Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

BIOS Consortium; Dorret Boomsma; René Pool; Jenny van Dongen; Jouke Jan Hottenga

doi:10.1093/hmg/ddz067

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

BIOS Consortium, Dorret Boomsma, René Pool, Jenny van Dongen, Jouke Jan Hottenga

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

Original language	English
Pages (from-to)	2477-2485
Number of pages	9
Journal	Human molecular genetics
Volume	28
Issue number	15
DOIs	https://doi.org/10.1093/hmg/ddz067
Publication status	Published - 1 Aug 2019

Bibliographical note

Funding Information:
Conflict of Interest statement. L.L. reports personal fees from Boehringer Ingelheim GmbH, non-financial support from Novartis, grants from AstraZeneca, grants and non-financial support from European Respiratory Society and grants and non-financial support from Belgian Respiratory Society, outside the submitted work. DSP reports: The University of Groningen has received money for D.S.P. regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. All other authors declare they have no actual or potential competing financial interest.

Funding Information:
The LifeLines Biobank initiative has been made possible by funds from FES (Fonds Economische Structuurversterking), SNN (Samenwerkingsverband Noord Nederland) and REP (Ruimtelijke Economisch Programma). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The Biobank-Based Integrative Omics Studies (BIOS) Consortium is funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007).

Funding Information:
Lung Foundation Netherlands (4.1.13.007, 4.113.007 to D.A.v.d.P. and N.A.); Research Foundation—Flanders (postdoctoral fellowship to L.L.).

Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press.

Funding

Conflict of Interest statement. L.L. reports personal fees from Boehringer Ingelheim GmbH, non-financial support from Novartis, grants from AstraZeneca, grants and non-financial support from European Respiratory Society and grants and non-financial support from Belgian Respiratory Society, outside the submitted work. DSP reports: The University of Groningen has received money for D.S.P. regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. All other authors declare they have no actual or potential competing financial interest. The LifeLines Biobank initiative has been made possible by funds from FES (Fonds Economische Structuurversterking), SNN (Samenwerkingsverband Noord Nederland) and REP (Ruimtelijke Economisch Programma). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The Biobank-Based Integrative Omics Studies (BIOS) Consortium is funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007). Lung Foundation Netherlands (4.1.13.007, 4.113.007 to D.A.v.d.P. and N.A.); Research Foundation—Flanders (postdoctoral fellowship to L.L.).

Funders	Funder number
BBMRI-NL
Belgian Respiratory Society
Department of Internal Medicine
Dutch Government
Fonds Economische Structuurversterking
Ministry for Health, Welfare and Sports
Ministry of Education, Culture and Science
Netherlands Organization for Scientific Research
Netherlands Organization for the Health Research and Development
Research Foundation—Flanders
Research Institute for Diseases in the Elderly
Samenwerkingsverband Noord Nederland
European Respiratory Society
European Commission
ZonMw
Erasmus Universiteit Rotterdam
Erasmus Medisch Centrum
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	184.021.007
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

UN SDGs

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@article{f3630b33b9dd429c92b2ecd05d9d015e,

title = "Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression",

abstract = "Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.",

author = "{Van Der Plaat}, {Diana A.} and Vonk, {Judith M.} and Natalie Terzikhan and {De Jong}, Kim and {De Vries}, Maaike and {La Bastide-Van Gemert}, Sacha and {Van Diemen}, {Cleo C.} and Lies Lahousse and Brusselle, {Guy G.} and Ivana Nedeljkovic and Najaf Amin and Hans Kromhout and Vermeulen, {Roel C.H.} and Postma, {Dirkje S.} and {Van Duijn}, {Cornelia M.} and Boezen, {H. Marike} and {BIOS Consortium} and Dorret Boomsma and Ren{\'e} Pool and {van Dongen}, Jenny and Hottenga, {Jouke Jan}",

note = "Funding Information: Conflict of Interest statement. L.L. reports personal fees from Boehringer Ingelheim GmbH, non-financial support from Novartis, grants from AstraZeneca, grants and non-financial support from European Respiratory Society and grants and non-financial support from Belgian Respiratory Society, outside the submitted work. DSP reports: The University of Groningen has received money for D.S.P. regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. All other authors declare they have no actual or potential competing financial interest. Funding Information: The LifeLines Biobank initiative has been made possible by funds from FES (Fonds Economische Structuurversterking), SNN (Samenwerkingsverband Noord Nederland) and REP (Ruimtelijke Economisch Programma). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The Biobank-Based Integrative Omics Studies (BIOS) Consortium is funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007). Funding Information: Lung Foundation Netherlands (4.1.13.007, 4.113.007 to D.A.v.d.P. and N.A.); Research Foundation—Flanders (postdoctoral fellowship to L.L.). Publisher Copyright: {\textcopyright} 2019 The Author(s) 2019. Published by Oxford University Press.",

year = "2019",

month = aug,

day = "1",

doi = "10.1093/hmg/ddz067",

language = "English",

volume = "28",

pages = "2477--2485",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "15",

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TY - JOUR

T1 - Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

AU - Van Der Plaat, Diana A.

AU - Vonk, Judith M.

AU - Terzikhan, Natalie

AU - De Jong, Kim

AU - De Vries, Maaike

AU - La Bastide-Van Gemert, Sacha

AU - Van Diemen, Cleo C.

AU - Lahousse, Lies

AU - Brusselle, Guy G.

AU - Nedeljkovic, Ivana

AU - Amin, Najaf

AU - Kromhout, Hans

AU - Vermeulen, Roel C.H.

AU - Postma, Dirkje S.

AU - Van Duijn, Cornelia M.

AU - Boezen, H. Marike

AU - BIOS Consortium

AU - Boomsma, Dorret

AU - Pool, René

AU - van Dongen, Jenny

AU - Hottenga, Jouke Jan

N1 - Funding Information: Conflict of Interest statement. L.L. reports personal fees from Boehringer Ingelheim GmbH, non-financial support from Novartis, grants from AstraZeneca, grants and non-financial support from European Respiratory Society and grants and non-financial support from Belgian Respiratory Society, outside the submitted work. DSP reports: The University of Groningen has received money for D.S.P. regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. All other authors declare they have no actual or potential competing financial interest. Funding Information: The LifeLines Biobank initiative has been made possible by funds from FES (Fonds Economische Structuurversterking), SNN (Samenwerkingsverband Noord Nederland) and REP (Ruimtelijke Economisch Programma). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The Biobank-Based Integrative Omics Studies (BIOS) Consortium is funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007). Funding Information: Lung Foundation Netherlands (4.1.13.007, 4.113.007 to D.A.v.d.P. and N.A.); Research Foundation—Flanders (postdoctoral fellowship to L.L.). Publisher Copyright: © 2019 The Author(s) 2019. Published by Oxford University Press.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

AB - Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

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Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

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