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Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p'-dde levels in a population-based sample
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.ORCID iD: 0000-0003-2256-6972
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA.
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2017 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 98, p. 212-218Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

Place, publisher, year, edition, pages
2017. Vol. 98, p. 212-218
Keyword [en]
CYP2B6, DDE, GWAS, Metabolism, Methylation
National Category
Medical Genetics Occupational Health and Environmental Health
Identifiers
URN: urn:nbn:se:uu:diva-311820DOI: 10.1016/j.envint.2016.11.010ISI: 000389913500025PubMedID: 27839851OAI: oai:DiVA.org:uu-311820DiVA, id: diva2:1061601
Funder
Swedish Research Council Formas, 216-2012-475Wellcome trust, WT098017
Note

Lars Lind and Esther Ng contributed equally to this work.

Available from: 2017-01-03 Created: 2017-01-03 Last updated: 2018-01-13Bibliographically approved

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Lind, LarsIngelsson, ErikSalihovic, SamiraLampa, ErikLind, P. Monica
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