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

Lind, Lars, Ng, Esther, Ingelsson, Erik, Lindgren, Cecilia, Salihovic, Samira, van Bavel, Bert, Mahajan, Anubha, Lampa, Erik, Morris, Andrew P and Lind, P Monica
(2017) Genetic and methylation variation in the CYP2B6 gene is related to circulating <i>p</i>,<i>p</i>′-dde levels in a population-based sample. ENVIRONMENT INTERNATIONAL, 98. pp. 212-218.

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<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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<sup>-31</sup>). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19:41520351; p=2.2×10<sup>-8</sup>). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p=6.2×10<sup>-9</sup>) located 7kb downstream the CYP2B6 gene (cg27089200, position chr19:41531976). This CpG-site was also related to the lead SNP (p=3.8×10<sup>-35</sup>), but mediated only 4% of the effect of the lead SNP on p,p'-DDE levels.<h4>Conclusion</h4>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.

Item Type: Article
Uncontrolled Keywords: GWAS, CYP2B6, DDE, Metabolism, Methylation
Depositing User: Symplectic Admin
Date Deposited: 29 Nov 2016 08:35
Last Modified: 12 Oct 2023 15:51
DOI: 10.1016/j.envint.2016.11.010
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