title: Genetic and non-genetic predictors of LINE-1 methylation in leukocyte DNA.
abstract: BACKGROUND
  Altered DNA methylation has been associated with various diseases.
  
  
  OBJECTIVE
  We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study.
  
  
  METHODS
  We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients (βs) by robust linear regression.
  
  
  RESULTS
  Women had lower levels of LINE-1 methylation than men (β = -0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (β = -0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (β = -3.6, p = 0.003). By contrast, iron (β = 0.002, p = 0.009) and nickel (β = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217-per allele, β = 0.3, p = 0.002), TCN2 (rs9606756-GG, β = 1.9, p = 0.008; rs4820887-AA, β = 4.0, p = 4.8 × 10-7; rs9621049-TT, β = 4.2, p = 4.7 × 10-9), AS3MT (rs7085104-GG, β = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: β = 0.5 and CC vs. TT: β = -0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: β = 0.3 and TT vs. CC; β = -0.8, global p = 0.05) were associated with LINE-1 methylation.
  
  
  CONCLUSIONS
  We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants.
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, CNIO, Madrid, Spain.
authors.forename: Salman M
authors.initials: SM
authors.lastname: Tajuddin
authors.forename: André F S
authors.initials: AF
authors.lastname: Amaral
authors.forename: Agustín F
authors.initials: AF
authors.lastname: Fernández
authors.forename: Sandra
authors.initials: S
authors.lastname: Rodríguez-Rodero
authors.forename: Ramón María
authors.initials: RM
authors.lastname: Rodríguez
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardón
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.forename: Brian P
authors.initials: BP
authors.lastname: Jackson
authors.forename: Reina
authors.initials: R
authors.lastname: García-Closas
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Cook
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Cantor
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D005260:Female; D005838:Genotype; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D015596:Nutrition Assessment; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics
references.citation: Tob Control. 2011 May;20 Suppl 1:i30-5
references.pmid: 21504922
references.citation: Eur J Cancer. 2007 Jul;43(11):1731-40
references.pmid: 17596928
references.citation: Epigenetics. 2011 Oct 1;6(10):1236-41
references.pmid: 21931279
references.citation: Nat Genet. 2011 Mar 13;43(4):309-15
references.pmid: 21399634
references.citation: Hum Mol Genet. 2007 Jun 1;16(11):1335-42
references.pmid: 17412760
references.citation: Nat Protoc. 2007;2(9):2265-75
references.pmid: 17853883
references.citation: Am J Hum Genet. 2011 Apr 8;88(4):450-7
references.pmid: 21457905
references.citation: Clin Cancer Res. 2010 Mar 1;16(5):1682-9
references.pmid: 20179218
references.citation: Hum Genet. 2007 Dec;122(5):505-14
references.pmid: 17851693
references.citation: Oncogene. 2010 Jun 24;29(25):3650-64
references.pmid: 20440268
references.citation: Nucleic Acids Res. 2004 Feb 18;32(3):e38
references.pmid: 14973332
references.citation: Ecotoxicol Environ Saf. 2004 Jul;58(3):285-93
references.pmid: 15223254
references.citation: PLoS One. 2011 Jan 19;6(1):e16252
references.pmid: 21311577
references.citation: J Med Genet. 2004 Jun;41(6):454-8
references.pmid: 15173232
references.citation: Epigenetics. 2011 Jul;6(7):828-37
references.pmid: 21636973
references.citation: Toxicol Appl Pharmacol. 2009 Sep 1;239(2):200-7
references.pmid: 19538983
references.citation: Nat Rev Genet. 2009 Nov;10(11):805-11
references.pmid: 19789556
references.citation: Nat Rev Genet. 2005 Aug;6(8):597-610
references.pmid: 16136652
references.citation: J Nutr. 2009 Dec;139(12):2402-5
references.pmid: 19812215
references.citation: Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R139-47
references.pmid: 15809266
references.citation: Am J Clin Nutr. 2006 Apr;83(4):835-41
references.pmid: 16600936
references.citation: Nat Rev Genet. 2010 Mar;11(3):191-203
references.pmid: 20125086
references.citation: Mol Cell Biol. 1995 May;15(5):2547-57
references.pmid: 7537850
references.citation: Nat Genet. 2010 Nov;42(11):978-84
references.pmid: 20972438
references.citation: Cell. 2011 Sep 16;146(6):866-72
references.pmid: 21925312
references.citation: N Engl J Med. 2010 Dec 16;363(25):2424-33
references.pmid: 21067377
references.citation: PLoS Genet. 2007 Feb 23;3(2):e29
references.pmid: 17319747
references.citation: Cancer Metastasis Rev. 2007 Mar;26(1):111-28
references.pmid: 17334909
references.citation: Int J Cancer. 2012 Mar 1;130(5):1151-9
references.pmid: 21445976
references.citation: Carcinogenesis. 1989 Mar;10(3):577-86
references.pmid: 2924402
references.citation: PLoS One. 2007 May 02;2(5):e399
references.pmid: 17476321
references.citation: Hum Mol Genet. 2012 Jan 1;21(1):219-35
references.pmid: 21972244
references.citation: Mutat Res. 1998 Jul 31;415(3):213-8
references.pmid: 9714811
references.citation: J Genet Genomics. 2009 May;36(5):277-82
references.pmid: 19447375
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5606-11
references.pmid: 11929966
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6634-9
references.pmid: 10841562
references.citation: BMC Med Genet. 2008 Jun 03;9:49
references.pmid: 18522750
references.citation: Environ Health Perspect. 2011 Jan;119(1):11-9
references.pmid: 20682481
references.citation: Am J Hum Genet. 2006 Feb;78(2):291-302
references.pmid: 16400609
references.citation: Blood. 1995 May 15;85(10):2711-9
references.pmid: 7742531
references.citation: Int J Epidemiol. 2012 Feb;41(1):126-39
references.pmid: 20846947
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9
references.pmid: 16009939
references.citation: Epigenomics. 2010 Feb;2(1):87-104
references.pmid: 20514360
references.citation: Gut. 2012 Nov;61(11):1583-8
references.pmid: 22184070
references.citation: Cancer Epidemiol Biomarkers Prev. 2001 Jun;10(6):649-55
references.pmid: 11401915
references.citation: Lancet. 2005 Aug 20-26;366(9486):649-59
references.pmid: 16112301
references.citation: Environ Health Perspect. 2011 Feb;119(2):182-8
references.pmid: 21247820
references.citation: Ann Hum Genet. 2004 May;68(Pt 3):196-204
references.pmid: 15180700