Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sample

• Published in: Environment international 2017-01, Vol.98, p.212-218
• Main Authors: Lind, Lars, Ng, Esther, Ingelsson, Erik, Lindgren, Cecilia, Salihovic, Samira, van Bavel, Bert, Mahajan, Anubha, Lampa, Erik, Morris, Andrew P., Lind, P. Monica
• Format: Article
• Language: English
• Subjects: Aged; Alleles; CYP2B6; Cytochrome P-450 CYP2B6 - genetics; DDE; DDT - metabolism; Dichlorodiphenyl Dichloroethylene - blood; DNA Methylation; Enviromental Science; Environmental Pollutants - blood; Female; Full Length; Genome-Wide Association Study; GWAS; Humans; Hydrocarbons, Chlorinated; Lipids; Male; Metabolism; Methylation; Miljövetenskap; Pesticides - metabolism; Polymorphism, Single Nucleotide; Prospective Studies
• ISSN: 0160-4120; 1873-6750; 1873-6750
• DOI: 10.1016/j.envint.2016.11.010

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. •A whole genome scan was used to investigate the metabolic route of p,p′-DDE in human.•Genetic variation in the CYP2B6 gene was associated with p,p′-DDE levels.•Methylation close to the same gene was associated with p,p′-DDE levels.•Modern genetic analyses showed CYP2B6 to be linked to p,p′-DDE levels in human.