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

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. Kjær; 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

doi:10.1002/mnfr.201400068

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

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. NarodHarvey 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. Kjær, 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

Epidemiology and Preventive Medicine Alfred Hospital

Research output: Contribution to journal › Article › Research › peer-review

10 Citations (Scopus)

Abstract

Scope: We reevaluated previously reported associations between variants in pathways of onecarbon (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.

Original language	English
Pages (from-to)	2023-2035
Number of pages	13
Journal	Molecular Nutrition & Food Research
Volume	58
Issue number	10
DOIs	https://doi.org/10.1002/mnfr.201400068
Publication status	Published - 1 Jan 2014

Keywords

Case-control
Dihydropyrimidine dehydrogenase
Folate
Polymorphism
Serine hydroxymethyltransferase 1 (soluble)

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10.1002/mnfr.201400068

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Kelemen, L. E., Terry, K. L., Goodman, M. T., Webb, P. M., Bandera, E. V., McGuire, V., Anne Rossing, M., Wang, Q., Dicks, E., Tyrer, J. P., Song, H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Timorek, A., Menon, U., Gentry-Maharaj, A., Gayther, S. A., Ramus, S. J., ... Le, N. D. (2014). Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk. Molecular Nutrition & Food Research, 58(10), 2023-2035. https://doi.org/10.1002/mnfr.201400068

@article{82761ebfbd4a4feb85d544729679cbe0,

title = "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 onecarbon (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.",

keywords = "Case-control, Dihydropyrimidine dehydrogenase, Folate, Polymorphism, Serine hydroxymethyltransferase 1 (soluble)",

author = "Kelemen, {Linda E.} and Terry, {Kathryn L.} and Goodman, {Marc T.} and Webb, {Penelope M.} and Bandera, {Elisa V.} and Valerie McGuire and {Anne Rossing}, Mary and Qinggang Wang and Ed Dicks and Tyrer, {Jonathan P.} and Honglin Song and Jolanta Kupryjanczyk and Agnieszka Dansonka-Mieszkowska and Joanna Plisiecka-Halasa and Agnieszka Timorek and Usha Menon and Aleksandra Gentry-Maharaj and Gayther, {Simon A.} and Ramus, {Susan J.} and Narod, {Steven A.} and Risch, {Harvey A.} and McLaughlin, {John R.} and Nadeem Siddiqui and Rosalind Glasspool and James Paul and Karen Carty and Jacek Gronwald and Jan Lubi{\'n}ski and Anna Jakubowska and Cezary Cybulski and Kiemeney, {Lambertus A.} and Massuger, {Leon F.A.G.} and {van Altena}, {Anne M.} and Aben, {Katja K.H.} and Olson, {Sara H.} and Irene Orlow and Cramer, {Daniel W.} and Levine, {Douglas A.} and Maria Bisogna and Giles, {Graham G.} and Southey, {Melissa C.} and Fiona Bruinsma and Kj{\ae}r, {Susanne K.} and Estrid H{\o}gdall and Allan Jensen and H{\o}gdall, {Claus K.} and Lene Lundvall and Engelholm, {Svend Aage} and Florian Heitz and {du Bois}, Andreas and Philipp Harter and Ira Schwaab and Ralf Butzow and Heli Nevanlinna and Pelttari, {Liisa M.} and Arto Leminen and Thompson, {Pamela J.} and Galina Lurie and Wilkens, {Lynne R.} and Diether Lambrechts and {Van Nieuwenhuysen}, Els and Sandrina Lambrechts and Ignace Vergote and Jonathan Beesley and {AOCS Study Group/ACS Investigators} and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Alexander Hein and Ekici, {Arif B.} and Doherty, {Jennifer A.} and Wu, {Anna H.} and Pearce, {Celeste L.} and Pike, {Malcolm C.} and Daniel Stram and Jenny Chang-Claude and Anja Rudolph and Thilo D{\"o}rk and Matthias D{\"u}rst and Peter Hillemanns and Runnebaum, {Ingo B.} and Natalia Bogdanova and Natalia Antonenkova and Kunle Odunsi and Edwards, {Robert P.} and Kelley, {Joseph L.} and Francesmary Modugno and Ness, {Roberta B.} and Karlan, {Beth Y.} and Christine Walsh and Jenny Lester and Sandra Orsulic and Fridley, {Brooke L.} and Vierkant, {Robert A.} and Cunningham, {Julie M.} and Xifeng Wu and Karen Lu and Dong Liang and Hildebrandt, {Michelle A.T.} and {Palmieri Weber}, Rachel and Iversen, {Edwin S.} and Tworoger, {Shelley S.} and Poole, {Elizabeth M.} and Salvesen, {Helga B.} and Camilla Krakstad and Line Bjorge and Tangen, {Ingvild L.} and Tanja Pejovic and Yukie Bean and Melissa Kellar and Nicolas Wentzensen and Brinton, {Louise A.} and Jolanta Lissowska and Montserrat Garcia-Closas and Campbell, {Ian G.} and Diana Eccles and Whittemore, {Alice S.} and Weiva Sieh and Rothstein, {Joseph H.} and Hoda Anton-Culver and Argyrios Ziogas and Phelan, {Catherine M.} and Moysich, {Kirsten B.} and Goode, {Ellen L.} and Schildkraut, {Joellen M.} and Andrew Berchuck and Pharoah, {Paul D.P.} and Sellers, {Thomas A.} and Angela Brooks-Wilson and Cook, {Linda S.} and Le, {Nhu D.}",

year = "2014",

month = jan,

day = "1",

doi = "10.1002/mnfr.201400068",

language = "English",

volume = "58",

pages = "2023--2035",

journal = "Molecular Nutrition & Food Research",

issn = "1613-4125",

publisher = "Wiley-VCH Verlag GmbH & Co. KGaA",

number = "10",

}

Kelemen, LE, Terry, KL, Goodman, MT, Webb, PM, Bandera, EV, McGuire, V, Anne Rossing, M, 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, Kjær, SK, Høgdall, E, Jensen, A, Høgdall, CK, Lundvall, L, Engelholm, SA, 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, Palmieri Weber, R, 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 2014, 'Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk', Molecular Nutrition & Food Research, vol. 58, no. 10, pp. 2023-2035. https://doi.org/10.1002/mnfr.201400068

TY - JOUR

T1 - Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

AU - Kelemen, Linda E.

AU - Terry, Kathryn L.

AU - Goodman, Marc T.

AU - Webb, Penelope M.

AU - Bandera, Elisa V.

AU - McGuire, Valerie

AU - Anne Rossing, Mary

AU - Wang, Qinggang

AU - Dicks, Ed

AU - Tyrer, Jonathan P.

AU - Song, Honglin

AU - Kupryjanczyk, Jolanta

AU - Dansonka-Mieszkowska, Agnieszka

AU - Plisiecka-Halasa, Joanna

AU - Timorek, Agnieszka

AU - Menon, Usha

AU - Gentry-Maharaj, Aleksandra

AU - Gayther, Simon A.

AU - Ramus, Susan J.

AU - Narod, Steven A.

AU - Risch, Harvey A.

AU - McLaughlin, John R.

AU - Siddiqui, Nadeem

AU - Glasspool, Rosalind

AU - Paul, James

AU - Carty, Karen

AU - Gronwald, Jacek

AU - Lubiński, Jan

AU - Jakubowska, Anna

AU - Cybulski, Cezary

AU - Kiemeney, Lambertus A.

AU - Massuger, Leon F.A.G.

AU - van Altena, Anne M.

AU - Aben, Katja K.H.

AU - Olson, Sara H.

AU - Orlow, Irene

AU - Cramer, Daniel W.

AU - Levine, Douglas A.

AU - Bisogna, Maria

AU - Giles, Graham G.

AU - Southey, Melissa C.

AU - Bruinsma, Fiona

AU - Kjær, Susanne K.

AU - Høgdall, Estrid

AU - Jensen, Allan

AU - Høgdall, Claus K.

AU - Lundvall, Lene

AU - Engelholm, Svend Aage

AU - Heitz, Florian

AU - du Bois, Andreas

AU - Harter, Philipp

AU - Schwaab, Ira

AU - Butzow, Ralf

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M.

AU - Leminen, Arto

AU - Thompson, Pamela J.

AU - Lurie, Galina

AU - Wilkens, Lynne R.

AU - Lambrechts, Diether

AU - Van Nieuwenhuysen, Els

AU - Lambrechts, Sandrina

AU - Vergote, Ignace

AU - Beesley, Jonathan

AU - AOCS Study Group/ACS Investigators

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Hein, Alexander

AU - Ekici, Arif B.

AU - Doherty, Jennifer A.

AU - Wu, Anna H.

AU - Pearce, Celeste L.

AU - Pike, Malcolm C.

AU - Stram, Daniel

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Dörk, Thilo

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Runnebaum, Ingo B.

AU - Bogdanova, Natalia

AU - Antonenkova, Natalia

AU - Odunsi, Kunle

AU - Edwards, Robert P.

AU - Kelley, Joseph L.

AU - Modugno, Francesmary

AU - Ness, Roberta B.

AU - Karlan, Beth Y.

AU - Walsh, Christine

AU - Lester, Jenny

AU - Orsulic, Sandra

AU - Fridley, Brooke L.

AU - Vierkant, Robert A.

AU - Cunningham, Julie M.

AU - Wu, Xifeng

AU - Lu, Karen

AU - Liang, Dong

AU - Hildebrandt, Michelle A.T.

AU - Palmieri Weber, Rachel

AU - Iversen, Edwin S.

AU - Tworoger, Shelley S.

AU - Poole, Elizabeth M.

AU - Salvesen, Helga B.

AU - Krakstad, Camilla

AU - Bjorge, Line

AU - Tangen, Ingvild L.

AU - Pejovic, Tanja

AU - Bean, Yukie

AU - Kellar, Melissa

AU - Wentzensen, Nicolas

AU - Brinton, Louise A.

AU - Lissowska, Jolanta

AU - Garcia-Closas, Montserrat

AU - Campbell, Ian G.

AU - Eccles, Diana

AU - Whittemore, Alice S.

AU - Sieh, Weiva

AU - Rothstein, Joseph H.

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Phelan, Catherine M.

AU - Moysich, Kirsten B.

AU - Goode, Ellen L.

AU - Schildkraut, Joellen M.

AU - Berchuck, Andrew

AU - Pharoah, Paul D.P.

AU - Sellers, Thomas A.

AU - Brooks-Wilson, Angela

AU - Cook, Linda S.

AU - Le, Nhu D.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Scope: We reevaluated previously reported associations between variants in pathways of onecarbon (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.

AB - Scope: We reevaluated previously reported associations between variants in pathways of onecarbon (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.

KW - Case-control

KW - Dihydropyrimidine dehydrogenase

KW - Folate

KW - Polymorphism

KW - Serine hydroxymethyltransferase 1 (soluble)

UR - http://www.scopus.com/inward/record.url?scp=84908428949&partnerID=8YFLogxK

U2 - 10.1002/mnfr.201400068

DO - 10.1002/mnfr.201400068

M3 - Article

C2 - 25066213

AN - SCOPUS:84908428949

SN - 1613-4125

VL - 58

SP - 2023

EP - 2035

JO - Molecular Nutrition & Food Research

JF - Molecular Nutrition & Food Research

IS - 10

ER -

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

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Keywords

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