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

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.

• Authors: Linda E Kelemen, Kathryn L Terry, Marc T Goodman, Penelope M Webb, Elisa V Bandera, Valerie McGuire, Mary Anne Rossing, Qinggang Wang, Ed Dicks, Jonathan P Tyrer, Honglin Song, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Joanna Plisiecka-Halasa, Agnieszka Timorek, Usha Menon, Aleksandra Gentry-Maharaj, Simon A Gayther, Susan J Ramus, Steven A Narod, Harvey A Risch, John R McLaughlin, Nadeem Siddiqui, Rosalind Glasspool, James Paul, Karen Carty, Jacek Gronwald, Jan Lubiński, Anna Jakubowska, Cezary Cybulski, Lambertus A Kiemeney, Leon F A G Massuger, Anne M van Altena, Katja K H Aben, Sara H Olson, Irene Orlow, Daniel W Cramer, Douglas A Levine, Maria Bisogna, Graham G Giles, Melissa C Southey, Fiona Bruinsma, Susanne K Kjaer, Estrid Høgdall, Allan Jensen, Claus K Høgdall, Lene Lundvall, Svend-Aage Engelholm, Florian Heitz, Andreas du Bois, Philipp Harter, Ira Schwaab, Ralf Butzow, Heli Nevanlinna, Liisa M Pelttari, Arto Leminen, Pamela J Thompson, Galina Lurie, Lynne R Wilkens, Diether Lambrechts, Els Van Nieuwenhuysen, Sandrina Lambrechts, Ignace Vergote, Jonathan Beesley, AOCS Study Group/ACS Investigators, Peter A Fasching, Matthias W Beckmann, Alexander Hein, Arif B Ekici, Jennifer A Doherty, Anna H Wu, Celeste L Pearce, Malcolm C Pike, Daniel Stram, Jenny Chang-Claude, Anja Rudolph, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo B Runnebaum, Natalia Bogdanova, Natalia Antonenkova, Kunle Odunsi, Robert P Edwards, Joseph L Kelley, Francesmary Modugno, Roberta B Ness, Beth Y Karlan, Christine Walsh, Jenny Lester, Sandra Orsulic, Brooke L Fridley, Robert A Vierkant, Julie M Cunningham, Xifeng Wu, Karen Lu, Dong Liang, Michelle A T Hildebrandt, Rachel Palmieri Weber, Edwin S Iversen, Shelley S Tworoger, Elizabeth M Poole, Helga B Salvesen, Camilla Krakstad, Line Bjorge, Ingvild L Tangen, Tanja Pejovic, Yukie Bean, Melissa Kellar, Nicolas Wentzensen, Louise A Brinton, Jolanta Lissowska, Montserrat Garcia-Closas, Ian G Campbell, Diana Eccles, Alice S Whittemore, Weiva Sieh, Joseph H Rothstein, Hoda Anton-Culver, Argyrios Ziogas, Catherine M Phelan, Kirsten B Moysich, Ellen L Goode, Joellen M Schildkraut, Andrew Berchuck, Paul D P Pharoah, Thomas A Sellers, Angela Brooks-Wilson, Linda S Cook, Nhu D Le
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 58 Issue 10 Pg. 2023-35 (Oct 2014) ISSN: 1613-4133 [Electronic] Germany
• PMID: 25066213 (Publication Type: Journal Article, 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.)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

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

Topics

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