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

Journal Article (Journal Article;Multicenter Study)

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.

Full Text

Duke Authors

Cited 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, LFAG; van Altena, AM; Aben, KKH; 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, S-A; 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, MAT; 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, PDP; Sellers, TA; Brooks-Wilson, A; Cook, LS; Le, ND

Published Date

  • October 2014

Published In

Volume / Issue

  • 58 / 10

Start / End Page

  • 2023 - 2035

PubMed ID

  • 25066213

Pubmed Central ID

  • PMC4197821

Electronic International Standard Serial Number (EISSN)

  • 1613-4133

Digital Object Identifier (DOI)

  • 10.1002/mnfr.201400068

Language

  • eng

Conference Location

  • Germany