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 s...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-01-01
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| Series: | Environment International |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412016307619 |
| _version_ | 1811274128740581376 |
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| author | Lars Lind Esther Ng Erik Ingelsson Cecilia Lindgren Samira Salihovic Bert van Bavel Anubha Mahajan Erik Lampa Andrew P. Morris P. Monica Lind |
| author_facet | Lars Lind Esther Ng Erik Ingelsson Cecilia Lindgren Samira Salihovic Bert van Bavel Anubha Mahajan Erik Lampa Andrew P. Morris P. Monica Lind |
| author_sort | Lars Lind |
| collection | DOAJ |
| description | 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 472 ng/g lipid, while the corresponding level for those being homozygote for the T allele was 192 ng/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 7 kb 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. Keywords: GWAS, CYP2B6, DDE, Metabolism, Methylation |
| first_indexed | 2024-04-12T23:13:29Z |
| format | Article |
| id | doaj.art-054313aa4c844b5ebcd5ca138e29404b |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-04-12T23:13:29Z |
| publishDate | 2017-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-054313aa4c844b5ebcd5ca138e29404b2022-12-22T03:12:45ZengElsevierEnvironment International0160-41202017-01-0198212218Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sampleLars Lind0Esther Ng1Erik Ingelsson2Cecilia Lindgren3Samira Salihovic4Bert van Bavel5Anubha Mahajan6Erik Lampa7Andrew P. Morris8P. Monica Lind9Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden; Corresponding author at: Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, 751 85 Uppsala, Sweden.Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UKDepartment of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USAWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USADepartment of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; MTM Research Centre, School of Science and Technology, Örebro University, SwedenMTM Research Centre, School of Science and Technology, Örebro University, SwedenWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UKDepartment of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, SwedenWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UKDepartment of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, SwedenObjectives: 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 472 ng/g lipid, while the corresponding level for those being homozygote for the T allele was 192 ng/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 7 kb 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. Keywords: GWAS, CYP2B6, DDE, Metabolism, Methylationhttp://www.sciencedirect.com/science/article/pii/S0160412016307619 |
| spellingShingle | Lars Lind Esther Ng Erik Ingelsson Cecilia Lindgren Samira Salihovic Bert van Bavel Anubha Mahajan Erik Lampa Andrew P. Morris P. Monica Lind Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sample Environment International |
| title | Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sample |
| title_full | Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sample |
| title_fullStr | Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sample |
| title_full_unstemmed | Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sample |
| title_short | Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sample |
| title_sort | genetic and methylation variation in the cyp2b6 gene is related to circulating p p dde levels in a population based sample |
| url | http://www.sciencedirect.com/science/article/pii/S0160412016307619 |
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