title: LINE-1 methylation in leukocyte DNA, interaction with phosphatidylethanolamine N-methyltransferase variants and bladder cancer risk.
abstract: BACKGROUND
  Aberrant global DNA methylation is shown to increase cancer risk. LINE-1 has been proven a measure of global DNA methylation. The objectives of this study were to assess the association between LINE-1 methylation level and bladder cancer risk and to evaluate effect modification by environmental and genetic factors.
  
  
  METHODS
  Bisulphite-treated leukocyte DNA from 952 cases and 892 hospital controls was used to measure LINE-1 methylation level at four CpG sites by pyrosequencing. Logistic regression model was fitted to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Interactions between LINE-1 methylation levels and environmental and genetic factors were assessed.
  
  
  RESULTS
  The risk of bladder cancer followed a nonlinear association with LINE-1 methylation. Compared with subjects in the middle tertile, the adjusted OR for subjects in the lower and the higher tertiles were 1.26 (95% CI 0.99-1.60, P=0.06) and 1.33 (95% CI 1.05-1.69, P=0.02), respectively. This association significantly increased among individuals homozygous for the major allele of five single-nucleotide polymorphisms located in the phosphatidylethanolamine N-methyltransferase gene (corrected P-interaction<0.05).
  
  
  CONCLUSIONS
  The findings from this large-scale study suggest that both low and high levels of global DNA methylation are associated with the risk of bladder cancer.
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: S M
authors.initials: SM
authors.lastname: Tajuddin
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: A F S
authors.initials: AF
authors.lastname: Amaral
authors.affiliation: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Asturias 33006, Spain.
authors.forename: A F
authors.initials: AF
authors.lastname: Fernández
authors.affiliation: Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-7335, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chanock
authors.affiliation: Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-7335, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Silverman
authors.affiliation: 1] Molecular Epidemiology Group, Instituto Universitario de Oncologia, Universidad de Oviedo, Oviedo, Asturias 33006, Spain [2] CIBERESP, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Tardón
authors.affiliation: 1] Molecular Oncology Group, Hospital General Universitario de Elche, Elche, Alicante 03203, Spain [2] Department of Medical Oncology, Hospital Ramon y Cajal, Madrid 28034, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Carrato
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: M
authors.initials: M
authors.lastname: García-Closas
authors.affiliation: Trace Element Analysis Core, Department of Earth Sciences, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Jackson
authors.affiliation: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Asturias 33006, Spain.
authors.forename: E G
authors.initials: EG
authors.lastname: Toraño
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Márquez
authors.affiliation: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Asturias 33006, Spain.
authors.forename: R G
authors.initials: RG
authors.lastname: Urdinguio
authors.affiliation: Unidad de Investigación, Hospital Universitario de Canarias, La Laguna 38320, Spain.
authors.forename: R
authors.initials: R
authors.lastname: García-Closas
authors.affiliation: Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-7335, USA.
authors.forename: N
authors.initials: N
authors.lastname: Rothman
authors.affiliation: Centre for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Kogevinas
authors.affiliation: 1] Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain [2] Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08002, Spain.
authors.forename: F X
authors.initials: FX
authors.lastname: Real
authors.affiliation: 1] Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo, Asturias 33006, Spain [2] Department of Immunology and Oncology, Centro Nacional de Biotecnología/CNB-CSIC, Cantoblanco, Madrid 28049, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Fraga
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Malats
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D050918:Phosphatidylethanolamine N-Methyltransferase