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

• 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.

Ämnesord

Medical and Health Sciences  (hsv)

Basic Medicine  (hsv)

Medical Genetics  (hsv)

Medicin och hälsovetenskap  (hsv)

Medicinska grundvetenskaper  (hsv)

Medicinsk genetik  (hsv)

Medical and Health Sciences  (hsv)

Health Sciences  (hsv)

Environmental Health and Occupational Health  (hsv)

Medicin och hälsovetenskap  (hsv)

Hälsovetenskaper  (hsv)

Miljömedicin och yrkesmedicin  (hsv)

Nyckelord

CYP2B6

DDE

GWAS

Metabolism

Methylation