Abstract
ObjectivesSince 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. MethodsIn 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. ResultsEvidence 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. ConclusionCirculating 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.
Highlights
Dichlorodiphenyltrichloroethane (DDT) is an insecticide heavily used since the second half of World War II
If both the lead single nuclear polymorphisms (SNP) and this secondary signal entered a regression model as independent variables and p,p′-DDE as dependent variable, these two SNPs explained 17% of the variation in p,p′-DDE levels in PIVUS, as determined from the R2-value given in the regression model
In an analysis conditioned on the two SNPs defining the CYP2B6*6 haplotype, several of the other SNPs in the CYP2B6 region were still significantly related to p,p′-DDE levels (p b 10−10 for the most strongly associated variant, Supplementary Fig. 2)
Summary
Dichlorodiphenyltrichloroethane (DDT) is an insecticide heavily used since the second half of World War II. Due to reproductive problems observed in wild animals, DDT was banned in the 1970s and 1980s in most high-income countries. DDT is not used as a pesticide any longer in high-income countries, due to its persistence in the environment and accumulation in the food chain in fish and meat, there is still exposure taking place. This exposure is not as high as before the ban. An accumulation occurs with ageing, so higher levels of DDT/p,p′-DDE are seen in older subjects than in younger individuals as a result from a continuous cumulative exposure (Ye et al, 2015). We have recently reported that high levels of p,p′-DDE are related to prevalent obesity, diabetes and hypertension (Lee et al, 2011; Lind et al, 2014b; Ronn et al, 2011)
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