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Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.

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Title: Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.
Authors: Domingo-Relloso, Arce1,2,3, Riffo-Campos, Angela L.4, Haack, Karin5, Rentero-Garrido, Pilar6,7, Ladd-Acosta, Christine8, Fallin, Daniele M.7,8, Wan Yee Tang9, Herreros-Martinez, Miguel10, Gonzalez, Juan R.11,12,13, Bozack, Anne K.1, Cole, Shelley A.5, Navas-Acien, Ana1, Tellez-Plaza, Maria2,9,14 m.tellez@isciii.es
Source: Environmental Health Perspectives. Jun2020, Vol. 128 Issue 6, p067005-1-067005-14. 14p. 3 Diagrams, 4 Charts.
Subject Terms: *Cadmium, *Smoking, Protein analysis, DNA metabolism, Confidence intervals, Metabolism, Research funding, Secondary analysis, Oligonucleotide arrays, DNA methylation, Descriptive statistics, Epigenomics, Adults
Abstract: BACKGROUND: The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. OBJECTIVES: We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. METHODS: We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45–74 years of age who participated in the Strong Heart Study in 1989–1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein–protein interaction networks to explore the biological relevance of the findings. RESULTS: At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smokingDMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. CONCLUSIONS: Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. [ABSTRACT FROM AUTHOR]
Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.
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  Data: <searchLink fieldCode="AR" term="%22Domingo-Relloso%2C+Arce%22">Domingo-Relloso, Arce</searchLink><relatesTo>1,2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Riffo-Campos%2C+Angela+L%2E%22">Riffo-Campos, Angela L.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Haack%2C+Karin%22">Haack, Karin</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Rentero-Garrido%2C+Pilar%22">Rentero-Garrido, Pilar</searchLink><relatesTo>6,7</relatesTo><br /><searchLink fieldCode="AR" term="%22Ladd-Acosta%2C+Christine%22">Ladd-Acosta, Christine</searchLink><relatesTo>8</relatesTo><br /><searchLink fieldCode="AR" term="%22Fallin%2C+Daniele+M%2E%22">Fallin, Daniele M.</searchLink><relatesTo>7,8</relatesTo><br /><searchLink fieldCode="AR" term="%22Wan+Yee+Tang%22">Wan Yee Tang</searchLink><relatesTo>9</relatesTo><br /><searchLink fieldCode="AR" term="%22Herreros-Martinez%2C+Miguel%22">Herreros-Martinez, Miguel</searchLink><relatesTo>10</relatesTo><br /><searchLink fieldCode="AR" term="%22Gonzalez%2C+Juan+R%2E%22">Gonzalez, Juan R.</searchLink><relatesTo>11,12,13</relatesTo><br /><searchLink fieldCode="AR" term="%22Bozack%2C+Anne+K%2E%22">Bozack, Anne K.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Cole%2C+Shelley+A%2E%22">Cole, Shelley A.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Navas-Acien%2C+Ana%22">Navas-Acien, Ana</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Tellez-Plaza%2C+Maria%22">Tellez-Plaza, Maria</searchLink><relatesTo>2,9,14</relatesTo><i> m.tellez@isciii.es</i>
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  Data: <searchLink fieldCode="JN" term="%22Environmental+Health+Perspectives%22">Environmental Health Perspectives</searchLink>. Jun2020, Vol. 128 Issue 6, p067005-1-067005-14. 14p. 3 Diagrams, 4 Charts.
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  Data: *<searchLink fieldCode="DE" term="%22Cadmium%22">Cadmium</searchLink><br />*<searchLink fieldCode="DE" term="%22Smoking%22">Smoking</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+analysis%22">Protein analysis</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+metabolism%22">DNA metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Confidence+intervals%22">Confidence intervals</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolism%22">Metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Research+funding%22">Research funding</searchLink><br /><searchLink fieldCode="DE" term="%22Secondary+analysis%22">Secondary analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Oligonucleotide+arrays%22">Oligonucleotide arrays</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+methylation%22">DNA methylation</searchLink><br /><searchLink fieldCode="DE" term="%22Descriptive+statistics%22">Descriptive statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Epigenomics%22">Epigenomics</searchLink><br /><searchLink fieldCode="DE" term="%22Adults%22">Adults</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: BACKGROUND: The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. OBJECTIVES: We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. METHODS: We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45–74 years of age who participated in the Strong Heart Study in 1989–1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein–protein interaction networks to explore the biological relevance of the findings. RESULTS: At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smokingDMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. CONCLUSIONS: Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1289/EHP6345
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        Text: English
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        PageCount: 14
        StartPage: 067005-1
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      – SubjectFull: Cadmium
        Type: general
      – SubjectFull: Smoking
        Type: general
      – SubjectFull: Protein analysis
        Type: general
      – SubjectFull: DNA metabolism
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      – SubjectFull: Confidence intervals
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      – SubjectFull: Metabolism
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      – SubjectFull: Research funding
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      – SubjectFull: Secondary analysis
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      – SubjectFull: Oligonucleotide arrays
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      – SubjectFull: DNA methylation
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      – SubjectFull: Descriptive statistics
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