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

AOCS Study Group/ACS Investigators

Research output: Contribution to journalArticle

5 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 (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.

Original languageEnglish (US)
Pages (from-to)2023-2035
Number of pages13
JournalMolecular Nutrition and Food Research
Volume58
Issue number10
DOIs
StatePublished - 2014

Fingerprint

pyrimidines
purines
Folic Acid
folic acid
carcinoma
Carcinoma
Dihydrouracil Dehydrogenase (NADP)
metabolism
Genes
glycine hydroxymethyltransferase
odds ratio
genes
Odds Ratio
pyrimidine
purine
gene transfer
Single Nucleotide Polymorphism
testing
genetic polymorphism

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Food Science

Cite this

Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk. / AOCS Study Group/ACS Investigators.

In: Molecular Nutrition and Food Research, Vol. 58, No. 10, 2014, p. 2023-2035.

Research output: Contribution to journalArticle

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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 = "{AOCS Study Group/ACS Investigators} and 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 Lubiński 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 Tanja Pejovic",
year = "2014",
doi = "10.1002/mnfr.201400068",
language = "English (US)",
volume = "58",
pages = "2023--2035",
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TY - JOUR

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

AU - AOCS Study Group/ACS Investigators

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 - Pejovic, Tanja

PY - 2014

Y1 - 2014

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)

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U2 - 10.1002/mnfr.201400068

DO - 10.1002/mnfr.201400068

M3 - Article

C2 - 25066213

AN - SCOPUS:84908428949

VL - 58

SP - 2023

EP - 2035

JO - Molecular Nutrition and Food Research

JF - Molecular Nutrition and Food Research

SN - 1613-4125

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