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 Kjaer; Estrid Høgdall; Allan Jensen; Claus K Høgdall; Lene Lundvall; Svend-Aage Engelholm; Florian Heitz; Andreas du Bois; AOCS Study Group/ACS Investigators

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 Kjaer, Estrid Høgdall, Allan Jensen, Claus K Høgdall, Lene Lundvall, Svend-Aage Engelholm, Florian Heitz, Andreas du Bois, AOCS Study Group/ACS Investigators

Department of Clinical Medicine

7 Citations (Scopus)

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.

Original language	English
Journal	Molecular Nutrition & Food Research
Volume	58
Issue number	10
Pages (from-to)	2023-2035
Number of pages	13
ISSN	1613-4125
DOIs	https://doi.org/10.1002/mnfr.201400068
Publication status	Published - Oct 2014

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Kelemen, L. E., Terry, K. L., Goodman, M. T., Webb, P. M., Bandera, E. V., McGuire, V., Rossing, M. A., 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., ... AOCS Study Group/ACS Investigators (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

Kelemen, LE, Terry, KL, Goodman, MT, Webb, PM, Bandera, EV, McGuire, V, Rossing, MA, 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, Kjaer, SK, Høgdall, E, Jensen, A, Høgdall, CK, Lundvall, L, Engelholm, S-A, Heitz, F, du Bois, A & AOCS Study Group/ACS Investigators 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

@article{80ddc5c5233c448bbeb8c840596b62cf,

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 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.",

author = "Kelemen, {Linda E} and Terry, {Kathryn L} and Goodman, {Marc T} and Webb, {Penelope M} and Bandera, {Elisa V} and Valerie McGuire and Rossing, {Mary Anne} 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 Kjaer, {Susanne K} and Estrid H{\o}gdall and Allan Jensen and H{\o}gdall, {Claus K} and Lene Lundvall and Svend-Aage Engelholm and Florian Heitz and {du Bois}, Andreas and {AOCS Study Group/ACS Investigators}",

note = "{\textcopyright} 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",

year = "2014",

month = oct,

doi = "10.1002/mnfr.201400068",

language = "English",

volume = "58",

pages = "2023--2035",

journal = "Molecular Nutrition & Food Research",

issn = "1613-4125",

publisher = "Wiley-VCH",

number = "10",

}

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 - Rossing, Mary Anne

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 - Kjaer, 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 - AOCS Study Group/ACS Investigators

PY - 2014/10

Y1 - 2014/10

N2 - 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.

AB - 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.

U2 - 10.1002/mnfr.201400068

DO - 10.1002/mnfr.201400068

M3 - Journal article

C2 - 25066213

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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