involved in DNA synthesis and methylation and may thereby influence carcinogenesis.


OBJECTIVE
We examined plasma folate (P-folate) concentration in relation to genotypes of the folate-metabolizing enzyme methylenetetrahydrofolate reductase [MTHFR 677C-->T (rs1801133) and 1298A-->C (rs1801131)]. We also explored whether P-folate was associated with risk of postmenopausal breast cancer overall and in subgroups with genetic variants of the MTHFR single nucleotide polymorphisms (SNPs).


METHODS
This nested case-control study included 313 cases (age 55-73 y at baseline) with invasive breast cancer and 626 control subjects, matched on age and blood-sample date, from the population-based Malmö Diet and Cancer cohort. P-folate and MTHFR genotypes were determined for 310 cases and 611 controls. P-folate according to genotype was calculated by using analysis of variance. Odds ratios were obtained by using logistic regression. All tests were 2-sided.


RESULTS
The variant 677T allele was associated with lower P-folate. In women with the 677T allele, a high P-folate concentration was associated with increased breast cancer risk (P for trend across P-folate tertiles = 0.03). Interaction was seen between the 677C-->T SNP and P-folate (P = 0.002). A positive association, which was seen between P-folate and breast cancer risk in 1298AA women (P = 0.01), was probably due to linkage between the 2 SNPs. Overall, and in women with other genotypes, no significant associations were observed.


CONCLUSIONS
Our results suggest an association of high P-folate concentration with increased risk of postmenopausal breast cancer in carriers of the 677T allele. The findings underline the importance of genetic variation of MTHFR in the complex relation between folate and cancer.
Ericson
Ulrika C
UC
Department of Clinical Sciences, Malmö, Nutrition Epidemiology, Lund University, Sweden. ulrika.ericson@med.lu.se
Ivarsson
Malin I L
MI
Sonestedt
Emily
E
Gullberg
Bo
B
Carlson
Joyce
J
Olsson
Håkan
H
Wirfält
Elisabet
E
D000368:Aged; D001943:Breast Neoplasms / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D017931:DNA Primers; D004261:DNA Replication; D005260:Female; D005492:Folic Acid / Q000097:blood; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D013548:Sweden; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D017931:DNA Primers; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013762:Tetrahydrofolate Dehydrogenase