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

Nephrology and Hypertension

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

112 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 (US)
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

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

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10.1186/s13059-016-1119-5

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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

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

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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 = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = dec,

day = "12",

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

language = "English (US)",

volume = "17",

journal = "Genome biology",

issn = "1474-7596",

publisher = "BioMed Central",

number = "1",

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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

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

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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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