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Published on: March 28, 2017
Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p'-dde levels in a population-based
Lars Lind1, Esther Ng2, Erik Ingelsson3
1Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
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.
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