title: Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p'-dde levels in a population-based sample.
abstract: Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p'-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.
  
  
  
  In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p,p'-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.
  
  
  
  Evidence for genome-wide significant association with p,p'-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472ng/g lipid, while the corresponding level for those being homozygote for the T allele was 192ng/g lipid (p=1.5×10-31). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19:41520351; p=2.2×10-8). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p=6.2×10-9) located 7kb downstream the CYP2B6 gene (cg27089200, position chr19:41531976). This CpG-site was also related to the lead SNP (p=3.8×10-35), but mediated only 4% of the effect of the lead SNP on p,p'-DDE levels.
  
  
  
  Circulating levels of p,p'-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p,p'-DDE levels.
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. Electronic address: lars.lind@medsci.uu.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: elengss@gmail.com.
authors.forename: Esther
authors.initials: E
authors.lastname: Ng
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: erik.ingeslsson@medsci.uu.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA. Electronic address: celi@broadinstitute.org.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lindgren
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; MTM Research Centre, School of Science and Technology, Örebro University, Sweden. Electronic address: samira.salihovic@medsci.uu.se.
authors.forename: Samira
authors.initials: S
authors.lastname: Salihovic
authors.affiliation: MTM Research Centre, School of Science and Technology, Örebro University, Sweden. Electronic address: Bert.VanBavel@oru.se.
authors.forename: Bert
authors.initials: B
authors.lastname: van Bavel
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: anubha@well.ox.ac.uk.
authors.forename: Anubha
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. Electronic address: erik.lampa@ucr.uu.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Lampa
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UK. Electronic address: amorris@well.ox.ac.uk.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Sweden. Electronic address: monica.lind@medsci.uu.se.
authors.forename: P Monica
authors.initials: PM
authors.lastname: Lind
mesh_terms: D000368:Aged; D000483:Alleles; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D003634:DDT / Q000378:metabolism; D019175:DNA Methylation; D003633:Dichlorodiphenyl Dichloroethylene / Q000097:blood*; D004785:Environmental Pollutants / Q000097:blood; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006843:Hydrocarbons, Chlorinated; D008055:Lipids; D008297:Male; D010575:Pesticides / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: D004785:Environmental Pollutants; D006843:Hydrocarbons, Chlorinated; D008055:Lipids; D010575:Pesticides; D003633:Dichlorodiphenyl Dichloroethylene; D003634:DDT; D065702:Cytochrome P-450 CYP2B6
keywords: CYP2B6; DDE; GWAS; Metabolism; Methylation