Kelemen, Linda E2; Terry, Kathryn L2; Goodman, Marc T2; Webb, Penelope M2; Bandera, Elisa V2; McGuire, Valerie2; Rossing, Mary Anne2; Wang, Qinggang2; Dicks, Ed2; Tyrer, Jonathan P2; Song, Honglin2; Kupryjanczyk, Jolanta2; Dansonka-Mieszkowska, Agnieszka2; Plisiecka-Halasa, Joanna2; Timorek, Agnieszka2; Menon, Usha2; Gentry-Maharaj, Aleksandra2; Gayther, Simon A2; Ramus, Susan J2; Narod, Steven A2; Risch, Harvey A2; McLaughlin, John R2; Siddiqui, Nadeem2; Glasspool, Rosalind2; Paul, James2; Carty, Karen2; Gronwald, Jacek2; Lubiński, Jan2; Jakubowska, Anna2; Cybulski, Cezary2; Kiemeney, Lambertus A2; Massuger, Leon F A G2; van Altena, Anne M2; Aben, Katja K H2; Olson, Sara H2; Orlow, Irene2; Cramer, Daniel W2; Levine, Douglas A2; Bisogna, Maria2; Giles, Graham G2; Southey, Melissa C2; Bruinsma, Fiona2; Kjaer, Susanne K4; Høgdall, Estrid2; Jensen, Allan2; Høgdall, Claus K4; Lundvall, Lene2; Engelholm, Svend-Aage5; Heitz, Florian2; du Bois, Andreas2; Harter, Philipp2; Schwaab, Ira2; Butzow, Ralf2; Nevanlinna, Heli2; Pelttari, Liisa M2; Leminen, Arto2; Thompson, Pamela J2; Lurie, Galina2; Wilkens, Lynne R2; Lambrechts, Diether2; Van Nieuwenhuysen, Els2; Lambrechts, Sandrina2; Vergote, Ignace2; Beesley, Jonathan2; Fasching, Peter A2; Beckmann, Matthias W2; Hein, Alexander2; Ekici, Arif B2; Doherty, Jennifer A2; Wu, Anna H2; Pearce, Celeste L2; Pike, Malcolm C2; Stram, Daniel2; Chang-Claude, Jenny2; Rudolph, Anja2; Dörk, Thilo2; Dürst, Matthias2; Hillemanns, Peter2; Runnebaum, Ingo B2; Bogdanova, Natalia2; Antonenkova, Natalia2; Odunsi, Kunle2; Edwards, Robert P2; Kelley, Joseph L2; Modugno, Francesmary2; Ness, Roberta B2; Karlan, Beth Y2; Walsh, Christine2; Lester, Jenny2; Orsulic, Sandra2; Fridley, Brooke L2; Vierkant, Robert A2; Cunningham, Julie M2; Wu, Xifeng2; Lu, Karen2; Liang, Dong2; Hildebrandt, Michelle A T2; Weber, Rachel Palmieri2; Iversen, Edwin S2; Tworoger, Shelley S2; Poole, Elizabeth M2; Salvesen, Helga B2; Krakstad, Camilla2; Bjorge, Line2; Tangen, Ingvild L2; Pejovic, Tanja2; Bean, Yukie2; Kellar, Melissa2; Wentzensen, Nicolas2; Brinton, Louise A2; Lissowska, Jolanta2; Garcia-Closas, Montserrat2; Campbell, Ian G2; Eccles, Diana2; Whittemore, Alice S2; Sieh, Weiva2; Rothstein, Joseph H2; Anton-Culver, Hoda2; Ziogas, Argyrios2; Phelan, Catherine M2; Moysich, Kirsten B2; Goode, Ellen L2; Schildkraut, Joellen M2; Berchuck, Andrew2; Pharoah, Paul D P2; Sellers, Thomas A2; Brooks-Wilson, Angela2; Cook, Linda S2; Le, Nhu D2
1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Section of Surgery and Internal Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet4 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet5 Section of Surgery and Internal Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Molecular Nutrition and Food Research, 2014, Vol 58, Issue 10, p. 2023-2035