DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Symen Ligthart; Carola Marzi; Stella Aslibekyan; Michael M. Mendelson; Karen N. Conneely; Toshiko Tanaka; Elena Colicino; Lindsay L. Waite; Roby Joehanes; Weihua Guan; Jennifer A. Brody; Cathy Elks; Riccardo Marioni; Min A. Jhun; Golareh Agha; Jan Bressler; Cavin K. Ward-Caviness; Brian H. Chen; Tianxiao Huan; Kelly Bakulski; Elias L. Salfati; Giovanni Fiorito; Simone Wahl; Katharina Schramm; Jin Sha; Dena G. Hernandez; Allan C. Just; Jennifer A. Smith; Nona Sotoodehnia; Luke C. Pilling; James S. Pankow; Phil S. Tsao; Chunyu Liu; Wei Zhao; Simonetta Guarrera; Vasiliki J. Michopoulos; Alicia K. Smith; Marjolein J. Peters; David Melzer; Pantel Vokonas; Myriam Fornage; Holger Prokisch; Joshua C. Bis; Audrey Y. Chu; Christian Herder; Harald Grallert; Chen Yao; Sonia Shah; Allan F. McRae; Honghuang Lin; Steve Horvath; Daniele Fallin; Albert Hofman; Nicholas J. Wareham; Kerri L. Wiggins; Andrew P. Feinberg; John M. Starr; Peter M. Visscher; Joanne M. Murabito; Sharon L.R. Kardia; Devin M. Absher; Elisabeth B. Binder; Andrew B. Singleton; Stefania Bandinelli; Annette Peters; Melanie Waldenberger; Giuseppe Matullo; Joel D. Schwartz; Ellen W. Demerath; André G. Uitterlinden; Joyce B.J. Meurs; Oscar H. Franco; Yii Der Ida Chen; Daniel Levy; Stephen T. Turner; Ian J. Deary; Kerry J. Ressler; Josée Dupuis; Luigi Ferrucci; Ken K. Ong; Themistocles L. Assimes; Eric Boerwinkle; Wolfgang Koenig; Donna K. Arnett; Andrea A. Baccarelli; Emelia J. Benjamin; Abbas Dehghan

doi:10.1186/s13059-016-1119-5

DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Symen Ligthart, Carola Marzi, Stella Aslibekyan, Michael M. Mendelson, Karen N. Conneely, Toshiko Tanaka, Elena Colicino, Lindsay L. Waite, Roby Joehanes, Weihua Guan, Jennifer A. Brody, Cathy Elks, Riccardo Marioni, Min A. Jhun, Golareh Agha, Jan Bressler, Cavin K. Ward-Caviness, Brian H. Chen, Tianxiao Huan, Kelly BakulskiElias L. Salfati, Giovanni Fiorito, Simone Wahl, Katharina Schramm, Jin Sha, Dena G. Hernandez, Allan C. Just, Jennifer A. Smith, Nona Sotoodehnia, Luke C. Pilling, James S. Pankow, Phil S. Tsao, Chunyu Liu, Wei Zhao, Simonetta Guarrera, Vasiliki J. Michopoulos, Alicia K. Smith, Marjolein J. Peters, David Melzer, Pantel Vokonas, Myriam Fornage, Holger Prokisch, Joshua C. Bis, Audrey Y. Chu, Christian Herder, Harald Grallert, Chen Yao, Sonia Shah, Allan F. McRae, Honghuang Lin, Steve Horvath, Daniele Fallin, Albert Hofman, Nicholas J. Wareham, Kerri L. Wiggins, Andrew P. Feinberg, John M. Starr, Peter M. Visscher, Joanne M. Murabito, Sharon L.R. Kardia, Devin M. Absher, Elisabeth B. Binder, Andrew B. Singleton, Stefania Bandinelli, Annette Peters, Melanie Waldenberger, Giuseppe Matullo, Joel D. Schwartz, Ellen W. Demerath, André G. Uitterlinden, Joyce B.J. Meurs, Oscar H. Franco, Yii Der Ida Chen, Daniel Levy, Stephen T. Turner, Ian J. Deary, Kerry J. Ressler, Josée Dupuis, Luigi Ferrucci, Ken K. Ong, Themistocles L. Assimes, Eric Boerwinkle, Wolfgang Koenig, Donna K. Arnett, Andrea A. Baccarelli, Emelia J. Benjamin, Abbas Dehghan

College of Public Health

Research output: Contribution to journal › Article › peer-review

197 Scopus citations

Abstract

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10^-7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10^-4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10^-5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10^-3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10^-5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

Original language	English
Article number	255
Journal	Genome Biology
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s13059-016-1119-5
State	Published - Dec 12 2016

Bibliographical note

Funding Information:
OHF works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript.

Funding Information:
The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). CHS: Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL092111, R01HL105756, R01HL103612, R01HL111089, R01HL116747, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA) as well as the Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. EPIC-Norfolk is supported by programme grants from the Medical Research Council (MRC) (G9502233; G0401527) and Cancer Research UK (C864/A8257). The generation and management of the Illumina 450 K methylation array data in this cohort is supported through the MRC Cambridge initiative in metabolomic science (MR/L00002/1). CEE, KKO, and NJW are supported by MRC programme grants (MC_UU_12015/1 and MC_UU_12015/2). FHS is funded by the U.S. NIH contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, and by a Director’s Challenge Award, NIH (DL). The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This study utilized the computational resources of the Biowulf system at the NIH, Bethesda, MD (https://hpc.nih.gov/docs/user_guides.html). MMM is partly supported by the Tommy Kaplan Fund, Boston Children’s Hospital. EJB was supported by 1RO1 HL64753, R01 HL076784, 1R01 AG028321, and 1P50HL120163. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the NHLBI (HL054457, HL100185, and HL119443) of the NIH. GOLDN is supported by NIH grant R01HL104135. Methylation and expression work for GTP was primarily supported by the National Institute of Mental Health (MH096764 and MH071537 to KJR). Support was also received from Emory and Grady Memorial Hospital General Clinical Research Center, the Max Planck Society, the Behrens-Weise Foundation, NIH National Centers for Research Resources (M01RR00039), and the National Center for Advancing Translational Sciences of the NIH (UL1TR000454). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 603288 (SysVasc) and HEALTH-F2-2013-602736 (PAIN-OMICS) and BMBF e:Med project: e:AtheroSysMed - Systems medicine of myocardial infarction and stroke. Furthermore, this study was supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD). In addition, part of this work was financed by the German National Genome Research Network (NGFNplus, project no. 01GS0834) and through additional funds from the University of Ulm. The present work on the US Department of Veterans Affairs (VA) Normative Aging Study has been supported by funding from the U.S. National Institute of Environmental Health Sciences (NIEHS) (R01ES015172, R01ES021733). The VA Normative Aging Study is supported by the Cooperative Studies Program/ERIC, US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Additional support to the VA Normative Aging Study was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. 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 were 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). 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.

Publisher Copyright:
© 2016 The Author(s).

Keywords

Body mass index
C-reactive protein
Coronary heart disease
DNA methylation
Diabetes
Epigenome-wide association study
Inflammation

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Genetics
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s13059-016-1119-5

Cite this

Ligthart, S., Marzi, C., Aslibekyan, S., Mendelson, M. M., Conneely, K. N., Tanaka, T., Colicino, E., Waite, L. L., Joehanes, R., Guan, W., Brody, J. A., Elks, C., Marioni, R., Jhun, M. A., Agha, G., Bressler, J., Ward-Caviness, C. K., Chen, B. H., Huan, T., ... Dehghan, A. (2016). DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biology, 17(1), Article 255. https://doi.org/10.1186/s13059-016-1119-5

@article{832d4c7e595c41f8b42619d34ef7b4b1,

title = "DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases",

abstract = "Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10-7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10-4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10-5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10-3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10-5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.",

keywords = "Body mass index, C-reactive protein, Coronary heart disease, DNA methylation, Diabetes, Epigenome-wide association study, Inflammation",

author = "Symen Ligthart and Carola Marzi and Stella Aslibekyan and Mendelson, {Michael M.} and Conneely, {Karen N.} and Toshiko Tanaka and Elena Colicino and Waite, {Lindsay L.} and Roby Joehanes and Weihua Guan and Brody, {Jennifer A.} and Cathy Elks and Riccardo Marioni and Jhun, {Min A.} and Golareh Agha and Jan Bressler and Ward-Caviness, {Cavin K.} and Chen, {Brian H.} and Tianxiao Huan and Kelly Bakulski and Salfati, {Elias L.} and Giovanni Fiorito and Simone Wahl and Katharina Schramm and Jin Sha and Hernandez, {Dena G.} and Just, {Allan C.} and Smith, {Jennifer A.} and Nona Sotoodehnia and Pilling, {Luke C.} and Pankow, {James S.} and Tsao, {Phil S.} and Chunyu Liu and Wei Zhao and Simonetta Guarrera and Michopoulos, {Vasiliki J.} and Smith, {Alicia K.} and Peters, {Marjolein J.} and David Melzer and Pantel Vokonas and Myriam Fornage and Holger Prokisch and Bis, {Joshua C.} and Chu, {Audrey Y.} and Christian Herder and Harald Grallert and Chen Yao and Sonia Shah and McRae, {Allan F.} and Honghuang Lin and Steve Horvath and Daniele Fallin and Albert Hofman and Wareham, {Nicholas J.} and Wiggins, {Kerri L.} and Feinberg, {Andrew P.} and Starr, {John M.} and Visscher, {Peter M.} and Murabito, {Joanne M.} and Kardia, {Sharon L.R.} and Absher, {Devin M.} and Binder, {Elisabeth B.} and Singleton, {Andrew B.} and Stefania Bandinelli and Annette Peters and Melanie Waldenberger and Giuseppe Matullo and Schwartz, {Joel D.} and Demerath, {Ellen W.} and Uitterlinden, {Andr{\'e} G.} and Meurs, {Joyce B.J.} and Franco, {Oscar H.} and Chen, {Yii Der Ida} and Daniel Levy and Turner, {Stephen T.} and Deary, {Ian J.} and Ressler, {Kerry J.} and Jos{\'e}e Dupuis and Luigi Ferrucci and Ong, {Ken K.} and Assimes, {Themistocles L.} and Eric Boerwinkle and Wolfgang Koenig and Arnett, {Donna K.} and Baccarelli, {Andrea A.} and Benjamin, {Emelia J.} and Abbas Dehghan",

note = "Funding Information: OHF works in ErasmusAGE, a center for aging research across the life course funded by Nestl{\'e} Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Nestl{\'e} Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript. Funding Information: The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). CHS: Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL092111, R01HL105756, R01HL103612, R01HL111089, R01HL116747, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA) as well as the Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. EPIC-Norfolk is supported by programme grants from the Medical Research Council (MRC) (G9502233; G0401527) and Cancer Research UK (C864/A8257). The generation and management of the Illumina 450 K methylation array data in this cohort is supported through the MRC Cambridge initiative in metabolomic science (MR/L00002/1). CEE, KKO, and NJW are supported by MRC programme grants (MC_UU_12015/1 and MC_UU_12015/2). FHS is funded by the U.S. NIH contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, and by a Director{\textquoteright}s Challenge Award, NIH (DL). The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This study utilized the computational resources of the Biowulf system at the NIH, Bethesda, MD (https://hpc.nih.gov/docs/user_guides.html). MMM is partly supported by the Tommy Kaplan Fund, Boston Children{\textquoteright}s Hospital. EJB was supported by 1RO1 HL64753, R01 HL076784, 1R01 AG028321, and 1P50HL120163. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the NHLBI (HL054457, HL100185, and HL119443) of the NIH. GOLDN is supported by NIH grant R01HL104135. Methylation and expression work for GTP was primarily supported by the National Institute of Mental Health (MH096764 and MH071537 to KJR). Support was also received from Emory and Grady Memorial Hospital General Clinical Research Center, the Max Planck Society, the Behrens-Weise Foundation, NIH National Centers for Research Resources (M01RR00039), and the National Center for Advancing Translational Sciences of the NIH (UL1TR000454). The KORA study was initiated and financed by the Helmholtz Zentrum M{\"u}nchen – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universit{\"a}t, as part of LMUinnovativ. The research leading to these results has received funding from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 603288 (SysVasc) and HEALTH-F2-2013-602736 (PAIN-OMICS) and BMBF e:Med project: e:AtheroSysMed - Systems medicine of myocardial infarction and stroke. Furthermore, this study was supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD). In addition, part of this work was financed by the German National Genome Research Network (NGFNplus, project no. 01GS0834) and through additional funds from the University of Ulm. The present work on the US Department of Veterans Affairs (VA) Normative Aging Study has been supported by funding from the U.S. National Institute of Environmental Health Sciences (NIEHS) (R01ES015172, R01ES021733). The VA Normative Aging Study is supported by the Cooperative Studies Program/ERIC, US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Additional support to the VA Normative Aging Study was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. 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 were 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). 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. Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = dec,

day = "12",

doi = "10.1186/s13059-016-1119-5",

language = "English",

volume = "17",

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Ligthart, S, Marzi, C, Aslibekyan, S, Mendelson, MM, Conneely, KN, Tanaka, T, Colicino, E, Waite, LL, Joehanes, R, Guan, W, Brody, JA, Elks, C, Marioni, R, Jhun, MA, Agha, G, Bressler, J, Ward-Caviness, CK, Chen, BH, Huan, T, Bakulski, K, Salfati, EL, Fiorito, G, Wahl, S, Schramm, K, Sha, J, Hernandez, DG, Just, AC, Smith, JA, Sotoodehnia, N, Pilling, LC, Pankow, JS, Tsao, PS, Liu, C, Zhao, W, Guarrera, S, Michopoulos, VJ, Smith, AK, Peters, MJ, Melzer, D, Vokonas, P, Fornage, M, Prokisch, H, Bis, JC, Chu, AY, Herder, C, Grallert, H, Yao, C, Shah, S, McRae, AF, Lin, H, Horvath, S, Fallin, D, Hofman, A, Wareham, NJ, Wiggins, KL, Feinberg, AP, Starr, JM, Visscher, PM, Murabito, JM, Kardia, SLR, Absher, DM, Binder, EB, Singleton, AB, Bandinelli, S, Peters, A, Waldenberger, M, Matullo, G, Schwartz, JD, Demerath, EW, Uitterlinden, AG, Meurs, JBJ, Franco, OH, Chen, YDI, Levy, D, Turner, ST, Deary, IJ, Ressler, KJ, Dupuis, J, Ferrucci, L, Ong, KK, Assimes, TL, Boerwinkle, E, Koenig, W, Arnett, DK, Baccarelli, AA, Benjamin, EJ & Dehghan, A 2016, 'DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases', Genome Biology, vol. 17, no. 1, 255. https://doi.org/10.1186/s13059-016-1119-5

TY - JOUR

T1 - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

AU - Ligthart, Symen

AU - Marzi, Carola

AU - Aslibekyan, Stella

AU - Mendelson, Michael M.

AU - Conneely, Karen N.

AU - Tanaka, Toshiko

AU - Colicino, Elena

AU - Waite, Lindsay L.

AU - Joehanes, Roby

AU - Guan, Weihua

AU - Brody, Jennifer A.

AU - Elks, Cathy

AU - Marioni, Riccardo

AU - Jhun, Min A.

AU - Agha, Golareh

AU - Bressler, Jan

AU - Ward-Caviness, Cavin K.

AU - Chen, Brian H.

AU - Huan, Tianxiao

AU - Bakulski, Kelly

AU - Salfati, Elias L.

AU - Fiorito, Giovanni

AU - Wahl, Simone

AU - Schramm, Katharina

AU - Sha, Jin

AU - Hernandez, Dena G.

AU - Just, Allan C.

AU - Smith, Jennifer A.

AU - Sotoodehnia, Nona

AU - Pilling, Luke C.

AU - Pankow, James S.

AU - Tsao, Phil S.

AU - Liu, Chunyu

AU - Zhao, Wei

AU - Guarrera, Simonetta

AU - Michopoulos, Vasiliki J.

AU - Smith, Alicia K.

AU - Peters, Marjolein J.

AU - Melzer, David

AU - Vokonas, Pantel

AU - Fornage, Myriam

AU - Prokisch, Holger

AU - Bis, Joshua C.

AU - Chu, Audrey Y.

AU - Herder, Christian

AU - Grallert, Harald

AU - Yao, Chen

AU - Shah, Sonia

AU - McRae, Allan F.

AU - Lin, Honghuang

AU - Horvath, Steve

AU - Fallin, Daniele

AU - Hofman, Albert

AU - Wareham, Nicholas J.

AU - Wiggins, Kerri L.

AU - Feinberg, Andrew P.

AU - Starr, John M.

AU - Visscher, Peter M.

AU - Murabito, Joanne M.

AU - Kardia, Sharon L.R.

AU - Absher, Devin M.

AU - Binder, Elisabeth B.

AU - Singleton, Andrew B.

AU - Bandinelli, Stefania

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Matullo, Giuseppe

AU - Schwartz, Joel D.

AU - Demerath, Ellen W.

AU - Uitterlinden, André G.

AU - Meurs, Joyce B.J.

AU - Franco, Oscar H.

AU - Chen, Yii Der Ida

AU - Levy, Daniel

AU - Turner, Stephen T.

AU - Deary, Ian J.

AU - Ressler, Kerry J.

AU - Dupuis, Josée

AU - Ferrucci, Luigi

AU - Ong, Ken K.

AU - Assimes, Themistocles L.

AU - Boerwinkle, Eric

AU - Koenig, Wolfgang

AU - Arnett, Donna K.

AU - Baccarelli, Andrea A.

AU - Benjamin, Emelia J.

AU - Dehghan, Abbas

N1 - Funding Information: OHF works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript. Funding Information: The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). CHS: Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL092111, R01HL105756, R01HL103612, R01HL111089, R01HL116747, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA) as well as the Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. EPIC-Norfolk is supported by programme grants from the Medical Research Council (MRC) (G9502233; G0401527) and Cancer Research UK (C864/A8257). The generation and management of the Illumina 450 K methylation array data in this cohort is supported through the MRC Cambridge initiative in metabolomic science (MR/L00002/1). CEE, KKO, and NJW are supported by MRC programme grants (MC_UU_12015/1 and MC_UU_12015/2). FHS is funded by the U.S. NIH contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, and by a Director’s Challenge Award, NIH (DL). The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This study utilized the computational resources of the Biowulf system at the NIH, Bethesda, MD (https://hpc.nih.gov/docs/user_guides.html). MMM is partly supported by the Tommy Kaplan Fund, Boston Children’s Hospital. EJB was supported by 1RO1 HL64753, R01 HL076784, 1R01 AG028321, and 1P50HL120163. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the NHLBI (HL054457, HL100185, and HL119443) of the NIH. GOLDN is supported by NIH grant R01HL104135. Methylation and expression work for GTP was primarily supported by the National Institute of Mental Health (MH096764 and MH071537 to KJR). Support was also received from Emory and Grady Memorial Hospital General Clinical Research Center, the Max Planck Society, the Behrens-Weise Foundation, NIH National Centers for Research Resources (M01RR00039), and the National Center for Advancing Translational Sciences of the NIH (UL1TR000454). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 603288 (SysVasc) and HEALTH-F2-2013-602736 (PAIN-OMICS) and BMBF e:Med project: e:AtheroSysMed - Systems medicine of myocardial infarction and stroke. Furthermore, this study was supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD). In addition, part of this work was financed by the German National Genome Research Network (NGFNplus, project no. 01GS0834) and through additional funds from the University of Ulm. The present work on the US Department of Veterans Affairs (VA) Normative Aging Study has been supported by funding from the U.S. National Institute of Environmental Health Sciences (NIEHS) (R01ES015172, R01ES021733). The VA Normative Aging Study is supported by the Cooperative Studies Program/ERIC, US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Additional support to the VA Normative Aging Study was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. 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 were 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). 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. Publisher Copyright: © 2016 The Author(s).

PY - 2016/12/12

Y1 - 2016/12/12

N2 - Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10-7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10-4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10-5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10-3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10-5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

AB - Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10-7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10-4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10-5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10-3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10-5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

KW - Body mass index

KW - C-reactive protein

KW - Coronary heart disease

KW - DNA methylation

KW - Diabetes

KW - Epigenome-wide association study

KW - Inflammation

UR - http://www.scopus.com/inward/record.url?scp=85003550816&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85003550816&partnerID=8YFLogxK

U2 - 10.1186/s13059-016-1119-5

DO - 10.1186/s13059-016-1119-5

M3 - Article

C2 - 27955697

AN - SCOPUS:85003550816

SN - 1474-7596

VL - 17

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 255

ER -

DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

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