Dataset Information

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??) and rs828054 (OR = 1.06; p = 1 × 10??). 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??) 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.

SUBMITTER: Kelemen LE

PROVIDER: S-EPMC4197821 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kelemen Linda E LE Terry Kathryn L KL Goodman Marc T MT Webb Penelope M PM Bandera Elisa V EV McGuire Valerie V Rossing Mary Anne MA Wang Qinggang Q Dicks Ed E Tyrer Jonathan P JP Song Honglin H Kupryjanczyk Jolanta J Dansonka-Mieszkowska Agnieszka A Plisiecka-Halasa Joanna J Timorek Agnieszka A Menon Usha U Gentry-Maharaj Aleksandra A Gayther Simon A SA Ramus Susan J SJ Narod Steven A SA Risch Harvey A HA McLaughlin John R JR Siddiqui Nadeem N Glasspool Rosalind R Paul James J Carty Karen K Gronwald Jacek J Lubiński Jan J Jakubowska Anna A Cybulski Cezary C Kiemeney Lambertus A LA Massuger Leon F A G LF van Altena Anne M AM Aben Katja K H KK Olson Sara H SH Orlow Irene I Cramer Daniel W DW Levine Douglas A DA Bisogna Maria M Giles Graham G GG Southey Melissa C MC Bruinsma Fiona F Kjaer Susanne K SK Høgdall Estrid E Jensen Allan A Høgdall Claus K CK Lundvall Lene L Engelholm Svend-Aage SA Heitz Florian F du Bois Andreas A Harter Philipp P Schwaab Ira I Butzow Ralf R Nevanlinna Heli H Pelttari Liisa M LM Leminen Arto A Thompson Pamela J PJ Lurie Galina G Wilkens Lynne R LR Lambrechts Diether D Van Nieuwenhuysen Els E Lambrechts Sandrina S Vergote Ignace I Beesley Jonathan J Fasching Peter A PA Beckmann Matthias W MW Hein Alexander A Ekici Arif B AB Doherty Jennifer A JA Wu Anna H AH Pearce Celeste L CL Pike Malcolm C MC Stram Daniel D Chang-Claude Jenny J Rudolph Anja A Dörk Thilo T Dürst Matthias M Hillemanns Peter P Runnebaum Ingo B IB Bogdanova Natalia N Antonenkova Natalia N Odunsi Kunle K Edwards Robert P RP Kelley Joseph L JL Modugno Francesmary F Ness Roberta B RB Karlan Beth Y BY Walsh Christine C Lester Jenny J Orsulic Sandra S Fridley Brooke L BL Vierkant Robert A RA Cunningham Julie M JM Wu Xifeng X Lu Karen K Liang Dong D Hildebrandt Michelle A T MA Weber Rachel Palmieri RP Iversen Edwin S ES Tworoger Shelley S SS Poole Elizabeth M EM Salvesen Helga B HB Krakstad Camilla C Bjorge Line L Tangen Ingvild L IL Pejovic Tanja T Bean Yukie Y Kellar Melissa M Wentzensen Nicolas N Brinton Louise A LA Lissowska Jolanta J Garcia-Closas Montserrat M Campbell Ian G IG Eccles Diana D Whittemore Alice S AS Sieh Weiva W Rothstein Joseph H JH Anton-Culver Hoda H Ziogas Argyrios A Phelan Catherine M CM Moysich Kirsten B KB Goode Ellen L EL Schildkraut Joellen M JM Berchuck Andrew A Pharoah Paul D P PD Sellers Thomas A TA Brooks-Wilson Angela A Cook Linda S LS Le Nhu D ND

Molecular nutrition & food research 20140728 10

<h4>Scope</h4>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.<h4>Methods and results</h4>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 correct ...[more]

PMID: 25066213

Similar Datasets

Project description:ObjectiveResponses to therapies, either with regard to toxicities or efficacy, are expected to involve complex relationships of gene products within the same molecular pathway or functional gene set. Therefore, pathways or gene sets, as opposed to single genes, may better reflect the true underlying biology and may be more appropriate units for analysis of pharmacogenomic studies. Application of such methods to pharmacogenomic studies may enable the detection of more subtle effects of multiple genes in the same pathway that may be missed by assessing each gene individually.MethodsA gene set analysis of 3821 gene sets is presented assessing the association between basal messenger RNA expression and drug cytotoxicity using ethnically defined human lymphoblastoid cell lines for two classes of drugs: pyrimidines [gemcitabine (dFdC) and arabinoside] and purines [6-thioguanine and 6-mercaptopurine].ResultsThe gene set nucleoside-diphosphatase activity was found to be significantly associated with both dFdC and arabinoside, whereas gene set γ-aminobutyric acid catabolic process was associated with dFdC and 6-thioguanine. These gene sets were significantly associated with the phenotype even after adjusting for multiple testing. In addition, five associated gene sets were found in common between the pyrimidines and two gene sets for the purines (3',5'-cyclic-AMP phosphodiesterase activity and γ-aminobutyric acid catabolic process) with a P value of less than 0.0001. Functional validation was attempted with four genes each in gene sets for thiopurine and pyrimidine antimetabolites. All four genes selected from the pyrimidine gene sets (PSME3, CANT1, ENTPD6, ADRM1) were validated, but only one (PDE4D) was validated for the thiopurine gene sets.ConclusionIn summary, results from the gene set analysis of pyrimidine and purine therapies, used often in the treatment of various cancers, provide novel insight into the relationship between genomic variation and drug response.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure