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

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 (pinteraction = 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.