title: A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children's Oncology Group.
abstract: Neuroblastoma is a childhood cancer of the sympathetic nervous system with embryonic origins. Previous epidemiologic studies suggest maternal vitamin supplementation during pregnancy reduces the risk of neuroblastoma. We hypothesized offspring and maternal genetic variants in folate-related and choline-related genes are associated with neuroblastoma and modify the effects of maternal intake of folate, choline, and folic acid.
  
  
  
  The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 affected children and their parents through the Children's Oncology Group's Childhood Cancer Research Network. We used questionnaires to ascertain pre-pregnancy supplementation and estimate usual maternal dietary intake of folate, choline, and folic acid. We genotyped 955 genetic variants related to folate or choline using DNA extracted from saliva samples and used a log-linear model to estimate both child and maternal risk ratios and stratum-specific risk ratios for gene-environment interactions.
  
  
  
  Overall, no maternal or offspring genotypic results met criteria for a false discovery rate (FDR) Q-value <0.2. Associations were also null for gene-environment interaction with pre-pregnancy vitamin supplementation, dietary folic acid, and folate. FDR-significant gene-choline interactions were found for offspring SNPs rs10489810 and rs9966612 located in MTHFD1L and TYMS, respectively, with maternal choline dietary intake dichotomized at the first quartile.
  
  
  
  These results suggest that variants related to one-carbon metabolism are not strongly associated with neuroblastoma. Choline-related variants may play a role; however, the functional consequences of the interacting variants are unknown and require independent replication.
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Campus Box 7435, 2106 McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA. amazul@unc.edu.
authors.forename: Angela L
authors.identifier: 0000-0002-1249-4613
authors.initials: AL
authors.lastname: Mazul
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Campus Box 7435, 2106 McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA.|Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Siega-Riz
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Clarice R
authors.initials: CR
authors.lastname: Weinberg
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Campus Box 7435, 2106 McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Engel
authors.affiliation: Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Campus Box 7435, 2106 McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA.
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Carrier
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Campus Box 7435, 2106 McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA.|Biospecimen Processing Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Basta
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Zalman
authors.initials: Z
authors.lastname: Vaksman
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.affiliation: Showers Center for Childhood Cancer and Blood Disorder, Akron Children's Hospital, Akron, OH, USA.
authors.forename: Charlene
authors.initials: C
authors.lastname: Maxen
authors.affiliation: Department of Biostatistics, Colleges of Medicine and Public Health & Health Professions, University of Florida, Gainesville, FL, USA.
authors.forename: Arlene
authors.initials: A
authors.lastname: Naranjo
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Campus Box 7435, 2106 McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Olshan
mesh_terms: D002675:Child, Preschool; D002794:Choline / Q000008:administration & dosage* / Q000378:metabolism; D019587:Dietary Supplements / Q000706:statistics & numerical data; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000378:metabolism; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009447:Neuroblastoma / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012042:Registries; D014481:United States / Q000453:epidemiology
chemical_list: D005492:Folic Acid; D002794:Choline
keywords: Case–parent triad; Choline; Folate; Genetics; Neuroblastoma