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Region Hovedstaden - en del af Københavns Universitetshospital
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Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

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  • 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
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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.

OriginalsprogEngelsk
TidsskriftMolecular Nutrition & Food Research
Vol/bind58
Udgave nummer10
Sider (fra-til)2023-35
Antal sider13
ISSN1613-4125
DOI
StatusUdgivet - okt. 2014

ID: 44866699