Null Results in Brief No Association between MTHFR 677 C!T or 1298 A!C Polymorphisms and Endometrial Cancer Risk Randi A. Paynter, 1 Susan E. Hankinson, 1,4 David J. Hunter, 1,2,3,4 and Immaculata De Vivo 1,3,4 Departments of 1 Epidemiology and 2 Nutrition, and 3 Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, Massachusetts, and 4 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts Introduction The enzyme 5,10-methylenetetrahydrofolate reductase, encoded by MTHFR , catalyzes the reduction of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate. The MTHFR 677 C!T polymorphism results in an amino acid change, Ala!Val. The Val allele is associated with decreased enzyme activity (1), and may potentially influence carcinogenesis through somatic DNA methyl- ation or through uracil misincorporation in DNA synthesis and repair. Another common non-synonymous polymorphism MTHFR 1298 A!C (Glu!Ala) has been associated with lower blood folate and higher homocys- teine levels in some (e.g., 2) but not all (e.g., 3) studies. There has been one study previously published examin- ing the MTHFR 677 C!T polymorphism and endome- trial cancer risk (4). Esteller et al. (4) reported in their study of 80 cases and 60 controls that women with a ‘‘T’’ allele had an increased risk of endometrial cancer compared with ‘‘CC’’ homozygotes [odds ratio (OR) = 2.8; 95% confidence interval (CI), 1.36-6.14]. Dietary folate, the substrate of MTHFR , has been associated with a decreased risk of endometrial cancer (5). We hypoth- esized that MTHFR polymorphisms may affect endome- trial cancer risk, and that the risk may be modified by folate intake. Materials and Methods Detailed information about this nested case-control study of endometrial cancer in the Nurses’ Health Study cohort (cases, n = 222; controls, n = 666) has been reported previously (6). Genotyping was done using the Taqman system. Taqman primers, probes, and conditions for genotyping assays are available on request. All geno- typing was done with laboratory personnel blinded to case-control status of the samples, which included quality control samples for validation. Concordance for quality control samples was 100%. Dietary information was collected prospectively for 201 cases and 603 controls, including energy-adjusted total folate from dietary intake and vitamin supplements, and weekly alcohol intake in grams (7). ORs and 95% CIs were calculated using conditional logistic regression and were adjusted for established endometrial cancer risk factors. Haplotype estimation and linkage disequilibrium meas- ures were done using SAS/Genetics version 8.2 (SAS Institute, Cary, NC). Results Both MTHFR polymorphisms were in Hardy-Weinberg equilibrium in the cases and the controls (P > 0.05). Comparing cases to controls, the prevalence of the variant allele was 32.8% versus 32.6% for 677 C!T and 33.3% versus 33.2% for 1298 A!C. We found little or no association between MTHFR genotype and endometrial cancer risk (Table 1). For the MTHFR 677 C!T polymorphism, we observed an adjusted OR = 1.10, 95% CI (0.77-1.57) comparing those having a ‘‘T’’ allele to the ‘‘CC’’ homozygotes. For the MTHFR 1298 A!C polymorphism, we observed no association comparing those with the ‘‘C’’ allele to the ‘‘AA’’ homozygotes (OR = 0.85; 95% CI, 0.61-1.20). Among our sample of 201 cases and 603 controls for whom we had prospectively collected dietary informa- tion, we observed a marginally reduced risk of endo- metrial cancer among women with energy-adjusted total folate z400 Ag/d (OR = 0.74; 95% CI, 0.52-1.07) compared with women with <400 Ag/d. Women with alcohol intake z15 g/d (approximately one alcoholic beverage) had an estimated endometrial cancer risk of OR = 1.36, 95% CI (0.77-2.40). We observed a modest inverse association between jointly high folate and low alcohol intake and endometrial cancer risk when we compared those with high folate (z400 Ag/d) and low alcohol intake (<15 g/d) to all others (OR = 0.72; 95% CI, 0.49-1.05). There was no statistically significant interaction of dietary factors with either MTHFR geno- type. Our study had >99% power to detect an OR = 2.8 for either locus, and >80% power to detect OR = 1.6. We had limited power, however, to detect an interaction between genotype and folate and alcohol intake, assuming OR genotype = 2.8 and OR low folate = 1.5; we had 41% power to detect u = 2.0 and 29% power to detect u = 0.5 (8). Cancer Epidemiol Biomarkers Prev 2004;13(6):1088 – 9 Received 1/13/04; accepted 2/3/04. Grant support: National Institutes of Health grants 5T32CA09001-27, R25GM55353 (R. Paynter); CA49449 (S. Hankinson); CA82838 (I. De Vivo); and American Cancer Society grant RSG-00-061-04-CCE (I. De Vivo). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Randi A. Paynter, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115. Phone: (617) 306-5611; Fax: (617) 566-7805. 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