Abstract
BackgroundEvidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects.MethodsOur case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk.ResultsOverall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk.ConclusionsOur data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.
Highlights
Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive
High intake of dietary folate was inversely associated with pancreatic cancer risk, with odds ratios (ORs) of 0.52 among individuals falling into the highest quartile when compare with those falling into the lowest quartile
No significant interactions were noted for C677T genotypes and alcohol drinking; the OR of pancreatic cancer was 1.05 for individuals who had the TT genotype and were ever smokers. In this genetic case-control association study, we found no statistically significant associations between polymorphisms in folate metabolizing gene pathways, including MTHFR C677T and A1298C, and the risk of pancreatic
Summary
Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects. Evidence on the diet-pancreatic cancer associations from epidemiologic studies remains elusive, in part because of wide variation in dietary habits and the difficulty of accurate diet measurement. Previous studies have shown mixed findings on the association between dietary folate intake and pancreatic cancer risk [6,7,8,9], a 2014 meta-analysis reported an inverse association [10]. Of numerous genes involved in the folate metabolizing pathway, MTHFR has been the most extensively studied [11, 12]. The 677 T variant has been associated with numerous conditions, including elevated homocysteine, spinal bifida, colon cancer, and Down syndrome [3] As for MTHFR A1298C, the homozygous CC genotype has approximately 60 % of normal MTHFR activity [12]
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