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Title: Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.
Authors: Kelemen LE,  Terry KL,  Goodman MT,  Webb PM,  Bandera EV,  McGuire V,  Rossing MA,  Wang Q,  Dicks E,  Tyrer JP,  Song H,  Kupryjanczyk J,  Dansonka-Mieszkowska A,  Plisiecka-Halasa J,  Timorek A,  Menon U,  Gentry-Maharaj A,  Gayther SA,  Ramus SJ,  Narod SA,  Risch HA,  McLaughlin JR,  Siddiqui N,  Glasspool R,  Paul J,  Carty K,  Gronwald J,  Lubiński J,  Jakubowska A,  Cybulski C,  Kiemeney LA,  Massuger LF,  van Altena AM,  Aben KK,  Olson SH,  Orlow I,  Cramer DW,  Levine DA,  Bisogna M,  Giles GG,  Southey MC,  Bruinsma F,  Kjaer SK,  Høgdall E,  Jensen A,  Høgdall CK,  Lundvall L,  Engelholm SA,  Heitz F,  du Bois A,  Harter P,  Schwaab I,  Butzow R,  Nevanlinna H,  Pelttari LM,  Leminen A,  Thompson PJ,  Lurie G,  Wilkens LR,  Lambrechts D,  Van Nieuwenhuysen E,  Lambrechts S,  Vergote I,  Beesley J,  AOCS Study Group/ACS Investigators,  Fasching PA,  Beckmann MW,  Hein A,  Ekici AB,  Doherty JA,  Wu AH,  Pearce CL,  Pike MC,  Stram D,  Chang-Claude J,  Rudolph A,  Dörk T,  Dürst M,  Hillemanns P,  Runnebaum IB,  Bogdanova N,  Antonenkova N,  Odunsi K,  Edwards RP,  Kelley JL,  Modugno F,  Ness RB,  Karlan BY,  Walsh C,  Lester J,  Orsulic S,  Fridley BL,  Vierkant RA,  Cunningham JM,  Wu X,  Lu K,  Liang D,  Hildebrandt MA,  Weber RP,  Iversen ES,  Tworoger SS,  Poole EM,  Salvesen HB,  Krakstad C,  Bjorge L,  Tangen IL,  Pejovic T,  Bean Y,  Kellar M,  Wentzensen N,  Brinton LA,  Lissowska J,  Garcia-Closas M,  Campbell IG,  Eccles D,  Whittemore AS,  Sieh W,  Rothstein JH,  Anton-Culver H,  Ziogas A,  Phelan CM,  Moysich KB,  Goode EL,  Schildkraut JM,  Berchuck A,  Pharoah PD,  Sellers TA,  Brooks-Wilson A,  Cook LS,  Le ND
Journal: Mol Nutr Food Res
Date: 2014 Oct
Branches: MEB, OD, OEEB
PubMed ID: 25066213
PMC ID: PMC4197821
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.