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Cancer Causes & Control

, Volume 23, Issue 8, pp 1265–1277 | Cite as

Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE)

  • Alicia Amigou
  • Jérémie Rudant
  • Laurent Orsi
  • Stéphanie Goujon-Bellec
  • Guy Leverger
  • André Baruchel
  • Yves Bertrand
  • Brigitte Nelken
  • Geneviève Plat
  • Gérard Michel
  • Stéphanie Haouy
  • Pascal Chastagner
  • Stéphane Ducassou
  • Xavier Rialland
  • Denis Hémon
  • Jacqueline Clavel
Original Paper

Abstract

Purpose

Fetal folate deficiency may increase the risk of subsequent childhood acute leukemia (AL), since folates are required for DNA methylation, synthesis, and repair, but the literature remains scarce. This study tested the hypothesis that maternal folic acid supplementation before or during pregnancy reduces AL risk, accounting for the SNPs rs1801133 (C677T) and rs1801131 (A1298C) in MTHFR and rs1801394 (A66G) and rs1532268 (C524T) in MTRR, assumed to modify folate metabolism.

Methods

The nationwide registry-based case–control study, ESCALE, carried out in 2003–2004, included 764 AL cases and 1,681 controls frequency matched with the cases on age and gender. Information on folic acid supplementation was obtained by standardized telephone interview. The genotypes were obtained using high-throughput platforms and imputation for untyped polymorphisms. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders.

Results

AL was significantly inversely associated with maternal folic acid supplementation before and during pregnancy (OR = 0.4; 95 % confidence interval: [0.3–0.6]). MTHFR and MTRR genetic polymorphisms were not associated with AL. However, AL was positively associated with homozygosity for any of the MTHFR polymorphisms and carriership of both MTRR variant alleles (OR = 1.6 [0.9–3.1]). No interaction was observed between MTHFR, MTRR, and maternal folate supplementation.

Conclusion

The study findings support the hypothesis that maternal folic acid supplementation may reduce the risk of childhood AL. The findings also suggest that the genotype homozygous for any of the MTHFR variants and carrying both MTRR variants could be a risk factor for AL.

Keywords

Childhood leukemia Folic acid Metabolism MTHFR MTRR Gene–environment interaction 

Notes

Acknowledgments

The authors are grateful to Claire Mulot, who was in charge of the biological collection at the Biological Resource Center of Saints-Pères, INSERM U775; the CEPH and the Centre National du Génotypage, which genotyped the cases; and IntegraGen, which genotyped the controls. The authors would also like to express their gratitude to Marie-Hélène Da Silva, Christophe Steffen, and Florence Menegaux (INSERM U1018, Environmental Epidemiology of Cancer), who contributed to the recruitment of the cases; Aurélie Guyot-Goubin and the staff of the French National Registry of Childhood Blood Malignancies, who contributed to case detection and verification; Sabine Mélèze and Marie-Anne Noel (Institut CSA), who coordinated the selection of the controls and the interviews; and Catherine Tricoche (Callson) and the team of interviewers, who interviewed the cases and controls.

The authors would also like to thank all of the Société Française de lutte contre les Cancers de l’Enfant et de l’Adolescent (SFCE) principal investigators: André Baruchel (Hôpital Saint-Louis/Hôpital Robert Debré, Paris), Claire Berger (Centre Hospitalier Universitaire, Saint-Etienne), Christophe Bergeron (Centre Léon Bérard, Lyon), Jean-Louis Bernard (Hôpital La Timone, Marseille), Yves Bertrand (Hôpital Debrousse, Lyon), Pierre Bordigoni (Centre Hospitalier Universitaire, Nancy), Patrick Boutard (Centre Hospitalier Régional Universitaire, Caen), Gérard Couillault (Hôpital d’Enfants, Dijon), Christophe Piguet (Centre Hospitalier Régional Universitaire, Limoges), Anne-Sophie Defachelles (Centre Oscar Lambret, Lille), François Demeocq (Hôpital Hôtel-Dieu, Clermont-Ferrand), Alain Fischer (Hôpital des Enfants Malades, Paris), Virginie Gandemer (Centre Hospitalier Universitaire—Hôpital Sud, Rennes), Dominique Valteau-Couanet (Institut Gustave Roussy, Villejuif), Jean-Pierre Lamagnere (Centre Gatien de Clocheville, Tours), Françoise Lapierre (Centre Hospitalier Universitaire Jean Bernard, Poitiers), Guy Leverger (Hôpital Armand-Trousseau, Paris), Patrick Lutz (Hôpital de Hautepierre, Strasbourg), Geneviève Margueritte (Hôpital Arnaud de Villeneuve, Montpellier), Françoise Mechinaud (Hôpital Mère et Enfants, Nantes), Gérard Michel (Hôpital La Timone, Marseille), Frédéric Millot (Centre Hospitalier Universitaire Jean Bernard, Poitiers), Martine Münzer (American Memorial Hospital, Reims), Brigitte Nelken (Hôpital Jeanne de Flandre, Lille), Hélène Pacquement (Institut Curie, Paris), Brigitte Pautard (Centre Hospitalier Universitaire, Amiens), Stéphane Ducassou (Hôpital Pellegrin Tripode, Bordeaux), Alain Pierre-Kahn (Hôpital Enfants Malades, Paris), Emmanuel Plouvier (Centre Hospitalier Régional, Besançon), Xavier Rialland (Centre Hospitalier Universitaire, Angers), Alain Robert (Hôpital des Enfants, Toulouse), Hervé Rubie (Hôpital des Enfants, Toulouse), Stéphanie Haouy (Hôpital Arnaud de Villeneuve, Montpellier), Christine Soler (Fondation Lenval, Nice), and Jean-Pierre Vannier (Hôpital Charles Nicolle, Rouen).

This work was supported by grants from INSERM, the Fondation de France, the Association pour la Recherche sur le Cancer (ARC), the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS), the Agence Française de Sécurité Sanitaire de l’Environnement et du Travail (AFSSET), the association Cent pour sang la vie, the Institut National du Cancer (INCa), the Agence Nationale de la Recherche (ANR), and Cancéropôle Ile de France.

Conflict of interest

No potential conflicts of interest were disclosed.

Supplementary material

10552_2012_4_MOESM1_ESM.doc (56 kb)
Supplementary material 1 (DOC 56 kb)

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Alicia Amigou
    • 1
    • 2
  • Jérémie Rudant
    • 1
    • 2
    • 3
  • Laurent Orsi
    • 1
    • 2
  • Stéphanie Goujon-Bellec
    • 1
    • 2
    • 3
  • Guy Leverger
    • 4
    • 5
  • André Baruchel
    • 6
    • 7
  • Yves Bertrand
    • 8
  • Brigitte Nelken
    • 9
    • 10
  • Geneviève Plat
    • 11
  • Gérard Michel
    • 12
  • Stéphanie Haouy
    • 13
  • Pascal Chastagner
    • 14
  • Stéphane Ducassou
    • 15
  • Xavier Rialland
    • 16
    • 17
  • Denis Hémon
    • 1
    • 2
  • Jacqueline Clavel
    • 1
    • 2
    • 3
  1. 1.Environmental Epidemiology of CancerInserm, U1018, CESPVillejuifFrance
  2. 2.Registre National des Hémopathies malignes de l’EnfantUniversité Paris-Sud 11, UMRS 1018VillejuifFrance
  3. 3.RNHE, National Registry of Childhood Hematopoietic MalignanciesVillejuifFrance
  4. 4.AP-HPHôpital Armand TrousseauParisFrance
  5. 5.Université Paris 6 Pierre et Marie CurieParisFrance
  6. 6.AP-HPHôpital Robert DebréParisFrance
  7. 7.Université Paris 7ParisFrance
  8. 8.Institut d’Hémato-Oncologie PédiatriqueLyonFrance
  9. 9.Hôpital Jeanne de FlandreCHRULilleFrance
  10. 10.Université Lille Nord de FranceLilleFrance
  11. 11.Hôpital des EnfantsToulouseFrance
  12. 12.AP-HMHôpital la TimoneMarseilleFrance
  13. 13.Hôpital Arnaud de VilleneuveMontpellierFrance
  14. 14.CHU de NancyVandoeuvreFrance
  15. 15.Hôpital Pellegrin TripodeBordeauxFrance
  16. 16.Hôpital Mère-EnfantCHU-NantesNantesFrance
  17. 17.CHU d’AngersAngersFrance

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