Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Mol Nutr Food Res. 2014 Oct;58(10):2023-35. doi: 10.1002/mnfr.201400068. Epub 2014 Jul 28.

Abstract

Scope: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.

Methods and results: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006).

Conclusion: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Keywords: Case-control; Dihydropyrimidine dehydrogenase; Folate; Polymorphism; Serine hydroxymethyltransferase 1 (soluble).

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carcinoma / epidemiology
  • Carcinoma / etiology
  • Carcinoma / genetics*
  • Carcinoma / prevention & control
  • Case-Control Studies
  • Diet / adverse effects
  • Dietary Supplements*
  • Dihydrouracil Dehydrogenase (NADP) / genetics*
  • Dihydrouracil Dehydrogenase (NADP) / metabolism
  • Energy Intake
  • European Continental Ancestry Group
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid / metabolism
  • Folic Acid / therapeutic use*
  • Folic Acid Deficiency / diet therapy
  • Folic Acid Deficiency / metabolism
  • Folic Acid Deficiency / physiopathology
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Global Health
  • Humans
  • Multivariate Analysis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Ovarian Neoplasms / epidemiology
  • Ovarian Neoplasms / etiology
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / prevention & control
  • Polymorphism, Single Nucleotide*
  • Risk Factors

Substances

  • Neoplasm Proteins
  • Folic Acid
  • Dihydrouracil Dehydrogenase (NADP)

Grant support